Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

e ISSN 2277 - 3290 Print ISSN 2277 - 3282 Journal of Science Medicine

www.journalofscience.net

CANTHARIDIN AS PROMISING CHEMOTHERAPEUTIC AGENT IN THE MODERN MEDICINE: A COMPREHENSIVE REVIEW

Karem Ghoneim

Faculty of Science, Al-Azhar University, Cairo, Egypt.

ABSTRACT Blister of the families Meloidae and Oedemeridae (Order Coleoptera, Insecta) release yellow oily droplets of haemolymph from their leg (and may be antennal) joints as a defensive measure when disturbed. The active ingredient in this exudation is cantharidin (CA). Historically, CA has been used as a chemotherapeutic agent in the traditional medicine among Asian, African and European peoples. CA, as a natural or chemically synthesized compound, is used in the modern medicine to treat various diseases. Norcantharidin is the most famous among the synthesized CA analogues and derivatives. CA and its analogues have been applied for some dermatological cases such as warts, verruca vulgaris, corn, molluscum contagiosum and leishmaniasis. In oncology, CA and its analogues exhibit promising therapeutic effects because they induce apop tosis of human cancer cells of hepatoma, colo-rectal carcinoma, oral carcinoma, esophageal carcinoma, leukemia, bladder carcinoma, melanoma, etc. In addition, CA and its analogues have been experimentally and clinically investigated for some other diseases such as heart failure, hepatitis, neurological disorders and innate immune system. Furthermore, CA and CA -related compounds, such as Endothall and palasonin, act as a potential source of antimalarials and antihelminthics. The multi-drug resistance is one of the major obstacles in the treatment of human cancer. CA and some of its analogues have been studied as promising agent to overcome this problem. On the other hand, several drug-delivery systems have been evaluated for improving the clinical uses of CA and its analogues.

Keywords: Dermatology, antileishmaniasis, antimalarials, antihelminthic, anticancer, chemotherapy.

INTRODUCTION In Coleoptera (Insecta: Arthropoda), only This exudation contains toxic material 'CA'. The main Meloidae (true blister beetles), Oedemeridae (false blister function of CA in the blister beetles is to preserve their beetles) and Staphylinidae (rove beetles) release vesicant eggs from predators beside some other functions [16-19]. chemicals, the first two release cantharidin (CA) and the However, CA, among the most widely known latter releases paederin [1]. Family Meloidae is virtually natural products, usually attracted a great attention of cosmopolitan but absent only from New Zealand, many investigators and research institutions because of its Antarctica and most Polynesian islands [2-5]. Global toxicosis for man and painful or fatal diseases for horses zoogeography and systematic approaches of this family and other livestock [20, 21]. Many reports on different had been reviewed by Ghoneim [6], different biological aspects of veterinary and medical impacts of CA are aspects of this family had been reviewed by Ghoneim [7], available in the literature [22-28]. and various agronomic and biodiversity impacts had been Natural products still play a major role as drugs, reviewed by Ghoneim [8]. Oedemeridae is a family of and as lead structures for the development of synthetic worldwide distribution. The available literature contains molecules [29]. In the future, natural compounds and their several reported works on the distribution and systematics derivatives will continue to be a rich source for drug of this family in the world [9-15]. Blister beetles are discovery [29-31]. Ratcliffeet al. [32] reviewed several commonly known as "oil beetles" because they release insect products derived from honey, venom, silk, CA, yellow oily droplets of haemolymph from their leg joints whole insect extracts, maggots, and blood-sucking (and may be from the antennal joints) when disturbed. . Traditional Chinese medicine (TCM) has

Corresponding Author:- Karem Ghoneim Email:[email protected]

272

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

been practiced by Chinese communities worldwide for product and its isolation and chemical synthesis beside its many generations, and there is rich information in the major forms and related compounds. available literature related to the therapeutic use of TCM [33]. Unfortunately, there are increased reports on the 1. CANTHARIDIN AS A NATURAL INSECT adverse reactions of some TCM products [34]. In some PRODUCT African and Asian countries, 80% of populations depend CA is one of the oldest-known toxins from on traditional medicine for primary health cure. and has been known to humans for more than Traditional African medicine (or "Muti") involves the use 2000 years due to its physiological activities such as remedies made of herbal and/or parts and blistering [20, 43]. The function and intrinsic role of CA traditional rituals in the treatment of a variety of ailments in the courtship behaviour of family Meloidae has been [35]. never fully established. It was suggested that CA might be CA has a long history in both folk and traditional used by female when selecting a mate at close range [20]. medicine. It, as contained in the bodies of blister beetles As pointed out in the iron cross blister Tegrodera or isolated from them, has been used by human since the alogaSkinner, individual males donated a large CA- time of Hippocrates, if not before, as a vesicant, containing spermatophore to their mates, and body size lubrificant, internal remedy for various diseases, was correlated with the size of the cantharidin-producing aphrodisiac, and poison [36, 37]. Although CA has a long, accessory glands [49]. When attacked or disturbed, adults infamous reputation for being an aphrodisiac [38],it is not of blister beetles release haemolymph droplets in so called a true aphrodisiac and can cause fatal poisoning [39]. In "reflex bleeding". The highly toxic CA in the addition to human and animal toxicosis caused by haemolymph, is a well defensive reaction against the cantharidin [40], human dermatosis had been reviewed by aggressive creatures. As reviewed by Ghoneim[19], CA is Ghoneim [41]. considered responsible for the repellent properties of Blister beetles are still used and misused by meloid haemolymph against a wide variety of predators. people as a type of 'Insect Viagra' (aphrodisiac agent) As pointed out by some authors [4, 50], adult female of [42]. In Europe, CA appeared in "Materia Medica", a uses her own CA and transferred CA for medical monograph written by Pedanios Dioskorides in herself and also to cover or coat her eggs for protecting 50 to 100 AD [43]. Hippocrates prescribed CA as a them against the potential predators. treatment for dropsy [44]. Later in history, the Marquis de Sade was brought to trial for poisoning an entire orgy 1.1. Cantharidin from the chemical standpoint with Spanish fly (blister beetle) in 1772. As late as the CA was isolated from some blister beetles [51]. last half of the 19th century, CA obtained from It was isolated and crystallized from the red-headed spp., as well as other blister beetles, was used as specific blister beetle Epicauta hirticornisin Assam, India treatments of hydrophobia, particularly in Europe and [52].Einbinder et al. [53] indicated that CA (2,3-di- northern Africa. Beside its use against hydrophobia, CA methyl-7-oxabicyclo [2.2.l] heptane-2.3- dicarboxylic obtained from the blister beetle Meloe proscarabaeus was acid anhydride) is the principal active ingredient amongst used as a diuretic [45] and as a cure for rheumatism in the various compounds present in Mylabris. The chemical Sweden [46]. In South Africa, the Tswanas grind CA- structure and properties of CA had been reported in the producing beetles into a powder and use it in a medicine literature (e.g., [54-56]). It is a bicyclic terpenoid or called "seletsa" as an aphrodisiac, as an abortifacient, and anhydride of cantharidic acid with chemical formula for "purifying the blood" [38]. C10H12O4. Today, there are many kinds of Mylabris-based Although the CA biosynthesis in the blister pharmaceutical preparations on the Chinese market, such beetles had been studied by some researchers [50], it was as compound Mylabris injection (Aidi injection, State a debatable issue along several decades ago and the Permit No.Z52020236) and compound Mylabris capsules mechanism in vivo was not completely understood. In (State Permit No.Z19993294; State Permit order to clarify the biosynthesis mechanism of CA in No.Z200003270; State Permit No.Z20000427), all of Mylabris calida Palla, Jia et al. [57] studied the protein which have proved to show good anticancer effects. In expression profile during the early and advanced stages of addition, so many companies synthesize the CA as a the process. Also, Jiang et al. [58] investigated the commercial product for the medicinal purposes in the relationship between CA biosynthesis and the mevalonate world, under different trade names [47, 48]. pathway. Although CA was purified and crystallized in The present review deals primarily with the uses of CA 1810 by Robiquet from Spanish fly Lytta vesicatoria [59], and its analogues as chemotherapeutic agents in the it took 150 years of research to be fully synthesized modern medicine focusing on dermatology, cancer, drug [50].The first attempt was carried out by a German resistance, parasitic infections, heart failure and some chemist von Bruchhausen [60] but the first effective liver diseases. It discussed, also, CA as a natural insect synthesis of this compound was made in 1951 by the

273

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

American chemist Stork who and co-workers reported the Afterwards, many experimental studies had been first natural product synthesis featuring a [4 + 2] conducted. Rosenberg et al. [78] suggested a self- cycloaddition in the stereo-controlled synthesis of CA application of CA (0.7% solution in acetone-flexible [61]. Then, some other efforts had been done for the CA collodion) for treatment of warts.Commercially, there are synthesis [62]. For review of different aspects of CA some formulations consisting of 0.7% - 0.9% CA can be physiology, see Ghoneim [63]. purchased. Camphor or pine oil is often added to proprietary formulations to lend a medicinal aroma [79]. 1.2. Major cantharidin forms and related compounds Also, topical preparation containing salicylic acid (30%), As pointed out by Li et al. [64], the content of podophyllin (5%) and CA (1%) was found effective to total CA is higher than the content of free CA in the treat the plantar warts in children [80]. Recently, a topical family Meloidae, as well as bound CA may exist in the combination of CA, podophyllotoxin, and salicylic acid forms of magnesium cantharidate and calcium was found to be safe and effective in the treatment of cantharidate. Using the gas chromatography, Li [65] simple and mosaic plantar warts [81]. Kartal et al. [82] determined the CA forms in 12 species of Meloidae in evaluated the efficacy and safety of topical CA in the China. Their results suggested that the existing form of treatment of recalcitrant facial flat warts. Pathological bound CA might be the magnesium cantharidate, calcium transformation of the skin into a thick and hard callus due cantharidate, potassium cantharidate. to repetitive trauma or friction is commonly known as In a related matter, there are few compounds corn. Effectiveness of tangential excision together with structurally similar to CA, known as CA-related topical CA had been evaluated on 72 patients. This compounds (CRCs), have been found in blister beetles. treatment method is a simple, minimally invasive and CA has never been detected in plants, but the first CRC, reliable treatment for calluses [83]. palasonin (demethylcantharidin)(C9H9O4) was discovered To treat Verruca vulgaris by using the blister [66]. This CRC was initially isolated from the seeds of the beetle's haemolymph, the CA content could kill efficiently Indian tree known as Flame of the forest, Butea V. vulgaris virus and had no side effect for natural skin monosperma [67], Synonym Butea frondosa [68]. [84]. In addition,Molluscum contagiosum (MC) is a However, analyses of species from the families Meloidae common viral disease of childhood caused by a poxvirus, [69], Cleridae, and Staphylinidae [70] gave the first which presents with small, firm, dome-shaped, evidence for simultaneous presence of CA and palasonin umbilicated papules. It can spread through close skin-to- in haemolymph and tissues of the individual insects. skin contact and many patients autoinoculate themselves, Moreover, variable titers of palasonin were detected in the making MC a dynamic disease [85]. In TCM and bodily extracts from some blister beetles [71], staphylinid traditional Vietnamese medicine, CA (derived from the beetles [70], and the clerid beetle (Trichodes apiaries, bodies of the Spanish fly L. vesicatoria) has been used to Cleridae) [72]. It is to be noted that the second CRC, treat MC virus infections and associated warts palasoninimide(C9H10O3N) was reported by Dettneret [86].Treatment options of MC include destructive al.[69]. Cantharimides (C10H13NO3), whose therapies (curettage, cryotherapy, CA, and keratolytics, anhydrideoxygen atoms are replaced by basic amino among others), immunomodulators (imiquimod, acids, and cantharimide dimers, which consist of two cimetidine, and candidaantigen), and antivirals cantharimide units combined with a tri-, tetra-, or (cidofovir). Because of concerns over its safety, some pentamethylene group, had been reported in the Chinese physicians has lost favor to use CA for MC. Silverberg et meloid Mylabris phalerata Pall. [73, 74]. Few years ago, al. [87] attempted to determine the safety, efficacy, and CA, palasonin and cantharidinimide were extracted from parental satisfaction of CA therapy for MC in 300 the blister beetle Mylabris impressa stillata (Baudi) [25]. children who were treated in a pediatric dermatology In addition, Endothall is a synthetic herbicide and known clinic at a large referral hospital. In these patients, CA as CA-related compound (7-oxabicyclo [2.2.1] heptane- therapy was extremely effective and well tolerated, and 2,3-dicarboxyli acid) [75]. parental satisfaction was high. Therefore, CA is a safe and 2. PHARMACEUTIC USES OF CANTHARIDIN IN effective therapy for MC in children. Recently, Mathes DERMATOLOGY and Frieden [88] discussed the use of CA as a treatment The CA uses against the skin cancer will be option for MC and described their first-line treatment discussed thereinafter but the uses of CA against skin approach for those MC needing CA treatment.Langley et diseases other than cancer can be reviewed herein. The al. [89] reported a case of toxic shock syndrome within 24 first suggestion to use CA as a chemotherapeutic agent in hours of topical application of a CA preparation for warts was provided by Epstein and Kligman [76].In cosmetic treatment of MC. This case highlighted a Epstein’s classic article, 56% of digital and 33% of potentially life-threatening complication of CA use for a periungual warts were cleared after a single application of common skin condition. Therefore, the survey achieved CA and the others required one or two additional by Coloe and Morrell [90] may be informative for the treatments with a long-term cure rate of about 70% [77].

