Cucurbitacins as Anticancer Agents: A Patent Review

Author(s): Hidayat Hussain* , Ivan R. Green , Muhammad Saleem , Khanzadi F. Khattak , Muhammad Irshad , Maroof Ali .

Journal Name: Recent Patents on Anti-Cancer Drug Discovery

Volume 14 , Issue 2 , 2019

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Background: Cucurbitacins belong to a group of tetracyclic triterpenoids that display a wide range of biological effects. In the past, numerous cucurbitacins have been isolated from natural sources and many active compounds have been synthesized using the privileged scaffold in order to enhance its cytotoxic effects.

Objective: This review covers patents on the therapeutic effects of natural cucurbitacins and their synthetic analogs published during the past decade. By far, the majority of patents published are related to cancer and Structure-Activity Relationships (SAR) of these compounds are included to lend gravitas to this important class of natural products.

Methods: The date about the published patents was downloaded via online open access patent databases.

Results: Cucurbitacins display significant cytotoxic properties, in particular cucurbitacins B and D which possess very potent effects towards a number of cancer cells. Numerous cucurbitacins isolated from natural sources have been derivatized through chemical modification at the C(2)-OH and C(25)- OH groups. Most importantly, an acyl ester of the C(25)-OH and, iso-propyl, n-propyl and ethyl ether groups of the C(2)-OH demonstrated the most increased cytotoxic activity.

Conclusion: The significant cytotoxic effects of natural and semi-synthetic cucurbitacins make them attractive as new drug candidates. Moreover, cucurbitacins have the capability to form conjugates with other anticancer drugs which will synergistically enhance their anticancer effects. The authors believe that in order to get lead compounds, there should be a greater focus on the synthesis of homodimers, heterodimers, and halo derivatives of cucurbitacins. In the opinion of the authors the analysis of the published patents on the cucurbitacins indicates that these compounds can be developed into a regimen to treat a wide spectrum of cancers.

Keywords: Anticancer, cucurbitaceae, cucurbitacins, in vitro, in vivo, plants.

