American Journal of Ethnomedicine, 2015, Vol. 2, No. 5 ISSN: 2348-9502 Available online at http://www.ajethno.com © American Journal of Ethnomedicine

Review on species:Deserving Potential Pharmacological Properties and Boon in Medical Applications

V P B REKHA, B.R.S.S SRINIVAS GUPTA, PRATTIPATI ANUSHA, JADA VENKTESWARALU, MULPURI RAMESH BABU and KOLLIPARA MANIDEEP*

Department of Biotechnology, R.V.R. & J.C College of Engineering,

*Corresponding author e-mail: [email protected] ABSTRACT

Trichosanthes species of the family, of this species are good potential sources of various phenolic compounds and antioxidants with anticancer, antiproliferative, cardioprotective and antioxidant properties. Many research studies on Trichosanthes species reported that it contains important protein constituent known as Ribosome Inactivating Protein (RIP), it helps in formulation of anticancer agents. Biological components in species are valued as a stimulant for it medical properties like Anti-inflammatory, Antidiabetic, Antiulcer and Cardioprotective activities. This review is focused on emphasizing varied pharmacological properties of Trichosanthes species and its future prospects for improved usage in treating numerous conditions.

Keywords- Trichosanthes species, Pharmacological properties, Anti-HIV, Anticancer and Apoptosis.

INTRODUCTION important role in the Ayurvedic and Siddha system of medicine due to its various 3 Among all biological life forms play medicinal values like anti HIV , 33 34 a crucial role in the environment by cardioprotective , anti-ulcer , anti- 35 37 supporting all types of biological life forms. diabetic , hepatoprotective , anti- 39 38 They also play a promising role in the inflammatory , larvicidal effects etc. treatment of diseases established by their In the present review focuses on employment in all important systems of update on the species mainly on medicine. One such plant species is Trichosanthes has been enlightened to bring Trichosanthes.Most of these plants species out the hidden medicinal values of are rich in flavonoids, carotenoids and thisspecies. The Trichosanthes is phenolic compounds. These species play an native to Southern and Eastern , and Islands of the western Pacific.

Page 303 www.ajethno.com American Journal of Ethnomedicine ______ISSN: 2348-9502

It was probably domesticated in ancient Cucurbitaceae lies within the class of times in India. It is grown as in dicotyledonous and in the division of many countries of tropical Asia and . anthophytha. It is known to many as the It is also reported from India through or pumpkin family. They usually Malayato tropical Australia Trichosanthes produce spiraling tendrils or modified species is an introduced crop of increasing that wrap around adjacent objects and use importance in several parts of Africa, them for their support. Cucurbits generally including Ghana and Nigeria. The genus are climbing plants with alternate, simple, Trichosanthes comprises about 100 species, palmately veined and dioecious of which a few have been domesticated in species. Many chemical studies reveal that Asia. They are the wide variation of in addition to a number of tetra and Trichosanthes species occurring from India, pentacyclic triterpenes, the toxic bitter Srilanka, , through South-East Asia, principles cucurbitaceous (a group of often northern Australia, tropical regions of highly oxygenated tetra cyclic compounds , India, , Srilanka, with a unique carbon skeleton and almost a , Vietnam, , and carbonyl group in ring C) may be considered , Philippines, in Australia it is as a taxonomic character of Cucurbitaceae1. found in Northern Territory, Queensland and in Western Australia1. Bacterial resistance is a worldwide It is a tropical or subtropical , emerging problem. During the last ten years raised for its strikingly long as well. It the pace of development of new antibacterial is used as a vegetable, medicine and a lesser drugs has slowed down, while the known use in crafting didgeridoos. Common prevalence of resistance (especially names include snake gourd (var. anguina), multiple) has increased astronomically. The serpent gourd, chichinga, and padwal. It is effects of plant extracts on bacteria have also known as chichi do in Nepali Formerly, been studied by a very large number of the cultivated form was considered a distinct researchers in different parts of the world. species, but nowadays it is regarding as Much work has been carried out on ethno mere variety of the wild ancestor, as they medicinal plants in India and other parts of freely interbreed Trichosanthes cucumerina the world very interestingly, Outcomes of var. anguina (L.). Haines–cultivated variant this research are very beneficial to the with Trichosanthes cucumerina var. human race to clear the problems of the Cucumerina-wild variant. It is rich in different diseases. It has been suggested that various essential proteins and vitamin C. the aqueous and ethanol extracts from plant The major active constituents of the drug are susedinallopathicthe antidiabetic, hepato- triterpenoid, saponins, and cucurbitacins; protective and antioxidant potential of chemical constituents like Flavonoids, Trichosanthes species. The present review carotenoids, phenolic acids which makes the explores the potential activity of plant pharmacologically as well Trichosanthes species against viral, therapeutically active. Trichosanthes bacterial, fungal diseases1. cucumerina is used in the treatment of headache, alopecia, fever, abdominal Cucurbitaceae family tumors, bilious, boils, acute colic, diarrhea, The family Cucurbitaceae (vine hematuria and skin allergy etc. crops) contains of various squashes, melons, Trichosanthes cucumerina is used as and , including crops like , an abortifacient, vermifuge, refrigerant, pumpkins and watermelons. The family of purgative, malaria, laxative, hem

Page 304

American Journal of Ethnomedicine ______ISSN: 2348-9502 agglutinant, emetic, cathartic, bronchitis and needed in small quantities. Pointed gourd is anthelmintic. A novel is flavone glucosidal, rich in vitamins and minerals. 5, 6, 6’‐trimethoxy‐3', 4'‐methylene- The seeds of dioxyisoflavone- 7‐O‐beta‐D‐ (2''‐O‐p‐ contain a large amount of peptides. These coumaroylgluco -pyranoside)1 has been peptides have the unique property of being characterized from the seeds of resistant to the action of silver nitrate, a Trichosanthes. The positive effects of the sensitive reagent commonly used to stain plant are due to the presenceantioxidants in proteins. The seed extract of Trichosanthes it. The dried seeds in are used for various dioica consists of oxidihydrokarounidol-3- ailments because of anthelmintic and benzoate as the most predominant antidiarrheal properties in it. Seeds have component in the highly polar fraction of the anti‐bacterial, anti‐spasmodic and non saponifiable lipid. Two main insecticidal properties. Hot aqueous extract phytosterols in Trichosanthes dioica are (HAE) of root tubers of Trichosanthes namely, 24α- ethylcholest-7-enol and 24β- cucumerina exhibited significant ethylcholest-7-enol. Seeds of Trichosanthes anti‐inflammatory activity. dioica also contain lectin, a carbohydrate The root extract of Trichosanthes (specifically galactose) binding protein cucumerina L. and the fruit juice tested which is homologous to Type-II ribosome cytotoxicity against human breast cancer inhibitory proteins (Type-II RIP)1. cell lines, lung cancer cell lines and one colon cancer cell line with positive effect. The root extract inhibited more strongly than It is a from the the fruit juice. Crude Ethanolic extract (EE) Cucurbitaceae family found particularly in of Trichosanthes cucumerina showed Henan, Shandong, , Shanxi, and significant blood glucose lowering activity . It is one of the 50 fundamental in alloxan diabetic albino rats. The acetone herbs used in traditional Chinese medicine, extract of leaves of Trichosanthes where it shares the name gualouwith the cucumerina showed moderate larvicidal related Trichosanthes rosthornii. The plant effects. Hot water extract (HWE) of aerial is a good source of the toxic anti-HIV type I parts of Trichosanthes cucumerinanoted to ribosome-inactivinglectin Trichosanthin improve glucose tolerance and tissue several multi-florane triterpenoid has been glycogen in non-insulin dependent diabetes isolated from the seed extract. The most mellitus induced rats. Recent studies have predominant ones include karounidiol and showed that the drug possess antidiabetic its 3-O-benzoate derivative. These activity with volume improvement in oral triterpenoid are expected to be potential anti- glucose tolerance and glucose uptake in tumor promoters1. peripheral tissues1. Trichosanthes tricuspidata Trichosanthes dioica It known as T. palmate Roxb, T. It is widely cultivated in the eastern bracteata Lamb, T. puberaBlume or part of the India from longtime. It is Modecccabracteatabelongs to the family of employs as an ingredient of soup, stew, Cucurbitaceae. The fruits consists curry, sweet, or eaten fried. It is a good cucurbitane, hexanorcucurbitane and source of carbohydrates, tannins, saponins, octanorcucurbitane glycosides. From the and C. It also contains trace fruits of T. tricuspidata, 14 cucurbitane elements (such as magnesium, potassium, glycosides were isolated namely copper, sulphur, and chlorine) which were cucurbitacins K, 2-O-β-glucopyranoside, a