274

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

breadth of CA usage, the most frequently used protocols, aberrant mitotic spindles and metaphase growth arrest. and common side effects. Although the activity of CA is usually attributed to its Leishmaniasis has been identified as a major high affinity towards Type 1 and 2A serine/threonine public health problem in many countries. Chemical drugs protein phosphatases, several studies suggest that CA has are the best way for treatment of leishmaniasis. Using additional cellular targets. Specifically, CA has been drugs for treatment of leishmaniasis are moderately toxic reported to stimulate xanthine oxidase activity and to and have the risks of recurrence and unsatisfactory side inhibit N-acyltransferase and cAMP phosphodiesterase in effects [91]. CA was assessed as anti-leishmaniasis agent liver cells, suggesting a complex mode of action [97, 114, since different doses were evaluated on Leishmania major 115]. Using the HIP and HOP genome-wide assays, (MRHO/IR/75/ER) both in vitro (promastigote and Hillenmeyer et al. [116] discovered that a large number of amastigote viability) and in experimentally-infected methyltransferase deletion mutants are sensitive to CA, BALB/c mice (skin lesions). Two weeks of topical suggesting that, as a class, these enzymes may interact treatment with 0.1% CA ointment was an effective directly or indirectly with CA and participate in the method for treating cutaneous leishmaniasis in infected response to CA stress. BALB/c mice [92]. For some details, CA induces There have been several reports to show that CA apoptosis in the L. major promastigotes and infected and its derivatives are relatively ineffective as an anti- macrophages with amastigotes in a time and dose cancer agent [117]. The contradiction may be related to dependent manner [93]. As concluded by Maroufi et al. CA being less effective at alkaline pH but more active at [94], CA has a cytotoxic effect on the promastigote and acidic pH. Fukamachi et al. [118] investigated the macrophages infected with L. major. However, further cytotoxicity of lovastatin and CA under controlled pH studies are recommended to investigate the efficacy of environments in mesothelioma or pancreatic carcinoma this compound in vivo. cells. They concluded that the acidic conditions would be useful for developing new chemotherapeutic reagents. 3. CANTHARIDIN USES IN ONCOLOGY In modern pharmacology, CA plays an important 3.1. Less toxic cantharidin analogues and derivatives role in control of cell cycle regulation [95] and on the Although CA is a natural toxin that possesses cellular growth of tumor cells transformed by SV40 potent anti-tumor properties, its clinical application is antigen [96]. The therapeutic efficacy of CA in the limited due to severe side-effects and highly toxic nature treatment of cancer and some refractory diseases had been mainly in the gastrointestinal tract, the ureter and the demonstrated [97]. For some details, CA has a cytotoxic kidney [111]. Its severe side effects include, also, activity against a number of primary tumor cells [97-100], dysphagia, hematemesis, dysuria [43] andmucous and clinical testing revealed little myelosuppression [43, membrane toxicity[119]. Ghoneim [40] provided a 101]. CA induces apoptosis of human hepatoma[102], comprehensive review on the CA toxicosis to human and human colon cancer, buccaland oesophageal animal. Therefore, thousands of modified analogues and carcinoma[103, 104], uterine cervical cancer, derivatives of CA had been chemically synthesized and nasopharyngeal carcinoma, cutaneous cancer, as well as their bioactivities had been studied [120] in order to human leukemia cells [102, 104, 105]. Human bladder achieve a comparable antitumor property to the mother carcinoma [100] and breast cancer [106] can be, also, compound but simultaneously produce a less toxic effect treated with CA. on non-cancer cells [105]. To understand the mode of action of CA in Kok et al. [121] reviewed their experience in the tumor and cancer treatments, earlier studies reported a chemical synthesis and biological screening of five strong affinity and specificity of it for a "CA-binding" chemically modified CA analogues on a series of human protein, which has been isolated and identified as protein carcinoma cell lines. Very recently, Deng et al. [122] phosphatase 2A (PP2A) [107]. As pointed out by provided up-to-date review on the therapeutic use, numerous authors [108-110], CA acts as a weak inhibitor mechanism and interesting properties of CA analogues. of calcineurin (PP2B) but as a potent inhibitor of three For some details, a series of glycerophospholipid families (PP1, PP2A, and PP5) of structurally related conjugates of CA and its analogues were synthesized in a PPases. It is known that the liver cytosol is one site that is one-pot reaction, using hexaehtyl phosphorus triamide, rich in PP2A [111] and from in vitro experiments, the activated by a catalytic amount of iodine, as the level of PP2A inhibition parallels cytotoxicity [112]. phosphorylating reagent [123]. Because thefluorinated Bonnesset al.[113]characterized the biological activity of CA analogues represent a rewarding synthetic target, also CA in culture cells (A549 and HeLa) and developed small with respect to an altered metabolism which was observed interfering RNA (siRNA) and antisense oligonucleotides for ∞-monofluoroalkanoic acids,Essers et al. [124] capable of markedly suppressing the expression of several reported the synthesis of four fluorinated CA analogues. CA-sensitive phosphatases. Their studies indicated that Williams et al. [106] screenedseven CA derivatives CA-induced apoptosis is preceded by the formation of against the human neuroblastoma and breast cancer cells

275

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

in vitro. Deng et al. [125] synthesizedtwelve novel In a study to clarify the mode of action of CA compounds by the [3+2] 1,3-dipolar cycloaddition analogues, Shan et al. [144] concluded that the reaction of 5,6-dehydronorcantharidin derivatives of cytotoxicity of synthetic CA analogues is likely to be substituted aromatic amines with nitrile oxides. Then, associated with their protein phosphatase 2A inhibitory they investigated their anti-tumor activities. Kok et al. activity. However, the exact anticancer mechanism of [126] synthesized two CA analogues and assessed their NCTD on human cancer cells remains poorly understood. cytotoxic activity on a series of human cancer cell lines. Jiang et al. [145] tried to understand this puzzle when Goksu et al. [127] had been interested in the synthesis of discovered that NCTD can induce the apoptosis of HL-60 bioactive CA analogues that represent aryl-modified cells and inhibit the fissiparism, and the domino effect bicyclic imide systems. They synthesized endo-N- was obviously correlated with the time and dosage. To phenylbicyclo [2.2.1] hept-5-ene-2,3 dicarboximide from explore the effects of NCTD on proliferation and killing cyclopentadiene and N-phenylmaleimide and exo-N- activity of cytokine-induced killer cells (CIK), Liu et al. phenyl-7-oxa-bicyclo [2.2.1] hept-5-ene-2,3- [146] carried out a study suggesting that NCTD promoted dicarboximide,from furan. the proliferation of CIK cells and enhanced their anti- One of the most famous synthetic demethylated tumor activity, which will provide a new approach for analogues of CA is norcantharidin (NCTD)(7- adoptive immunotherapy of CIK. oxabicycloheptane-2,3-dicarboxylic acid anhydride). It Thousands of platinum complexes have been synthesized was synthesized with furan and maleic anhydride through and evaluated for their anticancer activity. Several review Diels-Alder reaction [128].Many experiments have articles have appeared during recent years dealing with demonstrated that NCTD can inhibit the growth of tumor the synthesis, preclinical screening, and mechanism of cells in vitro and in vivo [24, 114, 129]. In comparison action of platinum-based anticancer drugs [147, 148]. The with CA, NCTD has the advantage of easy synthesis platinum complexes were found to exhibit potent in vitro and reduced intrinsic toxicity, while retaining its antitumor activity against L1210 mouseleukemia and a anticancer activity [104]. Its anticancer effectshad been range of human cancer cell lines [149]. Synergism or recorded against a diversity of malignancies by inducing combination of NCTD with a platinum moiety has cell anoikis and apoptosis, inhibiting invasion and produced a series of TCM-based platinum compounds angiogenesis [130] as well as suppressing metastasis which demonstrate selective cytotoxicity toward SK-Hep- [131]. Unlike the conventional chemotherapeutics, NCTD 1 (human liver) cell line and circumvention of cross- is preferentially toxic to cancer cells rather than normal resistance [33]. A series of platinum complexes derived cells [132], making this small molecule promising in from integrating NCTD with different isomers of 1, 2- cancer treatment [133-135]. diaminocyclohexane had been synthesized by Yu et al. Furthermore, a remarkable research effort had [150]. These integrated drugs had been found to exhibit been devoted to synthesize NCTD analogues with low superior in vitro anticancer activity against colorectal and biological toxicity [98, 136, 137]. A number of amide- human hepatocellular cancer cell lines. In general, some acid NCTD analogues were prepared containing two of the CA-based platinum complexes may possess a novel carboxylic acid residues. Although further studies are dual mechanism of antitumor action: inhibition of PP2A required to explore the anticancer properties of these and platination of DNA[33]. compounds in vivo, it is clear that the development of analogues more potent than the lead compound, NCTD, 3.2. Cantharidin and its analogues for cancer has been successful in the field of development of chemotherapy selective phosphatase inhibitor drugs [138]. CA and its analogues had been assessed for the Cantharimides, (or cantharidinimides) and chemotherapy of human breast cancer. The effects of norcantharimides are CA analogues. A number of NCTD on the growth of highly-metastatic human breast norcantharimides had been synthesized from NCTD and cancer cells were investigated by in vitro and ex vivo had been shown to possess interesting anticancer activity assays [121]. According to Huang et al. [151], NCTD [139, 140]. The cantharidinimide derivatives containing inhibited the in vitro growth of human breast cancer aliphartic, aryl, and pyridyl groups showed some effect in MDA-MB-231 cell line in dose- and time-dependent vitro against HepG2 and HL-60 cells [141]. Tseng et al. manners. The anti-cancer effect of NCTD on two human [142] obtained a novel type of cantharidimides for testing breast cancer cell lines, estrogen receptor (ER)- HS-578T their cytotoxicity in human carcinoma cell lines. Although and ER+ MCF-7 cells, had been investigated by Yang et the structural modification of CA to cantharidinimides al. [152]. Depending on their results, NCTD may be an might lead to the discovery of a novel class of antitumor effective anti-cancer drug against breast cancer. Effects of compounds [141],cantharimides with non-polar or acidic the same CA analogue on the cellular viability, reactive amino acid residues are only poor inhibitors of PP1 and oxygen species, mitochondrial membrane potential, and PP2A[143]. DNA damage in the human breast cancer cell line Bcap- 37 were evaluated with confocal and fluorescence

276

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

microscopy. The results indicated that NCTD induced a However, the available treatment and surgical options dose-dependent DNA damage and reduced the G1 peak in have proven to be inadequate in controlling the Bcap-37 cells. The G2/M peak of Bcap-37 was also mortality and morbidity associated with this disease. decreased by the higher concentration of NCTD [153]. Therefore, it is necessary to intensify the research efforts In connection with thehuman melanoma(the to develop new therapeutic agents for its prevention and most serious type of skin cancer), treatment of A375-S2 treatment [163]. Modern clinical studies have shown cells with NCTD led to several typical characteristics of thatCA has a certain inhibitory effect on ascites hepatoma apoptosis. The inhibitory effect of NCTD on human and primary liver cancer [164]. Treatments with NCTD, melanoma, A375-S2 cells, was partially reversed by the Adriamycin and hepatic artery ligation were studied. The inhibitors of pan-caspase, caspase-3 and caspase-9. results simply showed that NCTD may has a role in the Results of An et al. [154] suggested that NCTD induced chemotherapy of primary liver cancer [165]. Wang et al. A375-S2 cell apoptosis and the activation of caspase and [97] isolated CA from Mylabris phalerata Pallas and mitochondrial pathway were involved in the process. On examined its cytotoxicity on human hepatocellular the other hand, An et al. [155] investigated the roles of carcinoma cells (Hep 3B cells). It was found as a potent mitogen-activated protein kinase (MAPK) and protein inhibitor since it could prohibit the progression of all kinase C (PKC) in A375-S2 cell apoptosis induced by phases of the Hep 3B cell cycle. Recently, Chang et al. NCTD. Their results suggested that the activation of p38 [163] recorded an inhibitory effect of NCTD on the MAPK promotes the process of NCTD-induced A375-S2 proliferation and induced apoptosis of HepG2 cells in cell apoptosis and that PKC plays an important regulation a concentration-dependent manner. Gall bladder role in the activation of MAPKs. Recently, Liu et al. carcinoma is a highly lethal and aggressive disease with [156] suggested that NCTD is a potential therapeutic early metastasis, strong invasion and poor prognosis. agent for melanoma because NCTD inhibited melanoma Most patients with this disease are at the advanced and cell viability and induced apoptosis in vitro. unresectable stage and should be considered for palliative One of the most interesting aspects of the treatment such as chemotherapy and radiotherapy. NCTD chemotherapeutic uses of CA and its analogues is inhibits the proliferation of human gall bladder carcinoma thedigestive system cancer. Koket al. [104, 157] indicated GBC-SD cells in vitro and the expression of their that KB cells (in oral carcinoma) were more sensitive to proliferation-related gene proteins PCNA and Ki-67 NCTD-induced cytotoxicity compared to normal buccal [166]. keratinocytes. They concluded that NCTD may be of To et al. [167] investigated the potential value in treating oral cancers. NCTD was reported as an synergistic effect of combining NCTD with a platinum- anti-cancer agent against gastric cancer [119]. It inhibited based antitumor agent (such as cisplatin, carboplatin, or the activity of PP2A and was able to promote the cell oxaliplatin) in vitro against SK-Hep-1 human cycle from G1 to S phase with subsequent G2/M arrest hepatocellular carcinoma. Their results supported a new [150]. Effect of sodium cantharidinate on the approach for augmenting cytotoxic effect of established angiogenesis of nude mice with human gastric cancer was platinum-based drugs with NCTD in treating this studied. This CA analogue could inhibit the tumor growth carcinoma and other solid tumors. A novel palladium (II) by down-regulating VEGF expression of the tumor cell complex with demethylcantharate and 2,2΄-bipyridine was and the tumor angiogenesis [158]. Qinin® (semi-synthetic synthesized and the antiproliferative activity of the derivative of CA) injection had been developed and complex against human hepatoma cells (SMMC7721) in manufactured by Guizhou magic Pharmaceutical Co., Ltd vitro was evaluated by Wang et al. [168]. The synergistic in China. Zhan et al. [159] found Qinin® injection effect of CA analog'LB1' (a novel inhibitor of protein combined with chemotherapy enhancing clinical benefit phosphatase 2A) with doxorubicin on human Hep G2 response, improving quality of life of gastric cancer hepatocellular carcinoma cells was investigated. LB1 patients and reducing side effects of chemotherapy. CA could enhance the effect of doxorubicin in the uses against pancreatic cancer cells had been documented chemotherapy against hepatocellular carcinoma cells by some works. It efficiently inhibited the growth [169]. Recently, a relative successfulness of paclitaxel ofcancer cells, but presented a much lighter toxicity effect against tumors was observed. It was found that NCTD against normal pancreatic duct cells [160].Li et al. [161] enhanced paclitaxel-induced apoptosis in liver cancer cell investigated the apoptosis inducting effect of CA on HepG2 [170]. pancreatic cancer cell line PANC1 and CFPAC-1. They CA was reported to provoke apoptosis in colo-rectal concluded that CA can induce apoptosis in pancreatic cancer [171, 172]. Two series of demethylated CA cancer cell lines by activating caspase, up-regulating the analogues had been synthesized which showed selective expression of pro-apoptotic genes and down-regulating cytotoxicity in colon cancer cells while remaining the expression of anti-apoptotic genes. inactive in normal colon cells [173].The relationship As reported in the literature,hepatoma is one of between NCTD anticancer mechanism and integrin αvβ6 the most common and worldwide malignancies [162]. was investigated by Peng et al. [174]. They presumed that

