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 beetles 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 insect 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. arthropods. 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. insects 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 animal 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 beetle 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 blister beetle 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 Meloe 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].