Page 305

American Journal of Ethnomedicine ______ISSN: 2348-9502 hexanor cucurbitaneglucosidal and PHARMACOLOGICAL PROPERTIES octanorcucurbitane glucosidal were isolated along with two known cucurbitane Trichosanthen (TCS) is polypeptide glucosidal. An extract of the fruits of this composed of a single polypeptide chain with plant was found to be cytotoxic in KB cells, a molecular weight of 27 kDa. Its amino two new cucurbitacins were reported: acid sequence demonstrates homology to the tricuspid tin and 2-O-glucocucurbitacin. A chains of many type II RIPs, such as ricin The root of plant contains methyl A chain. It inhibits protein synthesis by palmitate, palmitic acid, suberic acid, α- cleavage of the N–C glycosidic bond of spinasterol, stigmast-7-en-3-beta-ol, α- adenine 4324, the 4324th base of 28S rRNA. spinasterol 3-o-beta-D-glucopyrano side, This action renders the ribosome incapable stigmast-7-en-3-beta-ol-3-O-beta-D- of binding elongation factor 2 and finally glucopyranoside, glyceryl 1-palmitate, terminates translation.TCS owns a wide glyceryl 1-stearate, bryonolic acid, spectrum of biological and pharmacological cucurbitacins B, isocucurbitacin B, 3-epi- activities. It can produce adverse effects on isocucurbitacin B, 23, 24-dihydro- reproduction in the mouse by causing follicular atresia and degeneration of cucurbitacin D, isocucurbitacin D and D- 2 glucose as well. And three new cycloartane ovulated oocytes . In fertilized animals, TCS glycosides have been isolated and named elicits death of syncytiotropho-blasts of cyclotricuspidosides A, B and C from the placental villi, and its results, the embryo and stem parts1. fails to develop. This action is related to its uptake by placental trophoblast cells. TCS Trichosanthis radix exhibits various activities such as This is a flowering plant in the immunomodulatory (immunosuppressive), family Cucurbitaceae. Trichosanthis radix anti-tumor, anti-viral, and anti-human extract has function to relieve pyreticosis, immunodeficiency virus (HIV) activities. Its polydipsia, swelling on the body surfaceand anti-HIV activity is attributed to inhibition ulcer as well.Extract can be used in food, of the replication of HIV and cytotoxicity to beverage, health supplement and medicine. HIV-infected cells mainly macrophages and Although Trichosanthes species have been lymphocytes. The fact that TCS was applied using from ancient times but the discovery in the treatment of choriocarcinoma is of significant activities of Trichosanthes consistent with its abortive activity, since species started a new era in drug this tumor also originates from fetal development mainly against the trophoblast cells. carcinogenic diseases. This biological component is easily available in nature, Effect of Trichosanthin (TCS) on HIV amenable to animals and hostile to wide Li et al., in the year 1991 range of diseases. demonstrated that TCS has anti-HIV The main aim of this review is to activity.TCS is a type I ribosome- investigate the past and current strategic inactivating protein (RIP) with potent developments in the use of Trichosanthen inhibitory activity against human species against wide range of diseases and immunodeficiency virus(HIV) type 1, and conditions. It also emphasizes on more has been clinically applied in acquired potential use of this plant species for immunodeficiency syndrome (AIDS) advanced drug developments. therapy. HIV is a lent virus (slowly replicating retrovirus) that causes the Acquired Immuno Deficiency Syndrome

Page 306

American Journal of Ethnomedicine ______ISSN: 2348-9502

(AIDS). HIV infects vital cells in the human without obvious ribosome inhibiting effects, immune system such as helper T cells whereas large amounts induce apoptosis in (specifically CD4+ Tcells) and macrophages. HIV-1 infected cells. TCS inhibits HIV-1 Since the beginning of the epidemic, almost integrase and cleaves supercoiled DNA 75 million people have been infected with invitro. It is also associated with and the HIV virus and about 36 million people stimulates the activation of chemokine have died of HIV recently. Globally, 35.3 receptors. TCS is a membrane-permeate million [32.2–38.8 million] people were peptide that is believed to act within the cell living with HIV at the end of 2012(retrieved and need cross the membrane barrier for its from W.H.O). action. TCS interacts with and inserts into In the late 1980s, the anti-viral artificial phospholipids membrane. It effects of TCS against HIV-1 were induces membrane fusion of liposome. It described Phase I and II clinical trials were was also reported that TCS hijacks the cell- conducted in the USA to evaluate the safety derived exosomes for intercellular transport. and potential efficacy of this drug. It was Li et alstudied the physical relationship shown that TCS elicits a moderate increase between TCS and HIV-1, showed that TCS in circulating CD4þ T cells and a significant penetrated into viral particles. The decrease of virus load in acquired penetration had no obvious effect on viral immunodeficiency syndrome (AIDS) by the integrity and also identified important sites time patients had failed treatment withazido for the penetration and revealed that this thymidine(i.e.TCS is more effective than penetration may be important for virus antiretroviral agents such as azidothymidine; elimination. Therefore Li et al concluded usedagainst AIDSvirus). In addition to TCS, that TCS having anti HIV activity results no many other RIPs including Momordica anti- side effects3. HIV protein, pokeweed anti-viral protein, and Gelonium anti-HIV protein (GAP31), Effect on various Cancer cell lines have been reported that these can inhibit Cancer known medically HIV-1 replication invitro successfully. It as malignant neoplasia, is a broad group of was initially thought that TCS inhibits HIV diseases involving unregulated cell growth. by halting protein translation through RIP In cancer, cells divide and grow activity but it inhibits the replication of uncontrollably, forming malignant tumors, HIV-1 invitro and decreases HIV markers, which may invade nearby parts of the body. good progress has been observed with the The cancer may also spread to more distant elucidation of the anti-tumour and anti- HIV parts of the body through the lymphatic mechanism of TCS, including the system or bloodstream. Cancer is a leading observation that N- terminal sequences of cause of death worldwide and accounted for TCS has anti-tumour activity and the anti- 7.6 million deaths (13% of all deaths) in HIV property of TCS is due to inhibition of 2008. Cancer is usually treated HIV-1 integrase. JAR cells (a human with chemotherapy, radiation therapy and choriocarcinomaline) are sensitive to TCS surgery in 2007, cancer caused about 13% and are useful model for cell biological of all human deaths worldwide study. Study the effects of TCS on JAR cells (7.9 million).The era of chemotherapy for going to help us to understand better the cancer began in the 1940s with the first use anti-tumour and anti-HIV mechanism of of nitrogen mustards and folic TCS. acid antagonist drugs. Namely carboplatin Li et al reported that even small (Paraplatin), cisplatin (Platinol, Platinol- amounts of TCS specifically inhibit HIV AQ), cyclophosphamide (Cytoxan, Neosar),