277

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

NCTD induced HT-29 colon cancer cell apoptosis extracellular matrix (ECM) must be degraded. CA was through the αvβ6–ERK signaling pathway. Recently, reported to inhibit the migration and invasion of A549 Huang et al. [172] studied colo 205 cells after treatment human lung cancer cell. Very recently, Kim et al. [183] with CA and demonstrated its molecular mechanisms in investigated the pharmacokinetics of CA in the A549 apoptosis. Their results indicated that CA induced growth human lung cancer cells. Shortly, CA inhibits the inhibition, G2/M phase arrest and apoptosis in colo 205 activation of phosphatidylinositol 3-kinase/Akt signaling cells. pathway. This leads to the selective attenuation of one of Taking into account thathematologic cancers the gelatinases, matrix metalloproteinase 2, which can include those cancers of the blood and blood-forming degrade components of ECM, and inhibits migration and tissues. They include acute and chronic leukemias, invasion of A549 human lung cancer cells. Hodgkin's and non-Hodgkin's lymphomas, and multiple With regard tohuman bladder carcinoma, Kuoet myeloma (a cancer of the bone marrow) [135]. CA and its al. [171] selected TSGH 8301 cells for examining the analogues had been used against the haematologic effects of CA on cell cycle arrest and apoptosis. Their cancers. In contrast to most other anticancer drugs, CA results showed that CA induced G2/M arrest and and NCTD stimulate the production of white blood cells apoptosis which is mitochondrial-dependent and via JNK by bone marrow, while other anticancer drugs have the signal pathways offering new information to show CA- unwanted side effect of inducing myelosuppression [135]. induced apoptosis in these bladder carcinoma cells. The available literature contains results of several Pharmacokinetically, Huang et al. [184] investigated the published works about this area. CA had been reported as effects of CA on migration and invasion of human a cause of leukocytosis (increase of number of white bladder cancer cells. Depending on their results, CA blood cells in the blood) [103, 175]. Sagawa et al. [176] potently inhibited the migration and invasion of TSGH- investigated the in vitro effects of CA for its antimyeloma 8301 cancer cells through inhibiting the p38 and JNK1/2- activity. They concluded that CA inhibited the cellular modulated MMP-2/-9 signaling in vitro. growth of human myeloma celllines.Koket al. [177] The inhibitory effect of CA on metastasis-related synthesized the CA analogues, CAN 029 and CAN 030. ability of human highly metastatic ovarian carcinoma cell Although both exhibited an apoptotic induction ability on line HO-8910PM was studied [185]. On the other hand, cancer cells, they were still relatively toxic towards non- the inhibitory effect of Nd3, a derivative of NCTD, on the malignant haematological disordered bone marrow. proliferation of human ovarian cancercell line SKOV3 Another CA analogue, CAN 037, was synthesized and was explored. Nd3 inhibited SKOV3 cell proliferation assessed on the acute myelogenous leukaemia cell lines. more than NCTD did, blocked cell cycle at G2/M phase, CAN 037 exerted a role on the acute myelogenous and induces apoptosis [186]. For chemotherapeutics of leukaemia (AML) cell line, KG1a. Apoptosis was ovarian carcinoma and prostate carcinoma, Hill et al. involved in the action of CAN 037 including the [139, 140] provided a valuable contribution to synthesize activation of the caspase family. Caspase-dependent cell a novel series of norcantharimides. death pathway may be necessary but not essential in CAN Medulloblastoma is a fast-growing and high- 037-induced apoptosis of KG1a cells [178]. As reported grade tumor. It is the most common of the embryonal by Dorn et al. [179], CA has been described to modulate tumors. It is one of the leading causes of morbidity and the hepatic leukemia factor competitor NFIL3. NCTD mortality in pediatric cancer. Cimmino et al. [187] may be suitable in the treatment of drug-resistant assessed the anticancer activity of CA and NCTD against leukemia [103]. With regard to the mechanism of CA medulloblastoma, as cell lines in vitro and in athymic action in leukemia cells, Efferth et al. [180] suggested that nude mice in vivo. Intra-peritoneal administration of it causes oxidative stress that provokes DNA damage and NCTD inhibited the growth of intra-cerebellum tumors in p53-dependent apoptosis. orthotopic xenograft nude mice. They suggested that It is important to point out that CA and some of NCTD has potential therapeutic applications in the its analogues have apoptosis-inducing effects in the treatment of medulloblastoma as a result of its ability to human lung cancer.As reported by Zhang et al. [181], CA cross the blood-brain barrier and its impairment of Wnt- can induce A549 cells apoptosis mainly via regulation of β-catenin signaling. Bax, bcl-2 and survivin expression. In addition, Kok et al. [126] synthesized two CA analogues and assessed them 4. CHEMOTHERAPEUTIC USES OF on the A549 non-small cell lung carcinoma cell lines by CANTHARIDIN FOR SOME OTHER DISEASES monitoring the intracellular adenosine triphosphate level. 4.1 Cantharidin for heart failure NCTD, in general, may has a wide therapeutic and/or CA has been demonstrated to act as a adjuvant therapeutic application in the treatment of vasoconstrictor and positive inotrope in guinea pig [188] human lung cancer [182]. Cancer cells invade into the and human cardiac tissue in vitro [189]. These effects are blood or lymphatic vessels leading to the spread of cancer mediated in part by CA’s action as a protein phosphatase into the organs in distant sites. For cancer cells to migrate, inhibitor [107, 108]. Effects of CA on the force of

278

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

contraction and phosphatase activity in nonfailing and compounds showing a slight stimulating effect on failing human hearts were evaluated. The positive xanthine oxidase [114]. inotropic effect of CA was similar in nonfailing and failing human hearts, accompanied by a similar inhibitory 4.3. Cantharidin for neurological disorders effect of CA on the phosphatase activity [189]. CA was The synaptic transmission at the mouse observed, also, to increases force of contraction in neuromuscular junction has been affected by CA since it isolated myocardial and vascular preparations by inhibits the mobilizations of synaptic vesicles and enhancing the phosphorylation state of myocardial and depresses Ca (2+) release from sarcoplasmic reticulum vascular regulatory proteins [164]. To shed some light on and that protein phosphatases participates in the this process, Narayan et al. [190] examined whether the modulation of motor function [196]. With regard to the protein phosphatase inhibitor CA blocks the anti- neurodegenerative diseases, both protein phosphatase adrenergic effect of adenosine A(1) receptor stimulation. inhibitors PP1 and PP2A are necessary for the splicing Their results suggested that activation of protein reaction [197]. As found by Novoyatleva et al. [198], phosphatases mediate, in part, the anti-adrenergic effect reducing PP1 activity promotes usage of numerous of adenosine A(1) receptor activation in ventricular alternative exons, demonstrating a role of PP1 activity in myocardium. Also, some experiments were carried out by splice site selection. Recently, CA was used as a starting Chu et al. [191] to examine whether the protein point to synthesize a series of phosphatase activity that phosphatase inhibitor CA inhibits the negative inotropic were subsequently tested for their effect on alternative effect induced by endothelin‐1 and carbachol in isolated neuronal splicing (for details, see Zhang et al. [199]). canine ventricular trabeculae. Their results indicated that Tauopathies are a class of neurodegenerative the activation of phosphatase that is susceptible to CA is diseases associated with the pathological aggregation of involved in both the endothelin‐1‐ induced and the tau protein in the human brain. Tau protein has a carbachol‐induced negative inotropic effect. However, causative role in Alzheimer’s disease and multiple other CA derivatives can be developed in the future, offering neurodegenerative disorders. The primary function of tau new therapeutic options for the treatment of human protein is to facilitate assembly and maintenance of cardiac failure [42]. In the guinea pig, cardiac effect of microtubules in neuronal axons. As found experimentally, CA was compared to that effect of the CA-related inhibition of PP2A by CA caused an increase in soluble compound endothall. In contrast to CA, endothall failed levels of total tau and phosphorylated tau. Inhibition of to increase force of contraction, though it inhibited PP2A also caused mislocalization of phosphorylated tau protein phosphatase activity. Thus, endothall is not an to cell bodies and initial neuritic segments [200]. On the appropriate tool to study the function of protein other hand, the drug abuse-induced neurodegeneration phosphatases in the mammalian heart [75]. can be triggered by elevated production of reactive oxygen species (ROS). The amphetamine (AMPH)- 4.2. Cantharidin for hepatitis mediated dopamine (DA) release increased nearly two- Since approximately 170 million people are fold in striatal rat brain slices pretreated for 30 min with infected with Hepatitis C virus (HCV) worldwide, HCV 1000 μM CA. These findings proved the lack of ROS infection is a serious global health problem [192]. HCV inhibitory action on protein phosphatase activity in acute causes acute and chronic hepatitis, often associated with AMPH-mediated DA efflux [201]. It is worth pointing out an increased risk of developing chronic liver disease and that antioxidants interfere with the oxidation process by hepatocellular carcinoma [193]. In TCM, three reacting with free radicals, chelating catalytic metals and compounds purified from natural products, CA, also by acting as oxygen scavengers. Therefore, the cephalotaxine andhomoharingtonine, are commonly used preparation of more effective new antioxidants is a very against the viral hepatitis B and C. Romero et al. [194] important area of research. Peksel et al. [202] investigated assessed the activity of these compounds against the reducing power, free radical scavenging, superoxide flavivirus using the bovine viral diarrhoea virus (BVDV) anion radical scavenging and metal chelating activities of as a surrogate for hepatitis C virus (HCV). It was some NCTD and bridged perhydroisoindole derivatives. suggested that these compounds are useless for the Among the synthesized derivatives, some had been found treatment of infection by flaviviruses, but potentially as potent antioxidants and thus they represent a new class useful in combined therapy against hepatitis B. CA uses of antioxidant and antiradical agents. in the treatment of hepatitis B was also reported [195]. NCTD has been used for the treatment of hepatitis. Since 4.4. Cantharidin for innate immune system the enzyme xanthine oxidase is involved in this disease, Innate immune system serves as the first defense fourteen CA analogues and cantharidimide derivatives to protect the host from the invading pathogens in a non- were tested for their effects on this enzyme. The disodium specific but instant way [203]. Different pathways have cantharidate, norcantharidin, dehydronorcantharidin, been involved to eliminate the invading pathogens in disodium dehydronorcantharidate were among the tested innate immune system which are different from acquired

279

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

immune system [204]. The recognition to pathogen- for P. falciparum during release of mature merozoits from associated molecular patterns by germ line-encoded erythrocytes [216]. pattern-recognition receptors is one of the most essential More than 16,000 species of nematodes pathways for host to distinguish the pathogens from self- (roundworms) are parasitic. Nematodes commonly tissues [205]. A family of innateimmune receptors, known parasitic on humans include ascarids (Ascaris), filarias, as Toll-like receptors (TLRs), is widely expressed on the hookworms, pinworms (Enterobius) and whipworms cell surface of most immune cells [206]. The activation of (Trichuris trichiura). Baylisascaris usually infests wild TLRs can stimulate immune cells and cause the secretion , but can be deadly to humans, as well. Dirofilaria of cytokines and chemokine to modulate innate and immitis heartworms are known for causing heartworm acquired immune response [207]. For investigating the disease by inhabiting the hearts, arteries, and lungs of function and mechanism of NCTD in regulation of TLR4- dogs and some cats.Haemonchus contortus is one of the associated immune response in macrophages, Zhao et al. most abundant infectious agents in sheep around the [208] investigated the influence of this CAanalogue on world, causing great economic damage to sheep (For host defense against invading pathogens by acute details, see [217-219]). peritonitis mouse model, ELISA, Q-PCR, nitrite With the major problems with resistance in quantification, phagocytosis assay and gelatin parasitic nematodes of livestock to anthelmintic drugs, zymography assay. Their results demonstrated that NCTD there is an urgent need to develop new nematocides. could facilitate lipopolysaccharide-mediated signaling Protein phosphatase inhibitors, such as CA and a number immune response through promoting the phosphorylation of analogues with the same pharmacophoric units but no of AKT/p65 and transcriptional activity of NF-kB adverse toxic effects on well-defined, cultured human (nuclear factor-kB). Thus NCTD can be considered a cells [139, 140, 220], show unique potential for the novel immune regulator in promoting host defense against development of nematocides [221]. Campbell et al. bacterial infection. [222]investigated the activity of more than fifty analogues against the barbers pole worm Haemonchus contortus, an 4.5. Cantharidin and cantharidin-related compounds intestinal parasite that affects livestock. They concluded against parasitic infections that a major advantage of NCTD analogues over some Plasmodium falciparum is a protozoan parasite other currently available anthelmintics is that they can be and the causative agent of the most virulent form of produced in one to two steps in large amounts at low cost malaria in humans [209]. As declared by Bajsa et al. and high purity, and do not require any additional steps [210], malaria is still a dangerous disease, despite the for the isolation of the active isomer. NCTD analogues availability of antimalarial drug. This situation is partly have been, also, shown to display anti-parasitic activity caused by the high ability of P. falciparum to evolve against the same nematode H. contortus [135]. Some resistance to the most commonly used drugs during the CA/NCTD analogues [140, 223, 224] are known to constant selection pressure. Therefore there is an urgent display relatively specific inhibitory activity against PP1 need of new drug development against new enzyme and PP2A phosphatases, which indicates that some of targets of this protozoan parasite. Bajsa et al. [211] them could be designed to selectively inhibit essential determined IC50 of 81 different CA analogues against serine⁄threonine phosphatase of nematodes [221]. chloroquine-susceptible (D6) and -resistant (W2) strains The anthelmintic activity of different species of of P. falciparum. At least two features of NCTD the tree Butea has been reported against Ascaridia galli, analogues make them a potential source of antimalarials. Ascaris lumbricoides, earthworms, Toxocara canis, Sixty NCTD analogues were tested and most chemical oxyurids, Dipylidium caninum and Taenia [225]. Extract modifications caused reduction in the antiplasmodial of Butea monosperma seeds showed significant activity below that of CA. Three of them had similar or anthelmintic activity in vitro [226].The crude extracts greater activity than CA [210]. were investigated for their anthelmintic activity of B. One of the CA-related compounds isEndothall. It monosperma against earthworms (Pheretima posthuma), has been widely used for effective control of several sub- roundworms (Ascardia galli) and tapeworms (Raillietina mersed aquatic plant species [212]. It wasreported to spiralis). The anthelmintic activity of alcohol and ethyl possess herbicidal activity in 1948 by Niagara Chemical acetate extracts of leaves of B. monosperma has been Company and was registered for use as a plant growth demonstrated [227]. Recently, some other regulator by the Sharples Chemicals Company in 1951 pharmacological properties had been reported for the [213]. Endothall has shown the best in vitro same tree [68, 228, 229]. The tree Butea frondosa (= B. antiplasmodial activity among the commercial herbicides monosperma) contains an antihelmintic principle [214]. This compound inhibits protein phosphatases (PP1 palasonin [230]. and PP2A) from mammals and plants [215]. Some studies Palasonin is a CA-related compound which was had shown that the function of enzyme PP1 is essential found to be effective against ascarids, stomach worms of sheep, oxyurids of mice, and hook worms of dogs [231].