Chudzik M, Korzonek-Szlacheta I, Król W. Triterpenes as potentially cytotoxic compounds. Molecules 2015; 20: 1610-25.
Hamid K, Alqahtani A, Kim MS, Cho JL, Cui PH, Li CG, et al. Tetracyclic triterpenoids in herbal medicines and their activities in diabetes and its complications. Curr Top Med Chem 2015; 15: 2406-30.
Chen JC, Chiu MH, Nie RL, Cordell GA, Qiu SX. Cucurbitacins and cucurbitane glycosides: Structures and biological activities. Nat Prod Rep 2005; 22: 386-99.
Miro M. Cucurbitacins and their pharmacological effects. Phytother Res 1995; 9: 159-68.
Stuppner H, Wagner H. New Cucurbitacin Glycosides from Picrorhiza kurrooa. Planta Med 1989; 55: 559-63.
Rodriguez N, Vasquez Y, Hussein AA, Coley PD, Solis PN, Gupta MP. Cytotoxic cucurbitacin constituents from Sloanea zuliaensis. J Nat Prod 2003; 66: 1515-6.
Reddy KS, Amonkar AJ, McCloud TG, Chang CJ, Cassady JM. Spinosides A and B. Two cytotoxic cucurbitacin glycosides from Desfontainia spinose. Phytochemistry 1988; 27: 3781-5.
Ahmad A, Manuel M, Jose J, Jose A, Dolores-Caracuel M, Garcia-Granados A, et al. Concepcion navarro, isolation of an anti-hepatotoxic principle from the juice of Ecballium elaterium. Planta Med 1999; 65: 673-5.
Sasamori H, Reddy KS, Kirkup MP, Shabanowitz J, Lynn DG, Hecht SM, et al. New cytotoxic principles from Datisca glomerata. J Chem Soc, Perkin Trans 1 1983; 1333-47.
Sarker SD, Whiting P, Sik V, Dinan L. Ecdysteroid antagonists (cucurbitacins) from Physocarpus opulifolius (Rosaceae). Phytochemistry 1999; 50: 1123-8.
Schun Y, Cordell GA. Studies in the Thymelaeaceae III. Constituents of Gyrinops walla. J Nat Prod 1985; 48: 684-5.
Fujimoto H, Hagiwara H, Suzuki K, Yamazaki M. New Toxic Metabolites from a Mushroom, Hebeloma vinosophyllum. II. Isolation and structures of hebevinosides VI, VII, VIII, IX, X, and XI. Chem Pharm Bull 1987; 35: 2254-60.
Jian-Wen T, Ze-Jun D, Zhi-Hui D, Ji-Kai L. Lepidolide, a novel seco-ring-A cucurbitane triterpenoid from Russula lepida (Basidiomycetes). Z Naturforsch C 2002; 57: 963-5.
Kaushik U, Aeri V, Mir SR. Cucurbitacins: An insight into medicinal leads from nature. Pharmacogn Rev 2015; 9: 12-8.
Oh H, Mun YJ, Im JS, Lee SY, Song JH, Lee SH, et al. Cucurbitacins from Trichosanthes kirilowii as the inhibitory components on tyrosinase activity and melanin synthesis of B16/F10 melanoma cells. Planta Med 2002; 68: 832-3.
Hylands PJ, Magd MS. Cucurbitacins from Acanthosicyos horridus. Phytochemistry 1986; 25: 1681-4.
Farias MR, Schenkel EP, Mayer R, Buecker G. Cucurbitacins as constituents of Wilbrandia ebracteata. Planta Med 1993; 59: 272-5.
Mukherjee S, Shaw AK, Ganguly SN, Ganguly T, Sahn PK. Amarinin: A new growth inhibitor from Luffa amara. Plant Cell Physiol 1986; 27: 935-8.
Afifi MS, Ross SA, Elsohly MA, Naeem ZE, Halaweish FT. Cucurbitacins of Cucumis prophetarum and Cucumis prophetarum. J Chem Ecol 1999; 24: 847-59.
Sekine T, Kurihara H, Wayumi M, Ikegami F, Ruangrungsi N. A New Pentacyclic Cucurbitane glucoside and a new triterpene from the fruits of Gymnopetalum integrifolium. Chem Pharm Bull 2002; 50: 645-8.
Roa MM, Meshulam H, Lavie D. The constituents of Ecballium elaterium L. Part XXIII. Cucurbitacins and hexanorcucurbitacins. J Chem Soc, Perkin Trans 1 1974; 22: 2552-6.
Kanchanapoom T, Kasai R, Yamasaki K. Cucurbitane, hexanorcucurbitane and octanorcucurbitane glycosides from fruits of Trichosanthes tricuspidata. Phytochemistry 2002; 59: 215-28.
Kupchan SM, Smith RM, Aynehchi Y, Maruyama M. Tumor inhibitors. LVI. Cucurbitacins O, P, and Q, the cytotoxic principles of Brandegea bigelovii. J Org Chem 1970; 35: 2891-4.
Chen X, Bao J, Guo J, et al. Biological activities and potential molecular targets of cucurbitacins: A focus on cancer. Anticancer Drugs 2012; 23: 777-87.
Lee DH, Iwanski GB, Thoennissen NH. Cucurbitacin: Ancient compound shedding new light on cancer treatment. ScientificWorldJournal 2010; 10: 413-8.
Cai Y, Fang X, He C, Li P, Xiao F, Wang Y, et al. Cucurbitacins: A systematic review of the phytochemistry and anticancer activity. Am J Chin Med 2015; 43: 1331-50.
Garg S, Kaul SC, Wadhwa R. Cucurbitacin B and cancer intervention: Chemistry, biology and mechanisms (Review). Int J Oncol 2018; 52: 19-37.
Alghasham AA. Cucurbitacins-A promising target for cancer therapy. Int J Health Sci (Qassim) 2013; 7: 77-89.