Page 307

American Journal of Ethnomedicine ______ISSN: 2348-9502 doxorubicin (Adriamycin), etoposide cells were found to be increased up to a (VePesid), fluorouracil (5-FU). Major side concentration of 4µg/ml of TDA, followed effects of cancer drug includes Numbness by a decrease i.e., on further increasing the or tingling in the fingers or toes, weakness , TDA concentration, the non-viable cells loss of reflexes, jaw pain, hair loss were found to be decreased there by (reversible), decrease in blood cell counts, demonstrating the maximum cytotoxic effect allergic reaction, nausea and vomiting, loss at the concentration of 4µg/ml. In case of of appetite, change in taste. MTT cell proliferation assay, the percent Trichosanthin (TCS) is a promising cytotoxicity increased up to a concentration agent for the treatment of cancer.Many of of 2µg/ml of TDA, followed by a decrease the reports showed that TCS inhibited i.e. further increase in TDA concentration cervical adenocarcinoma HeLa cell lead to gradual decrease in cytotoxicity there proliferation through the by demonstrating the maximum PKC/MAPK/CREB signal pathway. Antiproliferative effect at the concentration Furthermore, TCS down-regulated Bcl-2 of 2µg/ml. The hydro alcoholic extract of expression, which was abrogated by a cyclic T.dioica root has significant AMP-responsive element (CRE, Antiproliferative effect at lower TGACGTCA) decoy oligonucleotide concentrations against Ehrlich as cites (OGN), is blocking the CRE-binding protein carcinoma cells in vitro, thus suggesting the (CREB) binding site on Bcl-2 successfully. feasibility of its possible promise as natural These results suggest that CRE-mediated anticancer agent5. gene expression may play a pivotal role in Trichosanthin (TCS) has been HeLa cell proliferation. However, little is reported to be effective against a variety of known about the effect of TCS on cell cycle other tumors including hepatoma, colon arrest of HeLa cell, cervical squamous carcinoma, stomach cancer, lung cancer, carcinoma (Caski and C33a cell), and breast cancer, prostate cancer, and human pancreatic carcinoma (SW1990 cell), melanoma. Some early research reported especially, whether genes related to cell that TCS did not exert much toxicity to cycle are regulated by the CRE decoy OGN. hepatoma cell lines, including H35 and The effects of TCS on the proliferation of HepA-H. However, when epidermal growth cancer cells, cell cycle arrests in the progress factor (EGF) is conjugated to TCS, the of cell proliferation and the role of CRE in immunotoxin EGF-TCS is toxic to cell cycle regulation. hepatoma cells, for example BEL-7402, Bhattacharyaet alin the year 2011, MCF-7, and BGC-823. In addition, EGF- study evaluated Antiproliferative effect of Trichosanthin also has invivo anti-hepatoma hydroalcoholic extract from Trichosanthes effects when the hepatoma animal model is dioica root (TDA) on Ehrlich as cites constructed by injection of BEL-7402 cells. carcinoma (EAC) cells invitro. The Dexamethasone enhances the effects of cytotoxic activity of TDA against EAC cells Trichosanthin on apoptosis in HepG2 cells was assessed invitro by assays trypan blue by inhibiting the NF-JB Signaling pathway, cell viability assay and MTT cell which highlights the possibility of combined proliferation assay. Results of drug application of Trichosanthin and Bhattacharyaet alstudy revealed that TDA at dexamethasone in the clinical treatment of all test concentrations exhibited significant hepatoma6. increment in non-viable cells in trypan blue Studies also disclose that cell viability assay as compared to vehicle Trichosanthin exhibits an anti-colon control but the percentage of non-viable carcinoma effect in both invitro and invivo

Page 308

American Journal of Ethnomedicine ______ISSN: 2348-9502 experiments. When Trichosanthin gene is apoptosis in K562 cells13. Under similar cloned and expressed in colorectal conditions, TCS is more toxic to HUT78, carcinoma Lo Vo cells and it evokes MOLT-4, Jurkat, and CEM cells originating apoptosis in these cells. Not only colon from T lymphocytes and macrophages than carcinoma cell line CT-26, but also in vivo Raji and Daudi cells from B lymphoma14. colon carcinoma produced by Sw-1116 Trichosanthin inhibits the tumor cell cells, noticed that it is sensitive to proliferation by various mechanisms i.e. Trichosanthin toxicity7. TCS suppresses adenyl cyclase activity and Trichosanthin plays a distinct role by thus reduces cyclic AMP (cAMP) levels in producing toxic effects on MCG803 cells of HeLa cells. It was noticed that decrease in the stomach adenocarcinoma, another cancer protein kinase C (PKC) level rather than of the digestive system8. An animal model protein kinase A (PKA) level in these cells. of lung cancer was created by administration This is different from the conventionally of A549 cells to nude mice. In Li et al., accepted mechanism. In another research they observed that Trichosanthin experiment,Wang et alin the year, 2010 has the ability of either prevent or inhibit the reported that TCS inhibits cell proliferation process of lung tumor genesis9. In another in different tumor cells through different Invivo experiment, Trichosanthin elicits an pathways and mechanisms, which merit anti-tumor immune response in a murine further in-depth cell death pathway in HeLa Lewis lung cancer model by boosting the cells16. And also stated PKA and PKC interaction between tumor suppressor in activities were significantly inhibited in lung cancer 1(TSLC1) and class-I MHC- TCS-treated HeLa cells and although a restricted T cell-associated molecule specific PKA inhibitor failed to affect the (CRTAM). TCS inhibits the proliferation of effects of TCS, and PKC activator/inhibitor MDA-MB-231 and MCF-7 cells and the significantly attenuated/enhanced the growth of transplanted breast cancer in nude inhibitory effect of Trichosanthin on cell mice. For prostatic cancer, Trichosanthin proliferation. The inhibition of PKC was can induce apoptosis in RM-1 cells, and an found to be involved in the apoptotic induction of apoptosis is a very important pathway induced by TCS in K562 cells. mechanism of TCS to inhibit this type of The transcriptional factor cAMP response cancer. TCS can also markedly inhibit element binding (CREB) protein, a melanoma cells by the suppression of DNA downstream molecule in cAMP/PKA synthesis in S phase and cell mitosis as well pathway was found to participate in the as induction of cell apoptosis. TCS-induced cell death pathway in HeLa In the year 2007, Zhanget al., cellsactively. CREB phosphorylation was demonstrated that TCS has activity against significantly decreased through cAMP leukemia10. In 1990s, TCS was found to be inhibitor and but not by a PKA inhibitor. toxic to leukemia/lymphoma cells invitro11,12 These mechanisms infer that HeLa cell experiments.A decade later, TCS was proliferation was inhibited by TCS via reported to exert an antitumor action on suppression of the PKC/MAPK signaling chronic myelogenous leukemia K562 cells pathway. and acute T cell leukemia Jurkat cells. TCS Trichosanthin induces a rapid decline caused a down-regulation of p210Bcr-abl in nuclear factor kappa B (NF-kB) and and its downstream signals, results in cyclooxygenase-2 (COX-2) expression tyrosine kinase inhibition in K562 cells10. leading to apoptosis in hepatoma HepG2 Both PKC inhibition and caspase 3 cells. The suppression of NF-kB and COX-2 activation are involved in TCS-induced protein has been suggested to be the most