280

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

Palasonin was found an effective anthelmintic against 6. CANTHARIDIN AND ITS ANALOGUES IN THE Ascaris lumbricoides [232] and several other helminthes DRUG DELIVERY SYSTEMS [233]. The biochemical mechanism of the antihelminthic The clinical use of CA is limited because of its action of palasonin is based upon inhibition of glucose short half-life and toxicity (for review see Ghoneim, uptake affecting the energy generating mechanisms and [19]). CA was also shown to be a poorly water-soluble motor activity of the parasite [234]. Like CA, palasonin drug with low oral bioavailability (26.7%) in beagle also inhibits PPA2, albeit with much lower efficiency dogs[47]. To reduce the toxicity and other disadvantages [235]. of CA and its analogues in the clinical usage, some researchers evaluated other preparation methods of CA 5. CANTHARIDIN FOR OVERCOMING THE delivery, such as solid dispersions [241] and inclusion DRUG RESISTANCE complexes [242]. Chang et al. [243] prepared an Drug resistance, known as multi-drug resistance encapsulated CA into pegylated liposomes and studied its (MDR), to chemotherapeutic agents is one of the major activity against human breast cancer MCF-7 cells in vitro obstacles in the treatment of human cancers[236]. as well as its systemic toxicity in mice. Depending on Currently, many clinical anticancer drugs such as their results, the systemic toxicity of CA could be alkaloids, anthracycline antibiotics, and podophyllotoxins mitigated by liposome encapsulation;however, that did may easily induce MDR [237]. The mechanisms not decrease its antitumor activity. Because CA is underlying the MDR of cancer cells are complex, partially water-soluble, Dang et al. [241] investigated the including increase of drug efflux, reduction of drug solid dispersion of CA (CA-SD) in polyethylene glycol absorption, changes in the targets of anticancer drugs, 4000 (PEG 4000) to increase its dissolution rate and oral decrease of drug activity, enhancement of DNA repair bioavailability. As recorded in this study, the solubility following damage, changes in anti-apoptosis pathways, and dissolution rate of CA were improved by the solid etc. [238]. Development or discovery of safe and effective dispersion technique. In the field of developing targeting MDR reversal agents is urgently required [237]. Three drug delivery system, Li et al. [244] prepared CA- generations of the MDR inhibitors had been described by entrapped non-ionic surfactant vesicle (noisome) and Tan et al. [239]. Mamot et al. [240] discussed some evaluated its entrapment efficiency. The preparation of general approaches for overcoming MDR using liposomes CA noisome by TweenA and SpanB was found or other carriers and increasing bioavailability of drugs at practicable and successful. Very recently, Han et al. [245] sites of action. obtained similar results which revealed that the CA- The available literature contains several reports entrapped non-ionic surfactant vesicles could be a suggesting CA and its analogues as a novel and potent promising delivery system for enhancing the antitumor MDR reversal agent tumor chemotherapy. Exposure of activity and simultaneously reducing the toxicity of CA. HL-60 (Human promyelocytic leukemia) cells to CA Because NCTD injection causes urinary organ resulted in the decreased expression of multidrug damnification, Zhang et al. [246] prepared a NCTD w/o resistance-associated protein genes. Therefore, CA may microemulsion as an alternative to improve the solubility be used as an oncotherapy sensitizer, and the increased and enhance the liver uptake of this CA analogue. Their expression of genes in modulating cytokine production pharmacokinetic results showed that NCTD and inflammatory response, which may partly explain the microemulsion had relatively longer circulating time in stimulating effects on leukocytosis [175]. mice than NCTD (alone) injection after a single Also, Zheng et al. [26] reported that CA can intravenous injection at a dose of 5 mg/kg. On the other effectively reverse MDR via down-regulation of MDR1 hand, Poly(L-lactide-co-glycolide)-alginate microspheres gene expression. With regard to CA analogues, Yi et al. containing NCTD were effective in destroying the cancer [103] suggested the use of NCTD in the treatment of cells. These microspheres also exhibited excellent drug-resistantleukemia. Since oral cancer cells with embolization and therapeutic effects on rats with mutant p53 or elevated Bcl-XL levels showed resistance transplanted tumors [247]. Lipid microspheres (LM) have to multiple chemotherapeutic agents, NCTD may recently been used as intravenous carriers for drugs, overcome the chemoresistance of these cells and provide which are sufficiently soluble in oil. Because NCTD is potential new avenues for treatment [104]. To clarify the poorly soluble in both the water and oil phases, Lixin et effect of NCTD on drug resistance in breast cancer, Chen al. [248] prepared NCTD-loaded LM by transferring the et al. [134] developed doxorubicin (DOX)-sensitive and drug to the interfacial surface of the oil and aqueous DOX-resistant MCF-7 cells. Their study demonstrated phases to produce a less irritating intravenous formulation that NCTD may overcome multidrug resistance through of NCTD. In addition, Zhang et al. [249] modified the inhibiting Sonic hedgehog signaling and expression of its NCTD-encapsulated liposomes with a novel murine anti- downstream MDR-1/P-gp expression in human breast human CD19 monoclonal antibody 2E8 (2E8-NCTD- cancer cells. liposomes) and evaluated the targeting efficiency and

281

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

specific cytotoxicity of 2E8-NCTD-liposomes to [254]. Two novel liver-targeting nanoparticles, NCTD- CD19(+) leukemia cells. loaded chitosan nanoparticles and NCTD-associated Nanotechnology provides some benefits in the galactosylated chitosan nanoparticles, were prepared field of drug delivery systems. The production and using ionic cross-linkage. The results indicated that the physicochemical characterization of particles and chitosan nanoparticles can improve intestinal absorption associated drug incorporation had been reported in a of NCTD [255]. N-Trimethyl chitosan was synthesized number of studies [250]. We have compiled here some of for preparing lactosyl-NCTD TMC nanoparticles. N- the recently reported works in the literature. Solid lipid trimethyl chitosan-encapsulated lactosyl-NCTD nanoparticles (SLNs) are one example of a feasible nanoparticles displayed efficient targeting and sustained nanosized drug delivery system. The particle matrix of a release in a hepatocarcinoma SC murine model [256]. A SLN is composed of solid lipid, which is very attractive novel hepatocyte-targeting NCTD derivative lactosyl- for the controlled release of drugs because drug mobility NCTD (Lac-NCTD) was synthesized using in a solid lipid should be considerably lower than in liquid ethanediamine as a truss arm, and lactosyl-NCTD oil, so that retarded drug release after oral administration nanoparticles (Lac-NCTD-NPs) were obtained by an ionic can be achieved [47]. Dang and Zhu [48] carried out a cross-linkage process with an entrapment efficiency of study aiming to improve the oral bioavailability of CA (80.29 ± 0.56)%. The results suggested that tumour and control its release profile in vivo using SLNs growth was effectively inhibited by all treatments, formulation. They concluded that the CA-SLNs could including NCTD, Lac-NCTD and Lac-NCTD-NPs, with improve the solubility and oral bioavailability of CA. As Lac-NCTD-NPs being the most effective, followed by reported by Zhang [251], CA drug-loaded solid lipid Lac-NCTD [257]. nanoparticles will enable the effective targeting of drug To develop charge-reversal nanocarriers for delivery in the liver lesions, reducing its toxic side effects antitumor drug delivery, Lu et al. [258] utilized the and slow-release effect. characteristic anhydride structure of NCTD and the pH- In addition to CA, solid lipid nanoparticles dependent hydrolysis of its β-carboxylic amides and containing its analogue, NCTD, had been prepared and developed novel acid-labile conjugates for the targeted characterized by Tian and Zhai [252]. These solid lipid delivery of NCTD. These targeted acid-labile conjugates nanoparticles of NCTD have high entrapment efficiency may help to reduce the side effects of NCTD and improve and good stability. A new chitosan derivative, its clinical applications. Very recently, Ding et al. [259] galactosylated chitosan (GC), was synthesized and used to investigated the drug-loaded mechanism of ion-cross- prepare NCTD-associated GC nanoparticles [253]. A linked nanoparticles (NPs) in the presence of novel formulation containing polyvinylpyrrolidone (PVP) polyvinylpyrrolidone K30 (PVP K30) and set up the K30-coated NCTD chitosan nanoparticles(PVP–NCTD– optimal PVP-coated NCTD chitosan NPs method. They NPs) was prepared and its activity was assessed in the recorded that the PVP-NCTD-NP with dual physical kidney and liver tissues of rats and mice. It was concluded drug-loaded mechanisms (physical encapsulation and that PVP–NCTD–NPs are an adequate formulation for coating of PVP) possessed higher drug content and enhancing the absorption of NCTD, and significantly showed longer sustained release. improving therapeutic effects targeting the hepatic system

REFERENCES 1. Thayer DD, Langeland KA, Haller WT, Joyce JC, Weed control in Florida ponds. Cooperative Extension Service. Institute of Food and Agricultural Sciences. University of Florida, Gainesville, FL 32611. Circular No. 707, 2001, 24 . 2. Abtahi SM, Nikbakhtzadeh MR, Vatandoost H, Mehdinia A, Rahimi-Foroshani A, Shayeghi M, Quantitative characterization of cantharidin in the false blister beetle, Oedemera podagrariae ventralis, of the Southern slopes of Mount Elborz, Iran. J. Insect Sci, 12(152), 2012, 1-5. 3. Abu-Surrah AS, Kettunen M, Platinum group antitumor chemistry, design and development of new anticancer drugs complementary to cisplatin. Curr. Med. Chem, 13, 2006, 1337-1357. 4. Akdemir O, Bilkay U, Tiftikcioglu YO, Ozek C, Yan H, Zhang F, Akin Y, New alternative in treatment of callus. J. Dermatol, 38(2), 2011, 146-150. 5. Al-Basheer M, Hijazi M, Dama T, Blister beetles dermatosis, a report of 43 cases in a military unit in Eritrea. J. Royal Med. Serv, 9(2), 2002, 40-43. 6. Al-Binali AM, Shabana M, Al-Fifi S, Dawood S, Shehri AA, Al-Barki A, Cantharidin poisoning due to blister Beetle ingestion in children, two case reports and a review of clinical presentations. Sultan Qaboos Univ. Med. J, 10(2), 2010, 258-261. 7. Alcock J, Hadley NF, Tests of alternative hypotheses for assortative mating by size, a comparison of two meloid beetles (Coleoptera, Meloidae). J. Kansas Entomol. Soc, 60(1), 1987, 41-50.

282

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

8. An WW, Gong XF, Wang MW, Tashiro SI, Onodera S, Ikejima T, Norcantharidin induces apoptosis in HeLa cells through caspase, MAPK, and mitochondrial pathways. Acta Pharm. Sinica, 25(11), 2004, 1502-1508. 9. An WW, Wang MW, Tashiro S, Onodera S, Ikejima T, Mitogen-activated protein kinase-dependent apoptosis in norcantharidin-treated A375-S2 cells is proceeded by the activation of protein kinase C. Chin. Med. J. (Engl), 118(3), 2005, 198-203. 10. An WW, Wang MW, Tashiro S, Onodera S, Ikejima T, Norcantharidin induces human melanoma A375-S2 cell apoptosis through mitochondrial and caspase pathways. J. Korean Med. Sci, 19(4), 2004, 560-566. 11. Ao GF, Zeng Z, Zhou JW, Quantitative determination of cantharidin in Epicauta aptera Kaszab's haemolymph. J.Guizhou Normal University (Nat. Sci.), 1, 2008, 100-102. 12. Arnett RH, Thomas MC, Skelly PE, Frank JH, American Beetles, Vol. 2. Polyphaga, Scarab aeoidea through Curculionidaea. CRC Press, Boca Raton, Florida, 2002, 861. 13. Ayaydin F, Vissi E, Mészáros T, Miskolczi P, Kovács I, Fehér A, Dombrádi V, Erdödi F, Gergely P, Dudits D, Inhibition of serine/threonine-specific protein phosphatases causes premature activation of cdc2MsF kinase at G2/M transition and early mitotic microtubule organisation in alfalfa. Plant J, 23, 2000, 85-96. 14. Baba Y, Hirukawa N, Sodeok M, Optically active cantharidin analogues possessing selective inhibitory activity on Ser/Thr protein phosphatase 2B (calcineurin), implications for the binding mode. Bioorg. Med. Chem, 13(17), 2005, 5164-5170. 15. Bajsa J, Sahu R, McCluskey A, Duke SO, Tekwani BL, Antimalarial activity of cantharidin analogs, potential serine/threonine protein phosphatase inhibitors. Planta Med, 74, 2008, 55. 16. Bajsa J, Singh K, Nanayakkara D, Duke SO, Rimando AM, Evidente A, Tekwani BL, A survey of synthetic and natural phytotoxic compounds and phytoalexins as potential antimalarial compounds. Biol. Pharm. Bull, 30, 2007, 1740-1744. 17. Bajsa JN, Mccluskey A, Gordon CP, Stewart SG, Hill TA, Sahu R, Duke SO, Tekwani BL, The antiplasmodial activity of norcantharidin analogs. Bioorg. Med. Chem. Letters, 20(22), 2010, 6688-6695. 18. Baumeister S, Winterberg M, Przyborski JM, Lingelbach K, The malaria parasite Plasmodium falciparum, cell biological peculiarities and nutritional consequences. Protoplasma, 12, 2010, 03-12. 19. Becerro de BVR, Losa IME, Gómez-Martín B, Sánchez GR, Sáez CA, Alication of cantharidin and podophyllotoxin for the treatment of plantar warts. J. Am. Podiatr. Med. Assoc, 98(6), 2008, 445-450. 20. Bei YY, Chen XY, Liu Y, Xu JY, Wang WJ, Gu ZL, Xing KL, Zhu AJ, Chen WL, Shi LS, Wang Q, Zhang XN, Zhang Q, Novel norcantharidin-loaded liver targeting chitosan nanoparticles to enhance intestinal absorption. Int. J. Nanomedicine, 7, 2012, 1819- 1827. 21. Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, Rutschmann S, Du X, Hoebe K, Genetic analysis of host resistance, Toll-like receptor signaling and immunity at large. Annu. Rev. Immunol, 24, 2006, 353-389. 22. Bhattacharjee P, Brodell RT, Cantharidin. In, (Brodell RT, Johnson SM, eds.). "Warts, diagnosis and management - an evidence-based aroach". London, Martin Dunitz, 2003, 151-160. 23. Blisnick T, Vincensini L, Fall G, Braun-Breton C, Protein phosphatase 1, a Plasmodium falciparum essential enzyme, is exported to the host cell and implicated in the release of infectious merozoites. Cell Microbiol, 8(4), 2006, 591-601. 24. Bochis J, The structure of palasonin. Tetrahed. Lett, 16, 1960, 1971-1974. 25. Bokník P, Vahlensieck U, Huke S, Kna J, Linck B, Lüss H, Müller FU, Neumann J, Schmitz W, On the cardiac contractile, electrophysiological and biochemical effects of Endothall, a protein phosphatase inhibitor. Pharmacology, 61, 2000, 43-50. 26. Bologna MA, A new Oenas from Greece and synonymical note on another species from Middle East (Coleoptera, Meloidae). Revue française d'Entomologie, 13(4), 1991, 175-179. 27. Bologna MA, Fauna d’Italia, Coleoptera-Meloidae. Ed. Calderini, Bologna, 1991, 541 . 28. Bologna MA, Olverio M, Pitzalis M, Mariottini P, Phylogeny and evolutionary history of the blister beetles (Coleoptera, Meloidae). Mol. Phylogen. Evol, 48, 2008, 679-693. 29. Bonness K, Aragon IV, Rutland B, Ofori-Acquah S, Dean NM, Honkanen RE, Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suression of 2A∞. Mol. Cancer Ther, 5, 2006, 2727-2736. 30. Borkar VS, Gangurde HH, Gulecha VS, Bhoyar PK, Mundada AS, Evaluation of in vitro antihelmintic activity of leaves of Butea monosperma. Int. J. Phytomedicine, 2, 2010, 31-35. 31. Brustel H, Kakiopoulos G, Contribution à la connaissance de la faune de Gréce (Coleoptera, Oedemeridae). Biocosme Mésogéen (Nice), 26, 2009, 65-75. 32. Campbell BE, McCluskey A, Hofmann A, Gasser RB, Serine/threonine phosphatases in socioeconomically important parasitic nematodes -prospects as novel drug targets? Biotech. Adv, 29(1), 2011, 28-39. 33. Campbell BE, Tarleton M, Gordon CP, Sakoff JA, Gilbert J, McCluskey A, Gasser RB, Norcantharidin analogues with nematocidal activity in Haemonchus contortus. Bioorg. Med. Chem, 21(11), 2011, 3277-3281.

283

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

34. Cao BJ, Wang JZ, Improvement on synthesis of norcantharidin. Tianjin Pharmacy, 7(2), 1995, 35-36. 35. Cao JH, Xu B, Li M, Wu DZ, Huang W, Cui JR, Effect of norcantharidin's derivative Nd3 on proliferation of human ovarian cancer cell line SKOV3 and its possible mechanisms. Ai Zheng, 26(4), 2007, 361-366. 36. Capinera JL, Dermatitis linearis. Encyclopedia of Entomology. Springer, 2008, 1179. 37. Carrel JE, McCairel MH, Slagle AJ, Doom JP, Brill J, McCormick JP, Cantharidin production in a blister beetle. Experientia, 49(2), 1993, 171-174. 38. Cavalier-Smith T, A revised six-kingdom system of life. Biol. Rev, 73, 1998, 203-266. 39. Chang C, Wu J, Zhang JM, Zhu YQ, Norcantharidin (NCTD) induces mitochondria mediated apoptosis in human HepG2 cells. Afr. J. Biotechnol, 10(27), 2011, 5370-5376. 40. Chang CC, Liu DZ, Lin SY, Liang HJ, Hou WC, Huang WJ, Chang CH, Ho FM, Liang YC, Liposome encapsu lation reduces cantharidin toxicity. Food Chem. Toxicol, 46, 2008, 3116-3121. 41. Chen JX, Liu XL, Liu Y, Influence of norcantharidin on apoptosis of K562. J.Trad. Chinese Med.Pharm, 15(2), 2000, 21-23. 42. Chen YJ, Chang WM, Liu YW, Lee CY, Jang YH, Kuo CD, Liao HF, A small-molecule metastasis inhibitor, norcantharidin, downregulates matrix metalloproteinase-9 expression by inhibiting Sp1 transcriptional activity in colorectal cancer cells. Chem. Biol. Interact, 181, 2009, 440-446. 43. Chen YJ, Kuo CD, Chen SH, Chen WJ, Huang WC, Chao KSC, Liao HF, Small-molecule synthetic compound norcantharidin reverses multi-drug resistance by regulating sonic hedgehog signaling in human breast cancer cells. PLoS ONE, 7(5), 2012, e37006. 44. Chen YJ, Tsai YM, Kuo CD, Ku KL, Shie HS, Liao HF, Norcantharidin is a small-molecule synthetic compound with anti-angiogenesis characteristics. Life Sci, 85, 2009, 642-651. 45. Chen YN, Chen JC, Yin SC, Effector mechanisms of norcantharidin-induced mitotic arrest and apoptosis in human hepatoma cells. Int. J. Cancer, 100, 2002, 158-165. 46. Cheng KC, Lee HM, Shum SF, Yip CP, A fatality due to the use of cantharides from Mylabris phalerata as an abortifacient. Med. Sci. Law, 30, 1990, 336-340. 47. Chu L, Norota I, Ishii K, Endoh M, Inhibitory action of the phosphatase Inhibitor cantharidin on the endothelin‐1‐induced and the carbachol‐induced negative inotropic effect in the canine ventricular myocardium. J. Cardiovas. Pharmacol, 41, 2003, S89-S92. 48. Cimmino F, Scoettuolo MN, Carotenuto M, de Antonellis P, Dato VD, de Vita G, Zollo M, Norcantharidin impairs medulloblastoma growth by inhibition of Wnt/β-catenin signaling. J Neurooncol, 106(1), 2012, 59-70. 49. Clarke PR, Hoffmann I, Draetta G, Karsenti E, Dephosphorylation of cdc25-C by a type-2A protein phosphatase, specific regulation during the cell cycle in Xenopus egg extracts. Mol. Biol. Cell, 4, 1993, 397-411. 50. Coloe J, Morrell DS, Cantharidin use among Pediatric dermatologists in the treatment of molluscum contagiosum. Pediatr. Dermatol, 26(4), 2009, 405-408. 51. Coskey RJ, Treatment of plantar warts in children with a salicylic acid-podophyllin-cantharidin product. Pediatr.Dermatol, 2(1), 1984, 71-73. 52. Cui DL, Yao XX, Progress in the treatment of hepatitis B and digestive tumors with cantharidin and its analogues. World Chinese J. Digestol, 5, 2008, 13. 53. Dang YJ, An LN, Hu C, Zhu CY, Inclusion complex of cantharidin with β-cyclodextrin, preparation, characterization, in vitro and in vivo evaluation. J.Al. Polymer Sci, 123(3), 2012, 1557-1562. 54. Dang YJ, Hu CH, An LN, Zhu CY, Study of the physicochemical properties and oral bioavailability of the solid dispersion of cantharidin with polyethylene glycol 4000. Exp. Clin. Pharmacol, 32(3), 2010, 157-162. 55. Dang YJ, Zhu CY, Oral bioavailability of cantharidin-loaded solid lipid nanoparticles. Chinese Medicine, 8, 2013, 1-16. 56. Dang YY, Zhu CC, Pharmacokinetics and bioavailability of cantharidin in beagle dogs. J. Chinese Materia Medica, 34(16), 2009, 2088-2091. 57. Dauben WG, Krabbenhoft HO, Organic reactions at high pressure, cycloadditions with furans. J. Am. Chem. Soc, 98, 1976, 1992-1993. 58. Davidowitz EJ, Chatterjee I, Moe JG, Targeting tau oligomers for therapeutic development for Alzheimer’s disease and tauopathies. Curr. Top.Biotechnol, 4, 2008, 47-64. 59. Davidson RH, William FL, Insect Pests of Farm, Garden and Orchard. 8th ed, John Wiley & Sons, Inc, New York, 1987, 656. 60. Day RM, Harbord M, Forbes A, Segal AW, Cantharidin blisters, a technique for investigating leukocyte trafficking and cytokine production at sites of inflammation in humans. J. Immunol. Methods, 257(1-2), 2001, 213-220. 61. Dechun W, Xu T, Erlong Z, Shuguang W, Chunmeng S, Synergistic effect of a novel cantharidin analog LB1 with doxorubicin in chemotherapy against hepatocellular carcinoma cells. J. Third Military Med. Univ, 34, 2012, 522-525.