Page 309

American Journal of Ethnomedicine ______ISSN: 2348-9502 important factorfor the antiproliferative and place via attacking TSLCl and p16 genes. In proapoptotic effects on cancer cells. COX-2 the year 2009, Zhang Yet al. established an may lie downstream of NF-kB. Since the animal model of cervical cancer by repeated inhibition of NF-kB can ensue in down- injections of mouse U14 cell line into regulation of COX-2. TCS also down- Kunming mice. TCS potentiated the regulated p210 (Bcr-Abl), protein tyrosine humoral immunity in mice by a minor kinase (PTK), and heat shock protein 90 dosage levels18. (Hsp90) in chronic myelogenous leukemia Nget al., in the year 1991 reported K562 cells. All these genes and proteins are that Trichosanthin exert deleterious effects associated with proliferation of cancer cells, on reproduction and is a clinical medicine and their inhibitors have been studied to for abortion and they carried out their treat a variety of cancers in clinics. All these experiment on a mouse. In fertilized data suggested that HeLa cell proliferation animals, TCS causes necrosis of the was inhibited by TCS via suppression of the syncytiotrophoblasts of placental villi, and PKC/MAPK signaling pathway. results, the embryo fails to develop19. The Trichosanthin effects cervical cancer anti-tumor effects of TCS were first tested by its unique activity. Cervical cancer is the on the cells of choriocarcinoma and one of the majorly affecting caner in human malignant trophoblastic cancer. About two population. It was observed that when TCS decades ago, Dai and colleagues conjugated was added to cultured tumor cells, it brought colloidal gold to TCS molecules and found about a reduction in the uptake of that TCS specifically entered cultured radioactive precursors for protein synthesis. trophoblast and choriocarcinoma JAR cells This suggested that TCS killed cells by via receptor-mediated endocytosis. The LDL virtue of its RIP activity. Many Scientists receptor-related protein-1 (LRP1) has been first tested the toxic effects of TCS on HeLa suggested as a major receptor for cervical cancer cells and it has manifested phagocytosis of TCS in cultured JAR and inhibitory effectssignificantly. It heightened BeWo cells, which might be the molecular cytosolic calcium and suppressed basis of the abortifacient and anti- intracellular cAMP/protein kinase C (PKC) choriocarcinoma activities of TCS19,20. levels via PKC inhibition. Different from Influx of calcium and production of reactive usual RIP activities, TCS brings about oxygen species (ROS) were also observed as apoptotic cell death in HeLa cells, and well in TCS-treated JAR cells, and ROS activation of caspase 8, 9 and 3 has been production might be a consequence of observed15. The up regulation of ER calcium ion signaling21. chaperone immunoglobulin heavy chain- In the year 2010, Wang et al binding protein (BiP) and C/EBP investigated that Trichosanthin induces homologous protein (CHOP) and activation Apoptosis by its activity15. Apoptosis is a of caspase 4 suggest the participation of the form of cellular suicide that ensures that endoplasmic reticulum stresses pathway in super fluous or harmful cells are eliminated TCS-induced HeLa cell apoptosis17. Recent from multi-cellular organisms. Apoptosis is studies have also demonstrated the toxicity distinguished from necrosis through of TCS on cervical cancer Caski cells and it characteristic morphological and plays a role in demethylation by inhibiting biochemical changes, including compaction DNA (cytosine-5)-methyltransferase 1 and fragmentation of the chromatin, plasma (DNMT1) enzyme activity, DNM1 mRNA membrane blebbing and cell shrinkage. and protein expression in CaSki cells. The Apoptosis is mechanism in which activation demethylation of TCS in HeLa cells takes of certain types of proteases, nucleases, and

Page 310

American Journal of Ethnomedicine ______ISSN: 2348-9502 cytoskeleton breakdown. Apoptosis begins All these results O2-, H2O2 and OH- with the condensation of nuclear chromatin indicate that are involved in TCS-induced at the nuclear periphery, followed by ROS formation in JAR cells. In addition, blebbing of the nuclear and cytoplasmic TCS-induced activation of caspase 3 was membranes, culminates in the fragmentation initiated within 2 h; however, TCS-induced of residual nuclear structures into discrete production of ROS was initiated within membrane-bounded apoptotic bodies in 5min. These findings suggest that the sequential manner. Apoptosis occurs in production of ROS precedes the activation many different cell types and in response to of caspase 3.Thus the ROS is involved in the diverse stimuli. Apoptosis is now considered TCS-induced apoptosis of JAR cells may to be an essential cellular response to agents provide new insight into the anti-tumor and used for anti-tumor chemotherapy and anti-HIV mechanism of TCS. radiotherapy. TCS administration induced up Trichosanthinstimulates the regulation of the protein chaperone BiP, production of ROS in JAR cells and that transcription factor CHOP and also activated ROS are involved in the TCS-induced caspase 4 in HeLa-60 cells, which for the apoptosis of JAR cells. TCS treatment first time strongly supported the induced a transient elevation of intracellular involvement of ER stress pathway in TCS- calcium and a slow rise of ROS in human induced apoptosis17. On the other hand, chronic myeloid leukemia cell line K56217 inducible nitric oxide synthase (iNOS) was noticed. It was observed that calcium mRNA expression and protein levels were chelators and antioxidants did not have a elevated in cells treated with TCS and nitric conspicuous effect on TCS induced oxide (NO) production by cells was apoptosis, suggesting that calcium changes augmented in the presence of TCS. When L- and ROS may not be implicated in TCS- NIL, the specific inhibitor of iNOS was mediated apoptosis in K562 cells. In added to suppress NO production induced contrast, TCS elicited an increase in by TCS, OVA-specific cell death was cytosolic calcium and induced apoptosis in significantly inhibited; meanwhile, cellular HeLacell. In the year 2009, Wang et al., thymidine incorporation was restored to confirmed that this apoptotic cell death can normal levels. These observations suggest be reduced by a specific calcium chelators that TCS could suppress antigen-specific T and ethylene glycol bis (2-aminoethyl) tetra cell activation via an NO-mediated (acetoxymethyl Ester) (EGTA-AM). apoptosis pathway. TCS can induce specific Therefore mentioned discrepancies may be changes of cytoskeleton configuration ascribed to the different types of cells associated with the attenuated expression studied22. TCS may induce apoptosis via level of actin and tubulin genes in apoptotic distinctly different mechanisms in different HeLa cells23 successfully. cells. In other cell line JAR, TCS stimulated In the year 2012, Fanget alreported the production of ROS, which can be that TCS can induce apoptosis especially in inhibited by the superoxide radical anion breast tumor cells. Breast cancer ranks as a (O2--) scavenger superoxide dismutase, the common and severe neoplasia in women H2O2 scavenger catalyses, and the hydroxyl with increasing incidence as well as high radical (OH-) scavenger mannitol. The risk of metastasis and relapse.TCS antioxidant Trolox and an inhibitor of metal- manifested anti-proliferative and apoptosis- facilitated OH- formation, diethylene- inducing activities in both estrogen- triaminepenta acetic acid, also markedly dependent human MCF-7 cells and inhibited TCS induced cell death. estrogen-independent MDA-MB-231 cells.