284

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

62. Deng LP, Dong J, Cai H, Wang W, Cantharidin as an antitumor agent, a retrospective review. Curr. Med. Chem, 20(2), 2013, 159-166. 63. Deng LP, Liu FM, Wang HY, 1,3-Dipolar cycloaddition reaction, Synthesis of novel 5,6-dehydronorcantharidin derivatives of substituted aromatic amines with potential anti-tumor activities. J. Heterocyclic Chem, 42(1), 2005, 13-18. 64. Dettner K, Inter- and intra-specific transfer of toxic insect compound cantharidin. In, (Dettner K, Bauer G, Völkl W, eds). "Vertical Food Web Interactions". Springer Verlag. Berlin, 1997, 115-45. 65. Dettner K, Schramm S, Seidl V, Klemm K, Gäde G, Fietz O, Occurrence of terpene anhydride Palasonin and Palasoninimide in blister beetle Hycleus lunatus (Coleoptera, Meloidae). Biochem. Syst. Ecol, 31(1), 2003, 203-205. 66. Ding XY, Hong CJ, Liu Y, Gu ZL, Xing KL, Zhu AJ, Chen WL, Shi LS, Zhang XN, Zhang Q, Pharmacokinetics, tissue distribution, and metabolites of a polyvinylpyrrolidone-coated norcantharidin chitosan nanoparticle formulation in rats and mice, using LC-MS/MS. Int. J. Nanomedicine, 7, 2012, 1723-1735. 67. Ding XY, Hong CJ, Zhou XF, Sun JT, Liu Y, Gu ZL, Zhu AJ, Chen WL, Shi LS, Zhang XN, Mechanism of polyvinylpyrrolidone-coated norcantharidin chitosan nanoparticles. Curr. Nanosci, 9(3), 2013, 401-406. 68. Dorn DC, Kou CA, Png KJ, Moore MA, The effect of cantharidins on leukemic stem cells. Int. J. Cancer 2009, 124(9), 2186-2199. 69. Drury D, Exotic entomology, vol.1, Westwood JO, ed, Henry G. Bohn, London, 1837. 70. Efferth T, Rauh R, Kahl S, Tomicic M, Bochzelt H, Tome ME, Briehl MM, Bauer R, Kaina B, Molecular modes of action of cantharidin in tumor cells. Biochem. Pharmacol, 69, 2005, 811-818. 71. Einbinder JM, Parshley MS, Walzer RA, Sanders SL, The effect of cantharidin on epithelial cells in tissue culture. J. Invest. Dermatol, 52, 1969, 291-303. 72. Ellenhorn MJ, Ellenhorn's Medical Toxicology, diagnosis and treatment of human poisoning. 2nd ed, Baltimore, Md Williams & Wilkins, 1997. 73. Epstein JH, Epstein WL, Cantharidin treatment of digital and periungual warts. California Med, 93, 1960, 11-12. 74. Epstein WL, Kligman AM, Treatment of warts with cantharidin. Arch. Dermatol, 77(5), 1958, 508-511. 75. Essers M, Wibbeling B, Haufe G, Synthesis of the first fluorinated cantharidin analogues. Tetrahedron Letters, 42, 2001, 5429-5433. 76. Fan YZ, Fu JY, Zhao ZM, Chen CQ, Influence of norcantharidin on proliferation, proliferation -related gene proteins proliferating cell nuclear antigen and Ki-67 of human gall-bladder carcinoma GBC-SD cells. Hepatobiliary Pancreat. Dis. Int, 3(4), 2004, 603-607. 77. Fenyvesi I, Gounden V, Snyman T, Identification of cantharidin use in a South African traditional remedy. Oral presentation in South African Assoc. Clin.Biochemists, Cape Town, Sept. 1-4, 2011. 78. Fietz O, Cantharidin und palasonin, neue erkenntnisse zu zwei alten wirkstoffen. Ph.D. Thesis, Friedrich -Schiller University of Jena, Germany 2011, Available from, http,//deposit.ddb.de/cgi-bin/dokserv?idn= 96357972x&dok_var= d1&dok_ext =pdf & filename=96357972x.pdf. 79. Fietz O, Dettner K, Görls H, Klemm K, Boland W, (R)-(+)-palasonin, a cantharidin-related plant toxin, also occurs in insect hemolymph and tissues. J. Chem. Ecol, 28(7), 2002, 1315-1327. 80. Frenzel M, Dettner K, Quantification of cantharidin in canthariphilous Ceratopogonidae (Diptera), Anthomyiidae (Diptera) and cantharidin producing Oedemeridae (Coleoptera). J. Chem. Ecol, 1994, 20(8), 1795-1812. 81. Fukamachi T, Chiba Y, Wang X, Saito H, Tagawa M, Kobayashi H. Tumor specific low p H environments enhance the cytotoxicity of lovastatin and cantharidin. Cancer Letters, 297(2), 2010, 182-189. 82. Funt TR, Mehr KA, Cantharidin, a valuable office treatment of molluscum contagiosum. South Med. J, 72, 1979, 1019. 83. Geeta R, Rajak P, Navgeet S, Vasudeva N, Jindal S, Butea monosperma (Lam.) Kuntze, a review. Int. Res. J. Pharmacy, 7, 2011, 98-108. 84. Ghaffarifar F, Leishmania major, in vitro and in vivo anti-leishmanial effect of cantharidin. Exp. Parasitol, 126(2), 2010, 126-129. 85. Ghaffarifar F, The effect of cantharidin on inducing apoptosis in Leishmania major. The 87th Annual Meeting of the American Society of Parasitologists. Richmond, Virginia, July 13-16, 2012. 86. Ghaffarifar F, Treatment of cutaneous leishmaniasis by using insect product. International Conference and Exhibition on Clinical Research, Dermatology, Ophthalmology and Cardiology 5-6 July 2011 San Francisco, USA, 2011. 87. Ghoneim K, Agronomic and biodiversity impacts of the blister beetles (Coleoptera, Meloidae) in the world, a review. Int. J.Agric. Sci. Res, 2(2), 2013, 21-36. 88. Ghoneim KS, Behavioral characterization of blister beetles (Coleoptera, Meloidae) in the world, a bibliographic review. Int. J. Social Behav. Sci, 1(2), 2013, 33-48. 89. Ghoneim KS, Cantharidin toxicosis to animal and human in the world, a review. Standard Res. J. Toxicol. Environ. Health Sci, 1, 2013, 001-022.

285

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

90. Ghoneim KS, Embryonic and postembryonic development of blister beetles (Coleoptera, Meloidae) in the world, a synopsis. Int. J.Biol. Biol. Sci, 2(1), 2013, 06-18. 91. Ghoneim KS, Enhancement of research interests in physiology and biochemistry of blister beetles (Coleoptera, Meloidae), a review. Int. Res. J. Biochem.Bioinform, 3(4), 2013, 75-92. 92. Ghoneim KS, Global zoogeography and systematic aroaches of the blister beetles (Coleoptera, Meloidae), a bibliographic review. Int. J. Res. BioSciences, 2 (3), 2013, 1-45. 93. Ghoneim KS, Human dermatosis caused by vesicating beetle products (Insecta), cantharidin and paederin, An overview. World J. Med. Med. Sci, 1(1), 2013, 01-26. 94. Gnanaraj P, Venugopal V, Mozhi MK, An outbreak of Paederus dermatitis in a suburban hospital in south India, a report of 123 cases and review of the literature. J. Am. Acad. Dermatol, 57, 2007, 297-300. 95. Goksu G, Gul M, Ocal N, Kaufmann DE, Hydroarylation of bicyclic, unsaturated dicarboximides, access to aryl- substituted, bridged perhydroisoindoles. Tetrahedron Letters, 49, 2008, 2685-2688. 96. Gottesman MM, Fojo T, Bates SE, Multidrug resistance in cancer, role of ATP-dependent transporters. J. Nat. Rev. Cancer, 2, 2002, 48-58. 97. Graziano MJ, Pessah IN, Matsuzawa M, Casida JE, Partial characterization of specific cantharidin binding sites in mouse tissues. Mol. Pharmacol, 33, 1988, 706-712. 98. Graziano MJ, Waterhouse AL, Casida JE, Cantharidin poisoning associated with specific binding site in liver. Biochem. Biophys. Res. Commun, 149, 1987, 79-85. 99. Guan M, Zhou Y, Zhu QL, Liu Y, Bei YY, Zhang XN, Zhang Q, N-trimethyl chitosan nanoparticle-encapsulated lactosyl-norcantharidin for liver cancer therapy with high targeting efficacy. Int. J. Nanomedicine, 8(7), 2012, 1172- 1181. 100. Gupta P, Chauhan NS, Pande M, Pathak A, Phytochemical and pharmacological review on Butea monosperma (Palash). Int. J. Agro. Plant Production, 3 (7), 2012, 255-258. 101. Han W, Wang S, Liang R, Wang L, Chen M, Li H, Wang Y, Non-ionic surfactant vesicles simultaneously enhance antitumor activity and reduce the toxicity of cantharidin. Int. J. Nanomedicine, 8, 2013, 2187-2196. 102. Hart ME, Chamberlin AR, Walkom C, Sakoff JA, McCluskey A, Modified norcantharidins, synthesis, protein phosphatases 1 and 2A inhibition, and anticancer activity. Bioorg. Med. Chem. Lett, 14, 2004, 1969-1973. 103. Hastie CJ, Cohen PT, Purification of protein phosphatase 4 catalytic subunit, inhibition by the antitumour drug fostriecin and other tumour suressors and promoters. FEBS Letters, 431, 1998, 357-361. 104. He TP, Mo LE, Liang NC, Inhibitory effect of cantharidin on invasion and metastasis of highly metastatic ovarian carcinoma cell line HO-8910PM. Chinese J. Cancer, 24(4), 2005, 443-447. 105. Hill TA, Stewart SG, Ackland SP, Gilbert J, Sauer B, Sakoff JA, McCluskey A, Norcantharimides, synthesis and anticancer activity, synthesis of new norcantharidin analogues and their anticancer evaluation. Bioorg.Med.Chem, 15(18), 2007, 6126-6134. 106. Hill TA, Stewart SG, Gordon CP, Ackland SP, Gilbert J, Sauer B, Sakoff JA, McCluskey A, Norcantharidin analogues, synthesis, anticancer activity and protein phosphatase 1 and 2A inhibition. Chem. Med. Chem, 3(12), 2008, 1878-1892. 107. Hill TA, Stewart SG, Sauer B, Gilbert J, Ackland SP, Sakoff JA, McCluskey A, Heterocyclic substituted cantharidin and norcantharidin analogues - synthesis, protein phosphatase (1 and 2A) inhibition, and anti-cancer activity. Bioorg. Med. Chem. Lett, 17, 2007, 3392-3397. 108. Hillenmeyer ME, Fung E, Wildenhain J, Pierce SE, Hoon S, Lee W, Proctor M, St. Onge RP, Tyers M, Koller D, Altman RB, Davis RW, Nislow C, Giaever G, The chemical genomic portrait of yeast, uncovering a phenotype for all genes. Science, 320, 2008, 362-365. 109. Ho YP, To KKW, Au-Yeung SCF, Wang X, Lin G, Han X, Potential new antitumor agents from an innovative combination of demethylcantharidin, a modified traditional Chinese medicine, with a platinum moiety. J. Med. Chem, 44, 2001, 2065-2068. 110. Hong SJ, Inhibition of mouse neuromuscular transmission and contractile function by okadaic acid and cantharidin. Br. J. Pharmacol, 130(6), 2000, 1211-1218. 111. Honkanen RE, Cantharidin, another natural toxin that inhibits the activity of serine/threonine protein phosphatases types 1 and 2A. FEBS Letters, 330, 1993, 283-286. 112. Honkanen RE, Golden T, Regulators of serine/threonine protein phosphatases at the dawn of a clinical era? Curr. Med. Chem, 9, 2002, 2055-2075. 113. Hu ZH, Liu Y, Zhang L, Zhou Y, Wang Q, Bei YY, Xu JY, Wang WJ, Zhang XN, Zhang Q, Preparation of a novel liver-targeting nanoparticle of norcantharidin derivative and evaluation of its anti-tumour activity. J. Exper. Nanoscience, 6(2), 2011, 183-199. 114. Huan SK, Lee HH, Liu DZ, Wu CC, Wang CC, Cantharidin-induced cytotoxicity and cyclooxygenase 2 expression in human bladder carcinoma cell line. Toxicology, 223, 2006, 136-143.

286

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

115. Huang WW, Ko SW, Tsai HY, Chung JG, Chiang JH, Chen KT, Chen HY, Chen YF, Yang JS, Cantharidin induced G2/M arrest and apoptosis in colo 205 cancer cells through CDK1 inhibition and caspase-dependent pathway. Int. J. Oncology, 38 (4), 2011, 1067-1073. 116. Huang Y, Liu Q, Liu K, Yagasaki K, Zhang G, Suression of growth of highly-metastatic human breast cancer cells by norcantharidin and its mechanisms of action. Cytotechnology, 59(3), 2009, 201-208. 117. Huang YP, Ni CH, Lu CC, Chiang JH, Yang JS, Ko YC, Lin JP, Kuo JH, Chang SJ, Chung JG, Suressions of migration and invasion by cantharidin in TSGH-8301 human bladder carcinoma cells through the inhibitions of matrix metalloproteinase-2/-9 signaling. Evidence-Based Complementary and Alternative Medicine, Article ID 190281, 2013, 8. 118. Hugot JP, Baujard P, Morand S, Biodiversity in helminthes and nematodes as a field of study, an overview. Nematology, 3(3), 2001, 199-208. 119. Iqbal Z, Lateef M, Jabbar A, Ghayur MN, Gilani AH, In vivo anthelmintic activity of Butea monosperma against Trichostrongylid nematodes in sheep. Fitoterapia, 77(2), 2006, 137-140. 120. Janeway CA Jr, Medzhitov R, Innate immune recognition. Annu. Rev. Immunol, 20, 2002, 197-216. 121. Jemal A, Siegel R, Xu J, Ward E, Cancer statistics, CA Cancer. J. Clin, 60(5), 2010, 277-300. 122. Jia H, Liu Y, Yan W, Jia J, 4 and 2A regulate Hedgehog signaling by controlling Smo and Ci phosphorylation. Development, 136(2), 2009, 307-316. 123. Jiang L, Salmon E, Liu M, Activity of camptothecin, harringtonin, cantharidin and curcumae in the human tumor stem cell assay. Eur. J. Cancer Clin. Oncol, 19(2), 1983, 263-270. 124. Jiang M, Huo T, Lu SM, Zhang YL, Cloning and bioinformatical analysis of 3-hydroxy-3-methylglutaryl coenzyme A reductase gene from the blister beetle Epicauta mannerheimi (Coleoptera, Meloidae). Acta Entomol. Sinica, 55(7), 2012, 860-868. 125. Jiang YM, Meng ZZ, Yue GX, Chen JX, Norcantharidin induces HL-60 cells apoptosis in vitro. Evidence-Based Complementary and Alternative Medicine, Article, ID 154271, 2012, 4 . 126. Jin MS, Lee JO, Structures of the toll-like receptor family and its ligand complexes. Immunity, 29, 2008, 182-191. 127. Karras DJ, Farrell SE, Harrigan RA, Henretig FM, Gealt L, Poisoning from "Spanish fly" (cantharidin). Am. J. Emerg. Med, 14(5), 1996, 478-483. 128. Kartal DSP, Atacan D, Eskioglu F, Cantharidin treatment for recalcitrant facial flat warts, a preliminary study. J. Dermatol. Treat, 20(2), 2009, 114-119. 129. Kesisoglou F, Panmai S, Wu Y, Nanosizing-oral formulation development and biopharmaceutical evaluation. Adv. Drug Deliv. Rev, 59, 2007, 631-644. 130. Kim WR, The burden of hepatitis C in the United States. Hepatology, 36, 2002, 30-34. 131. Kim YM, Ku MJ, Son YJ, Yun JM, Kim SH, Lee SY, Anti-metastatic effect of cantharidin in A549 human lung cancer cells. Arch. Pharm. Res, 36(4), 2013, 479-484. 132. Kna J, Peter B, Sabine H, Iva G, Bettina L, Hartmut L, Frank U M, Thorsten M, Peter N, Wilhelm S, Ute V, Joachim N, Contractility and inhibition of protein phosphatases by cantharidin. Gen. Pharmac, 31, 1998, 729-733. 133. Ko RJ, A U.S. Perspective on the adverse reactions from Traditional Chinese Medicines, review article. J. Chinese Med. Assoc, 67(3), 2004, 109-116. 134. Kok SH, Cheng SJ, Hong CY, Lee JJ, Lin SK, Kuo YS, Norcantharidin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio. Cancer Lett, 217(1), 2005, 43-52. 135. Kok SH, Chui CH, Lam WS, Chen J, Lau FY, Wong RS, Cheng GY, Tang WK, Teo IT, Cheung F, Cheng CH, Chan AS, Tang JC, Apoptogenic activity of a synthetic cantharimide in leukaemia, implication on its structural activity relationship. Int. J. Mol. Med, 18(6), 2006, 1217-1221. 136. Kok SH, Hong CY, Kuo MY, Lee CH, Lee JJ, Lou IU, Lee MS, Hsiao M, Lin SK, Comparisons of norcantharidin cytotoxic effects on oral cancer cells and normal buccal keratinocytes. Oral Oncol, 39(1), 2003, 19-26. 137. Kok SHL, Chui CH, Lam WS, Chen J, Lau FY, Cheng GYM, Wong RSM, Lai S, Leung TWT, Tang JCO, Chan ASC, Apoptotic activity of a novel synthetic cantharidin analogue on hepatoma cell lines. Int. J. Mol. Med, 17(5), 2006, 945- 949. 138. Kok SHL, Chui CH, Lam WS, Chen J, Tang JCO, Lau FY, Cheng GYM, Wong RSM, Chan ASC, Induction of apoptosis on carcinoma cells by two synthetic cantharidin analogues. Int. J. Mol. Med, 17(1), 2006, 151-157. 139. Kok SHL, Gambari R, Chui CH, Lam WS, Chen J, Lau FY, Wong RSM, Cheng GYM, Lai PBS, Leung TWT, Chan ASC, Tang JCO, In vitro anti-cancer property of five synthetic cantharidin analogues, a mini-review. Minerva Biotecnologica, 18(3), 2006, 153-157. 140. Kumar D, Mishra SK, Tandan SK, Tripathi HC, Possible mechanism of anthelmintic action of palasonin in Ascardia galli. Indian J. Pharmacol, 27, 1995, 161-168.

287

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

141. Kuo JH, Chu YL, Yang JS, Lin JP, Lai KC, Kuo HM, Hsia TC, Chung JG, Cantharidin induces apoptosis in human bladder cancer TSGH 8301 cells through mitochondria-dependent signal pathways. Int. J. Oncology, 37(5), 2010, 1243- 1250. 142. Lal J, Chandra S, Sabir M, Modified method for isolation of Palasonin Ð the anthelmintic principle of Butea frondosa seeds. Indian J. Pharm. Sci, 1978, 97-98. 143. Langley JM, Soder CM, Schlievert PM, Murray S, Case report, Molluscum contagiosum. Can. Family Physician, 49, 2003, 887-889. 144. Lebwohl D, Canetta R, Clinical development of platinum complexes in cancer therapy, an historical perspective and an update. Eur. J.Cancer, 34, 1998, 1522-1534. 145. Lev E, Traditional healing with animals (zootherapy), medieval to present-day Levantine practice. J. Ethno-Pharm, 86, 2003, 107-118. 146. Li H, Fang Q, Zhang H, Zang C, Zhang B, Nie Q, Wang G, Preparation and characterization of non -ionic surfactant vesicle of cantharidin. Zhongguo Zhong Yao Za Zhi, 35(19), 2010, 2546-2550. 147. Li W, Chen Z, Zong Y, Gong FR, Zhu Y, Yin H, Xu ZK, Tao M, Miao Y, Cantharidin induces apoptosis in pancreatic cancer cell lines PANC1 and CFPAC-1. Chinese J. Pancreatol, 11(4), 2011, 255-258. 148. Li W, Xie L, Chen Z, Zhu Y, Sun Y, Miao Y, Xu Z, Han X, Cantharidin, a potent and selective 2A inhibitor, induces an oxidative stress-independent growth inhibition of pancreatic cancer cells through G2/M cell-cycle arrest and apoptosis. Cancer Sci, 101(5), 2010, 1226-1233. 149. Li XF, Chen XS, Wang XM, Hou XH, Contents and exis ting forms of cantharidin in Meloidae (Coleoptera). Acta Entomol. Sinica, 7, 2007, 750-754. 150. Li XF, Comparison of the bound cantharidin with metal elements in Meloidae. Hubei Agric. Sci, 2011, 13. 151. Li Y, Fang F, Chen S, Zhang C, NCTD enhancing paclitaxel-induced apoptosis in liver cancer cells involving up- regulation of Bim. World Automation Congress (WAC), Puerto Vallarta, Mexico, 24-28 June 2012, 1-4. 152. Li YM, Casida JE, Cantharidin binding protein, Identification as protein phosphatase 2A. Proc. Natl. Acad. Sci, 89, 1992, 11867-11870. 153. Liang F, Wang MY, Huang WB, Li AJ, Effect of sodium cantharidinate on the angiogenesis of nude mice with human gastric cancer. Zhong Yao Cai, 34(3), 2011, 343-346. 154. Liao HF, Su SL, Chen YJ, Chou CH, Kuo CD, Norcantharidin preferentially induces apoptosis in human leukemic Jurkat cells without affecting viability of normal blood mononuclear cells. Food and Chem. Toxicol, 45(9), 2007, 1678- 1687. 155. Lin LH, Huang HS, Lin CC, Lee LW, Lin PY, Effects of cantharidinimides on human carcinoma cells. Chem. Pharmaceut. Bull, 52 (7), 2004, 855-857. 156. Linck B, Boknik P, Kna J, Müller FU, Neumann J, Schmitz W, Vahlensieck U, Effects of cantharidin on force of contraction and phosphatase activity in nonfailing and failing human hearts. Br. J. Pharmacol, 119, 1996, 545-550. 157. Liu D, Chen Z, The effects of cantharidin and cantharidin derivates on tumour cells. Anticancer Agents Med. Chem, 9(4), 2009, 392-396. 158. Liu D, Shi P, Yin X, Chen Z, Zhang X, Effect of Norcantharidin on the human breast cancer Bcap-37 cells. Connect. Tissue Res, 53(6), 2012, 508-512. 159. Liu J, Qi Y, Fu Q, Effects of norcantharidin on proliferation and anti-tumor activity of cytokine-induced killer cells in vitro. Chinese J. Lymphol. Oncol, 9(3), 2010, 128-131. 160. Liu S, Yu H, Kumar S, Martin J, Xu X, Norcantharidin induces melanoma cell apoptosis through TR3 pathway. Proceedings of AACR 102nd Annual Meeting Apr 2-6, 2011, Orlando, Philadelphia, Cancer Research, 71(8)(Sul. 1) 2011 (Abstract 5043). 161. Liu X, Heng WS, Li Q, Chan L.W, Novel polymeric microspheres containing norcantharidin for chemoembolization. J. Control Release, 116(1), 2006, 35-41. 162. Liu YG, Mitsukawa N, Oosumi T, Whittier RF, Efficient isolation and maing of Arabidopsis thaliana T-DNA insert junctions by thermal asymmetric interlaced PCR. The Plant J, 8(3), 1995, 457-463. 163. Lixin W, Haibing H, Xing T, Ruiying S, Dawei C, A less irritant norcantharidin lipid microspheres, formulation and drug distribution. Int. J. Pharm, 323(1-2), 2006, 161-167. 164. Lu K, Cao M, Mao W, Sun X, Tang J, Shen Y, Sui M, Targeted acid-labile conjugates of norcantharidin for cancer chemotherapy. J. Mater. Chem, 22, 2012, 15804-15811. 165. Luan J, Duan H, Liu Q, Yagasaki K, Zhang G, Inhibitory effects of norcantharidin against human lung cancer cell growth and migration. Cytotechnology, 62(4), 2010, 349-355. 166. Mack P, Ha XF, Cheng LY, Efficacy of intra-arterial norcantharidin in suressing tumour 14C-labelled glucose oxidative metabolism in rat Morris hepatoma. H.P.B Surg, 10(2), 1996, 65-72.

288

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

167. Mamot C, Drummond DC, Hong K, Kirpotin DB, Park JW, Liposome-based aroaches to overcome anticancer drug resistance. Drug Resist. Updat, 6(5), 2003, 271-279. 168. Maroufi Y, Ghaffarifar F, Dalimi A, Sharifi Z, Hasan Z, A study on the cytotoxic effect of cantharidin on Leishmania major promastigote and amastigote survival in vitro. J. Kashan Univer. Med. Sci, 16(5), 2012, 406-413. 169. Massicot F, Dutertre-Catella H, Pham-Huy C, Liu XH, Duc HT, Warnet JM, In vitro assessment of renal toxicity and inflammatory events of two protein phosphatase inhibitors cantharidin and nor-cantharidin. Basic Clin. Pharmacol. Toxicol, 96(1), 2005, 26-32. 170. Mathes EFD, Frieden IJ, Treatment of molluscum contagiosum with cantharidin, a practical aroach. Pediatric Annals, 39(3), 2010, 124-130. 171. Mazumder PM, Das MK, Das S, Butea monosperma (Lam.) Kuntze, a comprehensive review. Int.J. Pharmaceut. Nanotech, 4(2), 2011, 1390-1393. 172. McCluskey A, Ackland SP, Bowyer MC, Baldwin ML, Garner J, Walkom CC, Sakoff JA, Cantharidin analogues, synthesis and evaluation of growth inhibition in a panel of selected tumour cell lines. Bioorg. Chem, 31, 2003, 68-79. 173. McCluskey A, Bowyer MC, Collins E, Sim ATR, Sakoff JA, Baldwin ML, Anhydride modified cantharidin analogues, synthesis, inhibition of protein phosphatases 1 and 2A and anticancer activity. Bioorg. Med. Chem. Lett, 10 (15), 2000, 1687-1690. 174. McCluskey A, Keane MA, Walkom CC, Bowyer MC, Sim AT, Young DJ, Sakoff JA, The first two cantharidin analogues displaying 1 selectivity. Bioorg. Med. Chem. Lett, 12, 2002, 391-393. 175. McCluskey A, Sakoff JA, Small molecule inhibitors of serine/threonine protein phosphatases. Mini Rev. Med. Chem, 1, 2001, 43-55. 176. McCluskey A, Sim AT, Sakoff JA, Serine-threonine protein phosphatase inhibitors, development of potential therapeutic strategies. J. Med. Chem, 45, 2002, 1151-1175. 177. McCluskey A, Walkom C, Bowyer MC, Ackland SP, Gardiner E, Sakoff JA, Cantharimides, a new class of modified cantharidin analogues inhibiting protein phosphatases 1 and 2A. Bioorg. Med. Chem. Letters, 11, 2001, 2941-2946. 178. McConnell JL, Wadzinski BE, Targeting protein Serine/Threonine phosphatases for drug development. Molecular Pharmacology, 75(6), 2009, 1249-1261. 179. McCormick JP, Carrel JE, Cantharidin biosynthesis and function in meloid beetles. In, (Prestwitch GD, Blomquist GJ, eds.). "Pheromone Biochemistry". Academic Press. Orlando, Florida, 1987, 307-350. 180. Mebs D, Pogoda W, Schneider M, Kauert G, Cantharidin and demethylcantharidin (palasonin) content of blister b eetles (Coleoptera, Meloidae) from southern Africa. Toxicon, 53(4), 2009, 466-468. 181. Medzhitov R, Recognition of microorganisms and activation of the immune response. Nature, 449, 2007, 819-826. 182. Mehta RK, Parashar GC, Effect of Butea frondosa, Vernonia anthelrnintica, and Carica papaya against Oxyurids in mice. Indian Vet. J, 43, 1966, 73-78. 183. Meyer FAA, Tentamen monographiae generis Meloes. Vandenhoek u. Ruprecht, Germany (In Latin), 1793, 32. 184. Mishra A, Verma S, Mishra AP, A Plant Review, Butea monosperma (Lam.) Kuntze. Res. J. Pharm. Biol. Chem. Sci, 3(1), 2012, 700-714. 185. Moed L, Shwayder TA, Chang MW, Cantharidin Revisited, a blistering defense of an ancient medicine. Arch. Dermatol, 137, 2001, 1357-1360. 186. Molinari G, Natural products in drug discovery, present status and perspectives. Adv. Exp. Med. Biol, 655, 2009, 13-27. 187. Nakatani T, Jinpo K, Noda N, Cantharimide dimers from the Chinese blister beetle, Mylabris phalerate Pallas. Chem. Pharm. Bull, 55(1), 2007, 92-94. 188. Nakatani T, Konishi T, Miyahara K, Noda N, Three novel cantharidin-related compounds from the Chinese blister beetle, Mylabris phalerata Pall. Chem. Pharm. Bull, 52(7), 2004, 807-809. 189. Narayan P, Mentzer RM Jr, Lasley RD, Phosphatase inhibitor cantharidin blocks adenosine A(1) receptor anti-adrenergic effect in rat cardiac myocytes. Am. J. Physiol. Heart Circ. Physiol, 278(1), 2000, H1-7. 190. Neumann J, Herzig S, Boknik P, Apel M, Kaspareit G, Schmitz W, Scholz H, Tepel M, Zimmermann N, On the cardiac contractile, biochemical and electrophysiological effects of cantharidin, a phosphatase inhibitor. J. Pharmacol. Exp. Ther, 274, 1995, 530-539. 191. Nikbakhtzadeh MR, Ebrahimi B, Detection of cantharidin related compounds in Mylabris impressa (Coleoptera, Meloidae). J. Venom. Anim. Toxins incl. Trop. Dis, 13(3), 2007, 686-693. 192. Nikbakhtzadeh MR, Naderi M, Safa P, Faunal diversity of Paederus Fabricius, 1775 (Coleoptera, Staphylinidae) in Iran. Insecta Mundi, 0267, 2012, 1-9 193. Nikitskyn B, Oedemeridae. In, (Ler, P.A, ed.) "A key to the insects of Far Eastern USSR", in six volumes. Vol. 3. Coleoptera or Beetles. Part 3. Dalnauka, Vladivostok, 1996, 556 .