Page 311

American Journal of Ethnomedicine ______ISSN: 2348-9502

As the accumulation of cells in sub-G1 ranking of potency: MDA-MB-231>MCF- phase is indicative of cell death. TCS 7>BT-474 cells. It was revealed that TCS treatment slowly increased the number of exhibited both cytostatic and cell-death apoptotic cells in MCF-7 cells. Similarly in inducing activities which in turn contributed MDA-MB-231 cells, the number increased to the inhibition of cell viability in both in TCS-treated groups compare to non- types of breast cancer cells. This cytostatic treated group. Furthermore, TUNEL assay activity was at least partially contributed by was applied to detect DNA fragmentation cell cycle arrest. It seems that TCS can and the data showed that more cells were induce G1 phase arrest in breast cancer cells undergoing DNA fragmentation after TCS as it did in human lung cancer A549 cells. treatment in both MCF-7 cells and MDA- Fanget al, in the year 2012 carried MB-231 cells.TCS-treated cells nuclear out investigation on the effect of TCS on morphological changes visualized by some G1 cell cycle-regulating proteins, such staining the cells with Hoechst 33342 dye. as cyclin D1 and phosphor-Rb are In MCF-7 cells, exposure to TCS caused warranted27. Furthermore, flow cytometric typical morphological changes of apoptosis, analysis using Annexing V/PI showed that such as karyorrhexis, significant nuclear TCS could dose-dependently induce in early condensation and fragmentation compared apoptosis and late apoptosis in both MDA- with the non-treated group. This type of MB-231 and MCF-7 cells. In accordance phenomenon was also observed in TCS- with this, stereotypical apoptotic features treated MDA-MB-231 cells24. were noticed; these include karyorrhexis, Fang et al in the year 2012 reported chromatin condensation and inter that Trichosanthinactivate caspase-mediated nucleosomal DNA fragmentation. The apoptosis in breast cancer cells28. Apoptosis results were reminiscent of the action of always executed in caspase-8-regulated other natural chemotherapeutic components plasma membrane extrinsic pathway and/or toward breast cancer cells. For instance, the caspase-9-regulated cell damage intrinsic ribonuclease from Momordica charantia pathway25. Immuno-blotting analysis seeds (RNase MC-2) manifested the same indicated that TCS treatment resulted in a effects on MCF-7 cells. Caspases are the dose-dependent activation of the initiator principal effectors of apoptosis involved in caspases 8, 9 and the executor caspase pathways such as caspase-8-regulated 3.And those were followed by proteolytic extrinsic and caspase-9-regulated intrinsic cleavage of PARPs shown in the right panel pathways. The caspase-9 pathway links of normalized expression levels of mitochondrial damage to caspase activation remaining caspases 8, 9 and 3 were and serves as an index of damage in decreased compared with control in assay. mitochondrial membrane function. Accordingly, there were increased levels of The antitumor efficacy of TCS both activated caspase-8 and caspase-9 in in invivo systems were substantiated by TCS-treated group compared with control. results from MDA-MB-231 bearing nude Three breast cancer cell lines, mice. Every other day, Trichosanthinwas including two estrogen-dependent breast administered intra peritoneal at a dose of 5.0 cancer cell lines are MCF-7 cells, highly mg/kg body weight regularly. Compared metastatic BT-474 cells and estrogen- with control, Trichosanthintreatment abated independent MDA-MB-231 cells were both tumor volume as well as tumor weight employed in Fang et al., study. from the 6th day of treatment constantly. Trichosanthin inhibited cell viability in all This antitumor effect correlated with three tested cell lines in the following increased levels of apoptosis in the tumors

Page 312

American Journal of Ethnomedicine ______ISSN: 2348-9502 of TCS-treated group, as supported by the MCF-7 cells and estrogen-independent increase of activated caspase-3, cleaved MDA-MB-231 cells in invitro and/ or in PARP, and DNA fragmentation (TUNEL- vivo experiments. Proteolytic processing of positive cells). Interestingly, necrosis was initiator caspases as well as executor caspase also detected in TCS-treated group and subsequent spawned apoptosis compared to the control group. This infers contributed to TCS-induced apoptosis. that reduction of tumor proliferation by Besides the function as an abortifacient, induction of apoptosis is a mechanism of application in the treatment of hydatidiform the invivo antitumor activity of TCS toward moles and invasive moles, Trichosanthin MDA-MB-231 xenograft. Protein may provide a plethora of treatments or even engineering studies on TCS, such as for the development of a novel therapy PEGylation and the construction of combined with other chemotherapeutic immuno-toxin, might help to increase its measures for both estrogen-dependent and drug specificity as well as reduce its side independent breast cancers. The most effects28. important thing that has been noticed in Lee-Huanget al, in the year 2000 clinical studies on the application of TCS reported that MAP30 inhibited cell against other human diseases showed that it proliferation and the expression of HER2 in was effective, the effective dose level was MDA-MB-231 cells29. More importantly, safe, relatively well tolerated, through with treatment of MDA-MB-231 bearing SCID some acceptable mild side effects31,32. mice with TCS in dose EOD for a total of Thus TCS was found to be active ten injections, resulted are effective and against a variety of tumors including impressive i.e pronounced prolongation of cervical cancer, choriocarcinoma, survival and nearly one quarter of the mice leukemia/lymphoma, stomach cancer, colon remained tumor-free for 96 days. The above cancer, hepatoma, breast cancer, and mentioned MCL was also active invivo in a prostate cancer. The toxic mechanisms of CNE-2 xenograft tumor model. It inhibited Trichosanthin tumor cells include inhibition tumor growth by inducing apoptosis of of the proliferation and induction of tumor cells. TCS manifested cytotoxicity in apoptosis of tumor cells, and the detailed both MDA-MB-231 cells and MCF-7 cells. mechanism varies in different tumor cells. In Fang et al(2012) study TCS was administered intraperitoneal at a dose of 5.0 Cardio protective Activity mg/kg body weight regularly. The dose Shah et al., in the year 2012 reported applied was acceptable since the mice did that methanol extract of fruit of not lose weight during the course of Trichosanthes cucumerina effective in treatment. Recently, a large clinical study doxorubicin-induced cardio toxicity in rats. has indicated that TCS was effective against Cardiovascular disease is caused by ectopic pregnancy in 140 women at the disorders of the heart and blood vessels, and dosage of 1.8 mg for each person using includes coronary heart disease (heart intramuscular injection. There no significant attacks), cerebrovascular disease (stroke), side effects were observed for most of the raised blood pressure (hypertension), patients and it seems there was no side peripheral artery disease, rheumatic heart effects o on their subsequent pregnancy as disease, congenital heart disease and heart well as giving birth to a healthy baby30. failure. The major reasons of cardiovascular Final conclusion of the Fanget al. disease are tobacco use, physical inactivity, (2012) report TCS manifested the ability to an unhealthy diet and harmful use of alcohol induce apoptosis in both estrogen-dependent Doxorubicin (DOXis toxic agent for all

Page 313

American Journal of Ethnomedicine ______ISSN: 2348-9502 cellular components; Adriamycin) which is Antibacterial Activity used as antitumor drug for treating several At Arawwawalaet al., (2011) study types of solid cancer, leukemia and reveals that Trichosanthes cucumerina has lymphomas. T. cucumerina contains many components that can exert significant different antioxidant components that antibacterial activity against S. aureus, S. provide protection against harmful free pyogenes, E. coli and P. aeruginosa that are radicals that are strongly associated with known well as wound pathogens. The CEE reduced risk of cardiovascular diseases33. (Cold Ethanol Extract) can exert consistently better antibacterial activity than Antiulcer Activity the HWE. This difference in activity of the Kannanet al., (2011) investigated the HWE and CEE may be related to the gastro protective effect of Trichosanthes polarity of antibacterial compounds tricuspidaagainst ethanol induced gastric presents. Both E. coli and P. aeroginosa ulceration on albino rats and it was observed were found to be more susceptible than S. that reduction in ulcer, index shows the aureus and S. pyogenes to the action of the ability of the extract either to protect the T. cucumerina extracts. This is possibly due gastric mucosal (cytoprotective) against to the differences in chemical composition ulceration or may be suppression of already and structure of cell wall of the established ulcers. Hexane extract and microorganisms. In result, Trichosanthes chloroform extract have more gastro cucumerina extracts exhibited antibacterial protective activity as compare toaqueous activity against both gram (+) ve bacterial and ethanol extract. It concludes that the strains such as S. aureus, S. pyogenes and active constituent responsible for gastro gram (-) ve bacterial strains such as E. coli protective activity is Polar in nature and also and P. aeroginosa mediating the presence of investigated the antioxidant properties34. a broad spectrum of antibacterial compounds in the plant36. Antidiabetic activity In the year 2009, Arawwawala et Hepatoprotective al.,investigation demonstrate that the HWE Aiyalu Rajasekaranand Muthusamy (Hot Water Extract) of Trichosanthes Periyasamy (2012) reported the cucumerina aerial parts can significantly Hepatoprotective effect of Ethanolic Extract reduce the blood glucose levels and improve of Trichosanthes lobata (EETL). the glucose tolerance of norm glycemic and Hepatotoxicity is a common cause of severe STZ–induced diabetic rats. The increased metabolic disorders and even death. The levels of serum glucose in STZ–induced EETL exhibits protective activities against diabetic rats were lowered constantly by T. paracetamol-induced Hepatotoxicity. cucumerina extract administration. It also Flavonoids exhibit vasoprotective, anti- suggests that HWE may act as an insulin inflammatory, anti-allergic, antimicrobial, secretagoue and/or sensitize insulin antioxidant, Hepatoprotective, anti- receptors, as proposed for some plant osteoporotic, and anti-neoplastic properties. extracts and some sulphonylurea.Results On administration of EETL and paractamol obtained in the Arawwawala et al., study silymarin group, the serum markers were provide supportive evidence for the view restored to the normal levels. that T. cucumerina exerts its hypoglycemic Histopathological studies of rats action by mechanisms similar to those of administered paracetamol showed severe sulphonylureas35. necrosis and disappearance of nuclei. This could be due to the formation of highly

Page 314

American Journal of Ethnomedicine ______ISSN: 2348-9502 reactive metabolites (e.g. NAPQI), because Anti-inflammatory activity of excessive administration of paracetamol. Fulzuleet al(2001) studied anti- All these histopathological changes were inflammatory activity of Trichosanthes significantly reduced in rats treated with cucumerinaand it was evaluated by use of EETL. The study of serum markers such as the carrageen an-induced paw edema model AST, ALT, ALP, and bilirubin, and total in Wistar rats. In addition, the mechanism protein were found to be of great value of by which T. cucumerina mediated the anti- assess to clinical and experimental liver inflammatory activity was assessed by damage. Pretreatment with T. lobata, determining its effects on membrane significantly attenuated elevated levels of stabilizing activity and nitric oxide serum markers.Thus Ethanolic Extract ofT. inhibitory activity. Inhibition of nitric oxide Lobata conditions the hepatocytes so as to (NO) production and membrane stabilization protect the integrity of the membrane from activities are probable mechanisms by paracetamol-induced leakage of serum which T. cucumerina mediates its anti- markers into circulation. Plants most inflammatory actions. These findings commonly used to treat liver disorders are rationalize the traditional usage of this plant Curcuma longa (turmeric), Glycyrrhizin as an anti-inflammatory agent and glabra (licorice) and Camellia sinensis membrane stabilizing properties and no (green tea), and they are all reported to be inhibitory activity are possible mechanisms Hepatoprotective37. through which Trichosanthes cucumerina mediates its anti-inflammatory Larvicidal activity action39. Sonwalkaret al., (2013) investigated and revealed that the fruit of Trichosanthes Antioxidant activity tricuspidata has new mosquitocidal In MukeshTanwaret al.,(2011) compound against the mosquito reported that Trichosanthes dioica Roxb CulexquinquefasciatusSay.Culexis a genus contains possess antioxidant activityi.e. due of mosquito, and is important in that several to its free radical scavenging activity and its species serve as vectors of important ability to reduce elevated levels of serum diseases, such as West Nile virus, filariasis, marker enzymes which may be due to Japanese encephalitis, St. Louis encephalitis presence of Antioxidants(such as vitamin C, and avian malaria. T. tricuspidata was used Beta carotene, carotene, saponins and to study the mortality of the mosquito C. tannins).Antioxidants plays an important quinquefasciatus. Larvicidal Bioassay role to protect the human body against method was used, these extract was divided damage by reactive oxygen species. into two parts i.e. Methanol Fruit Extract Ascorbic acid may have counteracted the (MFE) & Petroleum Ether Fruit Extract free radicals through effective scavenging (PEFE) was prepared. Both showed good and blocking the conjugation of reactive mortality but highest larval mortality was metabolite to GSH. The levels of vitamin C found in MFE. The MFE of T. and E were significantly depleted in tricuspidatamay have potential to develop as paracetamol intoxication which may be due natural larvicidal agent38. This plant can be to excessive utilization of quenching the used as natural mosquito repellent, which enormous free radicals produced during may be useful in the household to kill paracetamol intoxication40. mosquitoes, mice, etc. The antioxidant potential of Trichosanthes dioica was assessed by DPPH assay and H2O2 method. The DPPH assay is

Page 315

American Journal of Ethnomedicine ______ISSN: 2348-9502 based on the measurement of scavenging with high dose of EETC. Ethanol Extract of ability of antioxidants towards the stable whole plant of Trichosanthes cucumerina L. radical DPPH. Antioxidants reduce the var.cucumerina reduced the serum levels of radicals to the corresponding hydrazine gonado-tropins, might have affected when it reacts with the hydrogen donor in folliculogenesis and steroidogenesis in the antioxidant principles. DPPH radicals ovary44. react with suitable reducing agent, the electrons become paired off and the solution Anti-herpetic activity losses colourstoichiometrically depending Zheng et al, in the year 2001 noticed on the number of electrons taken up. that the Anti-herpetic activity of Hydrogen peroxide concentration is Trichosanthin can be enhanced by acyclovir decreased by scavenger compounds and and interferon. It was clearly demonstrated therefore absorbance value also decreases. that TCS is active against herpes simplex Antioxidant shows good scavenging activity virus (HSV) and its efficiency is similar to against H2O2 and DPPH free radicals. acyclovir (ACV) on a molar basis. Toxicity Trichosanthes dioica extracts show of TCS varies between cell types, for reduction in absorbance value in DPPH example, choriocarcinoma is much more assay and H2O2 method, which might be due sensitive to TCS than hepatoma. In Zheng et to radical scavenging activity of vitamin C al study they used Vero cells as hosts and and carotene. the synergistic effect of TCS with two other anti-viral agents namely ACV and INFs Antifertility Activity were investigated. ACVis commonly used In the year 2009, Kage et al., for treatment of HSV infection which targets investigated the antifertility activity in albin viral DNA polymerase after being rats with treatment of the Ethanol Extract of phosphorylated by HSV-specific thymidine Trichosanthes cucumerina L. var. kinase and at the only presence of infected cucumerina(EETC)showed a significant cells it was being activated. The other anti- increase in the duration of estrous cycle with viral agent is interferons (INFs). Its action prolonged estrus and metestrus phases and depends on the kind of INF and the type of decrease in diestrus and proestrus phases. cells. The difference in the duration of estrous It had known that treatment of HSV- cyclicity between the control and the infected cells resulted in a decrease of treatment groups is attributed to the vaginal ribonucleotide reductase leading to a fall in cornification, influenced by the more the size of deoxyribonucleotide pools. estrogen production by the extract which is Outcomes clearly demonstrated that ACV estrogenic in nature. Investigation suggested or INF enhanced the anti-viral action of that the level of cholesterol significantly TCS. In the presence of a fixed low dosage increased in the ovaries which are treated of either ACV or INF that has no significant with EETCare clearly defines the role of anti-viral effect, the potency of TCS was gonadotropins in consuming cholesterol for enhanced by over 100-fold. It wasalso steroid hormone biosynthesis within the noticed that all RIPs are not capable of anti- ovary. And also the alternative effect of this viral activity. The anti-viral action of protein drug upon cholesterol utilization enzymes is due to selective inhibition of DNA like 3b HSD and 17b HSD to synthesize synthesis. But it can be speculated that the steroid hormones cannot be ignored. This antiviral mechanism of TCS should not be effect is reflected in drastic decrease in the the same as that of ACV or INF enzyme activities of ovaries after treatment mechanisms. Alternatively, if the