289

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

194. Novoyatleva T, Heinrich B, Tang Y, Benderska N, Butchbach ME, Lorson CL, Lorson MA, Ben -Dov C, Fehlbaum P, Bracco L, Burghes AH, Bollen M, Stamm S, Protein phosphatase 1 binds to the RNA recognition motif of several splicing factors and regulates alternative pre-mRNA processing. Hum. Mol. Genet, 17, 2008, 52-70. 195. Oaks WW, Ditunnoi JF, Magnani T, Levy HA, Mills LC, Cantharidin poisoning. Arch. Intern. Med, 105(4), 1960, 574- 582. 196. Paszti-Gere E, Jakus J, Protein phosphatases but not reactive oxygen species play functional role in acute amphetamine- mediated dopamine release. Cell Biochem Biophys, 66(3), 2013, 831-841. 197. Peksel A, Celik C, Ocal N, Yanardag R, Antioxidant and radical scavenging activities of some norcantharidin and bridged perhydroisoindole derivatives. J. Serbian Chem. Soc, 78(1), 2013, 15-25. 198. Peng C, Liu X, Liu E, Xu K, Niu W, Chen R, Wang J, Zhang Z, Lin P, Wang J, Agrez M, Niu J, Norcantharidin induces HT-29 colon cancer cell apoptosis through the αvβ6-extracellular signal-related kinase signaling pathway. Cancer Sci, 100, 2009, 2302-2308. 199. Prashanth D, Asha MK, Amit A, Padmaja R, Anthelmintic activity of Butea monosperma. Fitoterapia, 72(4), 2001, 421- 422. 200. Prestwitch GD, Blomquist GJ, Pheromone Biochemistry. Academic Press. Orlando, 1987, 565 . 201. Raj RK, Kurup PA, Isolation and characterization of palasonin, an anthelmintic principle of the seeds of Butea frondosa. Indian J. Chem, 5(1), 1967, 86-87. 202. Ratcliffe NA, Mello CB, Garcia ES, Butt TM, Azambuja P, Insect natural products and processes, new trea tments for human disease. Insect Biochem. Mol. Biol, 41(10), 2011, 747-769. 203. Rauch R, Kahl S, Boechzelt H, Bauer R, Kaina B, Efferth T, Molecular biology of cantharidin in cancer cells. Chinese Medicine, 2, 2007, 8. 204. Romero MR, Serrano MA, Efferth T, Alvarez M, Marin JJ, Effect of cantharidin, cephalotaxine and homoharringtonine on "in vitro" models of hepatitis B virus (HBV) and bovine viral diarrhoea virus (BVDV) replication. Planta Medica, 73(6), 2007, 552-558. 205. Rosenberg EW, Amonette RA, Gardner JH, Cantharidin treatment of warts at home. Arch. Dermatol, 113(8), 1977, 1134. 206. Sagawa M, Nakazato T, Uchida H, Ikeda Y, Kizaki M, Cantharidin induces apoptosis of human multiple myeloma cells via inhibition of the JAK/STAT pathway. Cancer Sci, 99 (9), 2008, 1820-1826. 207. Sakoff JA, Ackland SP, Baldwin ML, Keane MA, McCluskey A, Anticancer activity and protein phosphatase 1 and 2A inhibition of a new generation of cantharidin analogues. Invest. New Drugs, 20 (1), 2002, 1-11. 208. Salama RB, Hammouda Y, Gassim I, Isolation of cantharidin from Cyaneolytta sahirina. J. Pharm. Pharmacol, 26(4), 1974, 268-269. 209. Schmidt J, Cantharidin and meloids, a review of classical history, biosynthesis and function [Internet]. Colorado, Department of Entomology, Colorado State University. Available from, http,//www.colostate.edu/Depts/Entomology/courses/en570/ papers_ 2002/ schmidt.htm. 210. Shan HB, Cai YC, Liu Y, Zeng WN, Chen HX, Fan BT, Liu XH, Xu ZL, Wang B, Xian LJ, Cytotoxicity of cantharidin analogues targeting protein phosphatase 2A. Anti-Cancer Drugs, 17(8), 2006, 905-911. 211. Sharma AK, Deshwal N, An Overview on phytochemical and pharmacological studies of Butea monosperma. Int. J. Pharm.Tech. Res, 3(2), 2011, 864-871. 212. Shi Y, Reddy B, Manley JL, Dephosphorylation of specific snRNP proteins is required for the second step of pre-mRNA splicing. Mol. Cell, 23, 2006, 819-829. 213. Silverberg NB, Pediatric molluscum contagiosum, optimal treatment strategies. Pediatr. Drugs, 5, 2003, 505-512. 214. Silverberg NB, Sidbury R, Mancini AJ, Childhood molluscum contagiosum, experience with cantharidin therapy in 300 patients. J.Am. Acad. Dermatol, 43(3), 2000, 503-507. 215. Sivilov O, Records of Oedemeridae (Insecta, Coleoptera) species from Strandzha Mountain (Bulgaria and Turkey). ZooNotes, 32, 2012, 1-5. 216. Sollmann T, A Manual of Pharmacology, Ed. 8, Philadelphia, W.B. Saunders Company 1955. 217. Sontag E, Fedorov S, Kamibayashi C, Robbins D, Cobb M, Mumby M, The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the map kinase pathway and induces cell proliferation. Cell, 75, 1993, 887-897. 218. Stewart SG, Hill TA, Gilbert J, Ackland SP, Sakoff JA, McCluskey A, Synthesis and biological evaluation of norcantharidin analogues, towards 1 selectivity. Bioorg Med Chem, 15, 2007, 7301-7310. 219. Stork G, van Tamelen EE, Friedman LI, Burgstahler AW, Stereospecific synthesis of cantharidin. J. Am. Chem. Soc, 75, 1953, 384-391. 220. Sun BT, Zheng LH, Bao YL, Yu CL, Wu Y, Meng XY, Li YX, Reversal effect of Dioscin on multidrug resistance in human hepatoma HepG2/adriamycin cells. Eur. J. Pharm, 654, 2011, 129-134.

290

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

221. Švihla V, Contribution to the knowledge of the Old World Oedemeridae (Coleoptera). Acta Societatis Zoologicae Bohemicae, 68, 2004, 61-78. 222. Švihla V, Sulementary notes on the family Oedemeridae (Coleoptera) as published in the Catalogue of Palaearctic Coleoptera with the new data of distribution. Klapalekiana, 47, 2011, 83-88. 223. Tagwireyi D, Ball DE, Blister beetles and cantharidin. Zimbabwe Science News, 34(2), 2000, 27-30. 224. Tan B, Piwnica-Worms D, Ratner L, Multidrug resistance transporters and modulation. Curr. Opin. Oncol, 12, 2000, 450-458. 225. Tarleton M, Synthesis and evaluation of norcantharidin and acrylonitrile derivatives as potential anti-cancer agents. Ph.D. Thesis, University of Newcastle. Faculty of Science & Information Technology, School of Environmental and Life Sciences, 2012. 226. Teodori E, Dei S, Martelli C, Scapecchi S, Gualtieri F, The functions and structure of ABC transporters, implications for the design of new inhibitors of Pgp and MRP1 to control multidrug resistance (MDR). Curr Drug Targets, 7, 2006, 893- 909. 227. Thomas DL, Hepatitis C epidemiology. Curr. Top. Microbiol. Immunol, 242, 2000, 25-41. 228. Tian HY, Zhai GX, Preparation and characterization of solid lipid nanoparticles of norcantharidin. Zhong Yao Cai, 30(9), 2007, 1146-1148.. 229. Tischler N, Bates JC, Quimba GP, A new group of defoliant herbicidal chemicals. Proc. N.E. Weed Conference, 4, 1950, 51-84. 230. To KK, Ho YP, Au-Yeung SC, Synergistic interaction between platinum-based antitumor agents and demethylcantharidin. Cancer Lett, 223(2), 2005, 227-237. 231. Tsauer W, Lin JG, Lin PY, Hsu FL, Chiang HC, The effects of cantharidin analogues on xanthine oxidase. Anticancer Res, 17 (3C), 1997, 2095-2098. 232. Tseng IJ, Sheu SY, Lin PY, Lee, JA, Ou KL, Lee LW, Synthesis and evaluation of cantharidinimides on human cancer cells. J. Exper. Clin. Med, 4(5), 2012, 280-283. 233. Ulevitch RJ, Molecular mechanisms of innate immunity. Immunol. Res, 21, 2000, 49-54. 234. Verma AK, Prasad SB, Kaliyaan RK, Arjun J, Crystal structure of cantharidin (2, 6-dimethyl-4, 10-dioxatricyclo- [5.2.1.02, 6] decane-3, 5-dione) isolated from red headed blister beetle, Epicauta hirticornis. Int. J. Bioassays, 2(3), 2013, 527-530. 235. von Bruchhausen F, Bersch HW, Constitution of cantharidin. Arch. Pharm, 266, 1929, 697-702. 236. Vuorela P, Leinonenb M, Saikkuc P, Tammelaa P, Rauhad JP, Wennberge T, Vuorela H, Natural products in the process of finding new drug candidates. Curr. Med. Chem, 11, 2004, 1375-1389. 237. Wang , Wang YJ, Lin QY, Shen LL, Zhao YL, Synthesis, crystal structure and bioactivity of a Pd (II) complex with demethylcantharate and 2,2΄-Bipyridine. Chinese J. Struct. Chem, 31(8), 2012, 1175-1181. 238. Wang CC, Wu CH, Hsieh KJ, Yen KY, Yang LL, Cytotoxic effects of cantharidin on the growth of normal and carcinoma cells. Toxicology, 147, 2000, 77-87. 239. Wang D, Liard SJ, Cellular processing of platinum anticancer drugs. Nature Reviews Drug Discovery, 4, 2005, 307-320 240. Wang GS, Medical uses of Mylabris in ancient China and recent studies. J. Ethnopharmacol, 26, 1989, 147-162. 241. Wang Q, Zhang L, Hu W, Hu ZH, Bei YY, Xu JY, Wang WJ, Zhang XN, Zhang Q, Norcantharidin-associated galactosylated chitosan nanoparticles for hepatocyte-targeted delivery. Int. J. Nanomedicine, 6(2), 2010, 371-381. 242. Weischer B, Brown DJF, An Introduction to Nematodes, General Nematology. Sofia, Bulgaria, Pensoft, 2000, .75-76. 243. Williams LA, Möller W, Merisor E, Kraus W, Rösner H, In vitro anti-proliferation/cytotoxic activity of cantharidin (Spanish Fly) and related derivatives. West Indian Med. J, 52(1), 2003, 10-13. 244. Wu LT, Chung JG, Chen JC, Tsauer W, Effect of norcantharidin on N-acetyltransferase activity in HepG2 cells. Am. J. Chinese Medicine, 32, 2001, 161-172. 245. Yang PY, Chen MF, Kao YH, Hu DN, Chang FR, Wu YC, Norcantharidin induces apoptosis of breast cancer ce lls, Involvement of activities of mitogen activated protein kinases and signal transducers and activators of transcription. Toxicology in vitro, 25(3), 2011, 699-707. 246. Yi SN, Wass J, Vincent P, Iland H, Inhibitory effect of norcantharidin on K562 human myeloid leukemia cells in vitro. Leuk. Res, 15, 1991, 883-886. 247. Yoo S, Park HC, Kim JI, Taxonomic review of the subfamily Nacerdinae (Coleoptera, Oedemeridae) in Korea. Entomol. Res, 38(4), 2008, 287-298. 248. Yu CW, Li KKW, Pang SK, Au-Yeung SCF, Ho YP, Anti-cancer activity of a series of platinum complexes integrating demethylcantharidin with isomers of 1,2-diaminocyclohexane. Bioorg. Med. Chem. Letters, 16(6), 2006, 1686-1691. 249. Zeng WN, Lu Y, Advance on the synthesis and activities of cantharidin and its derivatives. Chinese J. Org. Chem, 26(05), 2006, 579-591.

291

Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

250. Zhan Y.P, Huang XE, Cao J, Lu YY, Wu XY, Liu J, Xu X, Xu L, Xiang J, Ye LH, Clinical study on safety and efficacy of Qinin® (cantharidin sodium) injection combined with chemotherapy in treating patients with gastric cancer. Asian Pacific J. Cancer Prev, 13 (9), 2012, 4773-4776. 251. Zhang J, Tang Y, Qian B, Sheng H, Preparation and evaluation of norcantharidin -encapsulated liposomes modified with a novel CD19 monoclonal antibody 2E8. J. Huazhong. Univ. Sci. Technolog. Med. Sci, 30(2), 2010, 240-247. 252. Zhang JP, Ying K, Xiao ZY, Zhou B, Huang QS, Wu HM, Yin M, Xie Y, Mao YM, Rui YC, Analysis of gene expression profiles in human HL-60 cell exposed to cantharidin using cDNA microarray. Int. J. Cancer, 108, 2004, 212- 218. 253. Zhang L, Sun X, Zhang ZR, An investigation on liver-targeting microemulsions of norcantharidin. Drug Deliv, 12(5), 2005, 289-295. 254. Zhang WD, Zhao HR, Yan Y, Wang XH, Zong ZH, Liu Y, Apoptosis induced by cantharidin in human pulmonary carcinoma cells A549 and its molecular mechanisms. Chinese J. Oncol, 27(6), 2005, 330-334. 255. Zhang Z, Kelemen O, van Santen MA, Yelton SM, Wendlandt AE, Sviripa VM, Bollen M, Beullens M, Urlaub H, Luhrmann R, Watt DS, Stamm S, Synthesis and characterization of pseudocantharidins, novel phosphatase modulators that promote the inclusion of exon7 into the SMN (survival of motoneuron) pre-mRNA. J. Biol. Chem, 286(12), 2011, 10126-10136. 256. Zhang ZY, Study on hepatic targeted solid liquid nanoparticles of cantharidin. M.Sc. Thesis, Shandong University of Traditional Chinese Medicine, China 2011. 257. Zhao Q, Qian Y, Li R, Tan B, Han H, Liu M, Qian M, Du B, Norcantharidin facilitates LPS-mediated immune responses by up-regulation of AKT/NF-kB signaling in macrophages. PLoS ONE, 7(9), 2012, 11. 258. Zheng LH, Bao YL, Wu Y, Yu CL, Meng XY, Li, YX, Cantharidin reverses multidrug resistance of human hepatoma HepG2/ADM cells via down-regulation of P-glycoprotein expression. Cancer Letters, 272, 2008, 102-109. 259. Zhou ZH, Chen RY, Synthesis of glycerophospholipid conjugates of cantharidin and its analogues. Synthetic Communications, 30(19), 2000, 3527-3533.

292