Page 316

American Journal of Ethnomedicine ______ISSN: 2348-9502 mechanisms were the same, the synergistic alexiteric, astringent, diuretic and emetic. effect would have been summative rather Wound healing is the process of repair that than 100-fold potentiated as found in Zheng follows injury to the skin and other soft et alstudy.TCS is active against HSV and tissues. Following injury an inflammatory this action can be potentiated by ACV or response occurs and the cells below the INF45. dermis begins to increase collagen production. Later the epithelial tissue is OTHER ACTIVITIES regenerated. Wound healing management is a complicate and expensive one. CHOLESTEROL-LOWERING ACTIVITY Trichosanthes cucumerinacontains Sharmila et al (2007) observed Flavonoids fraction using ex-vivo porcine cholesterol lowering activity of the aqueous skin wound healing model (PSWHM)43. fruit extract of Trichosanthes dioica Roxb. Plant phenolics act as primary anti-oxidants In normal and streptozotocin diabetic rats. or free radical scavangers and its derivatives The influence of alcoholic extract of whole were reported to be effective against viruses, fruit of T. dioica on blood sugar, serum bacteria and fungi, and many diseases lipids, lipoproteins and faecal sterols in including wound healing effectively. Lipid normal albino rabbits. Effect of oral peroxidation is an important process in administration of alcoholic extract of whole burns, wounds and skin ulcers. Collagen fruit of Trichosanthes dioica Roxb with fibrils viability increases by inhibiting lipid basal diet for four weeks was studied in the peroxidation which cause increases the normal albino rabbits. It was observed that strength of collagen fibers. Finally it this extract lowered the blood sugar, total prevents cell damage and promotes DNA cholesterol, low density lipoprotein synthesis. Therapeutically potential phenolic cholesterol and triglyceride levels, and compounds possesses anti-infective, anti- increased the high density lipoprotein inflammatory, decreasing level of lipid cholesterol, phospholipids and faecal sterol 41 peroxidation which improve vascularity, levels . increase collagen synthesis and promotes cross linking of collagen. The present IN SKIN DISORDER findingprovides scientific evidence to ethno In the year 1999, Bhujbal showed medical properties of Trichosanthes that polyhebral formulation including T. cucumerina leaves in wound healing dioica is useful in skin disorder. Bhujbal property43. investigated about fifty cases of various skin diseases were treated with decoction of a CONCLUSION mixture of Trichosanthes& other herbal crude drugs in a dose of 20ml to 40ml empty Trichosanthesspecies contains stomach with hot water & honey for 4 to 6 significant protein known as ribosome weeks. It was observed that the drug was inactivating protein (RIP). RIP play a found to be useful and no side effect was significant role in developing formulations observed42. for geriatric care as it is having almost all the properties of pharmaceutical care. As a WOUND HEALING ACTIVITY result it is effectively used for the cure of In Periyanayagam et al (2014) minor skin diseases to life threatening demonstrated that Trichosanthes cancers and HIV. RIP protein helps in cucumerina has the ability to repair the formulation of anticancer agents. Effect of wound and leaves of this plant used as RIP on various cancer lines includes

Page 317

American Journal of Ethnomedicine ______ISSN: 2348-9502

Carcinoma, leukemia/lymphoma, tumor cell, apoptosis of tumor cells. Anat Rec 293:986– cervical, choriocarcinoma, breast tumor 992. cells. RIP is active against these cell lines 7. Huang YL, Huang LM (2010) Recent either by inhibition or by Apoptosis.It can be advance on the structure - function also used against free radicals, heart relationship of Trichosanthin and its cell entry. Lishizhen Med Mat Med Res 21:268– diseases, liver disorders, ulcers, diabetes, 269. cholesterol and skin disorders. 8. Xu J, Gao DF, Yan GL, Fan JM (2009) Trichosanthesspecies are also good potential Induced apoptotic action of recombinant sources of antioxidants and minerals. Trichosanthin in human stomach adenocarcinoma MCG803 cells. MolBiol ACKNOWLEDGEMENT Rep 36:1559–1564. 9. Li CT, Lin CH, Kao TY, Wu MF, Yeh CS et We are thankful to R.V.R & J.C al (2010) The mechanisms of action of College of engineering and other faculty TianhuaTM on antitumor activity in lung members in the Department of cancer cells. Pharm Biol 48:1302–1309. Biotechnology for their kind co-operation 10. Zhang K, Xu J, Huang X, Wu L, Wen C et and facilitation for successfully completion al (2007) Trichosanthindown-regulated of this review work. p210Bcr-Abl and enhanced imagined induced growth arrest in chronic myelogenous leukemia cell line K562. Can REFERENCES Chemother Pharmacol 60:581–587. 1. Saboo Shweta S, Thorat Priyanka, Tapadiya 11. Takemoto DJ (1998) EffectofTrichosanthin Ganesh G, Khadabadi S (2012),Distribution an anti-leukemia protein on normal mouse and ancient-recent medical uses of spleen cells. Anticancer Res 18:357–361. Trichosanthes Species. International. 12. Zheng YT, Zhang WF, Ben KL, Wang JH Journal of Phytopharmacy Vol. 2 (4), pp. (1995) Invitroimmunotoxicity and 91-97. cytotoxicity of Trichosanthin against human 2. Ng TB, Chan WY, Sze LY, Yeung HW normal immunocytes and leukemia- (1991) Trichosanthin induces atresia of lymphoma cells. Immunopharmacol ovarian follicles and inhibits steroidogenesis Immunotoxicol 17:69–79. in gonadotropin-primed immature mice. Gen 13. Li J, Xia X, Nie H, Smith MA, Zhu X Pharmacol 22:847–849. (2007) PKC inhibition is involved in 3. Ming-Xiang Li, H.-W.Yeung, Lian-Ping Pan Trichosanthin-induced apoptosis in human and Sunney Chan. Trichosanthin, a potent chronic myeloid leukemia cell line K562. HIV-1 inhibitor, can cleave supercoiled Biochim Biophys Acta1770:63–70 DNA in vitro Nucleic Acids Research, Vol. 14. Wang Y, Huang L (2007) Study on the 19, No. 22 6309-6312 relevancy of TSLCl gene methylation and 4. OuSha , JunfeiNiu , Tzi-Bun Ng, Eric Yu- HeLa cell apoptosis. China J Mod Med Pang Cho , Xiaoyuan Fu, Wenqi Jiang 17:2575–2578 (2013) Anti-tumor action of Trichosanthin, a 15. He JF, Li JC (2006) The growth inhibition type 1 ribosome-inactivating protein. and apoptosis of HeLa cells induced with Cancer ChemotherPharmacol 71:1387– TCS. ActaAnat Sin 37:309–314 1393. 16. Wang P, Xu J, Zhang C (2010) CREB, a 5. Sanjib Bhattacharya, AngelenePrasannaand possible upstream regulator of Bcl-2 in Pallab K. Haldar (2011) Evaluation of Trichosanthin-induced HeLa cell apoptosis. Antiproliferative Activity of Trichosanthes MolBiol Rep 37:1891–1896 dioica against Carcinoma Cells. Academic J 17. Li J, Xia X, Ke Y, Nie H, Smith M (2007) Cancer Res 4 (2): 38-42. Trichosanthininduced apoptosis in HL-60 6. Li M, Li X, Li JC (2010) possible cells via mitochondrial and endoplasmic mechanisms of Trichosanthininduced

Page 318

American Journal of Ethnomedicine ______ISSN: 2348-9502

reticulum stress signaling pathways. WenLiang Pan, Xiu Li Dan, Cui Ming Yin, Biochim Biophys Acta 1770:1169–1180 Chi Hin Cho, Tzi Bun Ng Trichosanthin 18. Zhang Y, Huang L, Wu J (2009) Inhibits Breast Cancer Cell Proliferation in Experimental Study on the Inhibitory Effect Both Cell Lines and Nude Mice by of Trichosanthinon Tumor in U14 M ice. Promotion of Apoptosis. PLOSone Shizhen Med Mat Med Res 20:2389–2390 September 2012, Volume 7, Issue 9, 19. Xia XF, Wang F, Sui SF (2001) Effect of e41592ONE phospholipid on trichosanthin adsorption at 29. Lee-Huang S, Huang PL, Sun Y, Chen HC, the air-water interface. Biochim BiophysActa Kung HF, et al. (2000) Inhibition of MDA- 1515:1–11 MB-231 human breast tumor xenografts and 20. Jiao Y, Liu W (2010) Low-density HER2 expression by antitumor agents lipoprotein receptor-related protein 1 is an GAP31 and MAP30. Anticancer Res 20: essential receptor for Trichosanthin in 2 653–659. choriocarcinoma cell lines. BiochemBiophys 30. Xiang DJ, Chen LM, Gu JS, Stone P, Chen Res Commun 391: 1579–1584. Q (In press) Trichosanthin, a Chinese 21. Xia X, Hou F, Li J, Ke Y, Nie H (2006) Medicine for the Medical Treatment of Two novel proteins bind specifically to Ectopic Pregnancy with High Levels of b- Trichosanthin on choriocarcinoma cell hCG.Reprod Sci. membrane.JBiochem 139:725–731. 31. Fang EF, Ng TB, Shaw PC, Wong RNS 22. Wang P, Chen LL, Yan H, Li JC (2009) (2011) Recent Progress in Medicinal Trichosanthin suppresses HeLa cell Investigations on Trichosanthin and other proliferation through inhibition of the Ribosome Inactivating Proteins fromthe PKC/MAPK signaling pathway. Cell Plant Genus Trichosanthes. Curr Med Chem BiolToxicol 25:479–488 18: 4410–4417. 23. Wang YY, Ou-Yang DY, Zheng YT (2007) 32. Jin YC (1990) [Crystal trichosanthin protein Mechanism of Trichosanthin against human intramuscular or intracervical injection for leukemia/lymphoma cells in vitro. J the termination of pregnancy at 10 to 14 ExpHematol 15:729–732 weeks gestation: clinical analysis of 200 24. Fang EF, Zhang CZY, Zhang L, Wong JH, cases]. Shengzhi Yu Biyun 10: 34–37. Chan YS, et al. (2012) Trichosanthin 33. Sagar L. Shah, Vishal R. Mali, [...], and Inhibits Breast Cancer Cell Proliferation in Subhash L. Bodhankar (2012) Toxicology Both Cell Lines and Nude Mice by International MedknowToxicol Int. 19(2): Promotion of Apoptosis. PLoS ONE 7(9): 167–172. PMCID: PMC3388762 e41592. doi:10.1371/journal.pone.0041592 34. Kannan.M, Pugazenthi.R, Karthikeyan.M, 25. Bao Q, Shi Y (2007) Apoptosome: a Rajasekar.S (2011) Gastroprotective Effect platform for the activation of initiator of Hydroalcoholic Extract of Aloe buettneri. caspases. Cell Death Differ 14: 56–65. Iranian Journal of Pharmaceutical Research 26. Krajewski S, Krajewska M, Ellerby LM, 10 (1). Welsh K, Xie Z, et al. (1999) Release of 35. Menuka Arawwawala, Ira Thabrewand caspase-9 from mitochondria during Lakshmi Arambewela (2009) Antidiabetic neuronal apoptosis and cerebral ischemia. activity of Trichosanthes cucumerinain ProcNatl AcadSci U S A 96: 5752–5757 normal and streptozotocin– induced diabetic 27. Fang EF, Zhang CZY, Ng TB, Wong JH, rats. Int.J. Biol. Chem. Sci. 3(2):287-296. Pan WL, et al. (2012) Momordica Charantia 36. Arawwawala, M.I. Thabrew, L.S.R. Lectin, a Type II Ribosome Inactivating Arambewela, N. Fernando and L.D. Protein, Exhibits Antitumor Activity toward GurugeAntibacterial Activity of Human Nasopharyngeal Carcinoma Cells In Trichosanthes cucumerina Linn. Extracts Vitro and In Vivo. Cancer Prevention L.D.A.M.International Journal of Research 5: 109–121. Pharmaceutical & Biological Archives 28. EvandroFei Fang, Chris Zhi Yi Zhang, Lin 2011; 2(2):808-812. Zhang, Jack Ho Wong, Yau Sang Chan,

Page 319

American Journal of Ethnomedicine ______ISSN: 2348-9502

37. Aiyalu Rajasekaran and Muthusamy aqueous fruit extract of Trichosanthes dioica Periyasamy. Hepatoprotective effect of in normal and streptozotocin diabetic rats. J ethanolic extract of Trichosanthes lobata on ClinDia Res, 1(4): 561-569 paracetamol-induced liver toxicity in rats. 42. Bhujbal MM, PatoladiQuath (1999) in the Chinese Medicine 2012, 7:12 management of skin disorder. Deerghayu doi:10.1186/1749-8546-7-12 58:72-76. 38. Sonwalkar R.P And Kadam P.S. (2013) 43. Periyanayagam K, Jegadeesh S, Karthikeyan Trichosanthes tricuspidata Methanol and V, Jancy GraceletRal (2014). Int.J.Pharm. Petroleum ether extract effect on Culex Anal Vol: 2 Issue:5 Page:417-424 Journal DOI: 10.9780/ 2321- 44. Kage , D. N.; Malashetty, V. B.; Seetharam, 7871/162013/16 Y. N.; Suresh, P. &Patil, S. B. (2009)Effect 39. Fulzule SV, Satturwar D, Joshi SB (2001) of ethanol extract of whole plant of Studies on anti-inflammatory activity of a Trichosanthes cucumerina var. Cucumerina poly herbal formulation- JatydiGhrita. L. On gonadotropins, ovarian follicular Indian drugs, 39(1). kinetics and estrous cycle for screening o 40. Mukesh Tanwar, Ashok Sharma, Kedar antifertility Activity in albin rats. Int. J. Prasad Swarnkar, Monit Singhal,Kailash Morphol., 27(1). Yadav(2011) International Journal of 45. Y.T. Zheng, W.L. Chan, P. Chan, H. Huang, Pharmaceutical Studies and Research E- S.C. Tam; Enhancement of the anti-herpetic ISSN 2229-4619 effect of trichosanthin by acyclovir and 41. Sharmila BG, Kumar G, Rajasekhara PM interferon FEBS Letters 496 (2001) 139- (2007) Cholesterol-lowering activity of the 142.

Page 320

American Journal of Ethnomedicine ______ISSN: 2348-9502

Table 1. Type of Trichosanthen species, General name and respective activities are tabulated below

Trichosanthes S.no General name Activities species Anthelmintic, Antidiarrhoeal, anti-inflammatory, Anticancer agent,

Trichosanthes larvicidal effects, Antidiabetic, cardio 1. Snake gourd (var. anguina), Serpent cucumerina protective, Antibacterial, wound gourd, Chichinga, and Padwal healing, Antifertility activities.

Gourd Parwal Type-II ribosome inhibitory proteins 2. Trichosanthes (Hindi) (Type-II RIP), Anti proliferative, dioica Paror(Maithili). Anticancer agent, Antioxidant, Anti- Green potato(India) Cholesterol activity, in skin disorder

Anti-HIV type I ribosome- Trichosanthes 3. Chinese cucumber inactivinglectinAntitumor promoters, kirilowii Antiulceractivity

LalIndrayan(Hindi); Redball snake gourd (English); Trichosanthes Kalayar(Malaya); Kaundal(Marathi); 4. tricuspidata Avuduta(Telugu); Anti Larvicidal activity KheKaDaeng(Thai); and Indreni(Nepal);

Trichosanthis ra Relieves pyreticosis, polydipsia, swelling 5. dix Tianhua fen (Mandarin) and ulcer, RIP, Anti-hepatitis B virus

Trichosanthes Hepatoprotective effect, Anti-malarial 6. ------lobata agent.

Page 321