Wakimoto N, Yin D, O’Kelly J, Haritunians T, Karlan B, Said J, et al. Cucurbitacin B has a potent antiproliferative effect on breast cancer cells in vitro and in vivo. Cancer Sci 2008; 99: 1793-7.
Kongtun S, Jiratchariyakul W, Kummalue T, Tan-ariya P, Kunnachak S, Frahm AW. Cytotoxic properties of root extract and fruit juice of Trichosanthes cucumerina. Planta Med 2009; 75: 839-42.
Jayaprakasam B, Seeram NP, Nair MG. Anticancer and anti-inflammatory activities of cucurbitacins from Cucurbita andreana. Cancer Lett 2003; 189: 11-6.
Zhang M, Zhang H, Sun C, Shan X, Yang X, Li-Ling J, et al. Targeted constitutive activation of signal transducer and activator of transcription 3 in human hepatocellular carcinoma cells by cucurbitacin B. Cancer Chemother Pharmacol 2009; 63: 635-42.
Chan KT, Meng FY, Li Q, Ho CY, Lam TS, To Y, et al. Cucurbitacin B induces apoptosis and S phase cell cycle arrest in BEL-7402 human hepatocellular carcinoma cells and is effective via oral administration. Cancer Lett 2010; 294: 118-24.
Thoennissen NH, Iwanski GB, Doan NB, Okamoto R, Lin P, Abbassi S, et al. Cucurbitacin B induces apoptosis by inhibition of the JAK/STAT pathway and potentiates antiproliferative effects of gemcitabine on pancreatic cancer cells. Cancer Res 2009; 69: 5876-84.
Zhang M, Sun C, Shan X, Yang X, Li-Ling J, Deng Y. Inhibition of pancreatic cancer cell growth by cucurbitacin B through modulation of signal transducer and activator of transcription 3 signaling. Pancreas 2010; 39: 923-9.
Matsuda H, Nakashima S, Abdel-Halim OB, Morikawa T, Yoshikawa M. Cucurbitane- type triterpenes with anti-proliferative effects on U937 cells from an Egyptian natural medicine, Bryonia cretica: Structures of new triterpene glycosides, bryoniaosides A and B. Chem Pharm Bull 2010; 58: 747-51.
Haritunians T, Gueller S, Zhang L, Badr R, Yin D, Xing H, et al. Cucurbitacin B induces differentiation, cell cycle arrest, and actin cytoskeletal alterations in myeloid leukemia cells. Leuk Res 2008; 32: 1366-73.
Yasuda S, Yogosawa S, Izutani Y, Nakamura Y, Watanabe H, Sakai T. Cucurbitacin B induces G2 arrest and apoptosis via a reactive oxygen species-dependent mechanism in human colon adenocarcinoma SW480 cells. Mol Nutr Food Res 2010; 54: 559-65.
Chan KT, Li K, Liu SL, Chu KH, Toh M, Xie WD. Cucurbitacin B inhibits STAT3 and the Raf/MEK/ERK pathway in leukemia cell line K562. Cancer Lett 2010; 289: 46-52.
Yin D, Wakimoto N, Xing H, Lu D, Huynh T, Wang X, et al. Cucurbitacin B markedly inhibits growth and rapidly affects the cytoskeleton in glioblastoma multiforme. Int J Cancer 2008; 123: 1364-75.
Liu T, Zhang M, Zhang H, Sun C, Deng Y. Inhibitory effects of cucurbitacin B on laryngeal squamous cell carcinoma. Eur Arch Otorhinolaryngol 2008; 265: 1225-32.
Liu T, Zhang M, Deng Y, et al. Effects of cucurbitacin B on cell proliferation and apoptosis in Hep-2 cells. J Clin Otorhinol 2008; 22: 403-47.
Doskotch RW, Malik MY, Beal JL, Cucurbitacin B. The cytotoxic principle of Begonia tuberhybrida var. alba. Lloydia 1969; 32: 115-22.
Konopa J, Zielinski J, Matuszkiewicz A. Cucurbitacins, cytotoxic and antitumor substances from Bryonia alba L. I: Isolation and identification. Arzneimittelforschung 1974; 24: 1554-7.
Konopa J, Matuszkiewicz A, Hrabowska M, Onoszka K. Cucurbitacines, cytotoxic and antitumor substances from Bryonia alba L. Part II: Biological studies. Arzneimittelforschung 1974; 24: 1741-3.
Ding N, Yamashita U, Matsuoka H, et al. Apoptosis induction through proteasome inhibitory activity of cucurbitacin D in human T-cell leukemia. Cancer 2011; 117: 2735-46.
Liu K, Xing H, Zhang S, Liu S, Fung M. Cucurbitacin D induces fetal hemoglobin synthesis in K562 cells and human hematopoietic progenitors through activation of p38 pathway and stabilization of the gammaglobin mRNA. Blood Cells Mol Dis 2010; 45: 269-75.
Takahashi N, Yoshida Y, Sugiura T, Matsuno K, Fujino A, Yamashita U. Cucurbitacin D isolated from Trichosanthes kirilowii induces apoptosis in human hepatocellular carcinoma cells in vitro. Int Immunopharmacol 2009; 9: 508-13.
Nakashima S, Matsuda H, Kurume A, et al. Cucurbitacin E as a new inhibitor of cofilin phosphorylation in human leukemia U937 cells. Bioorg Med Chem Lett 2010; 20: 2994-7.
Li Y, Wang R, Ma E, et al. The induction of G2/M cell- cycle arrest and apoptosis by cucurbitacin E is associated with increased phosphorylation of eIF2alpha in leukemia cells. Anticancer Drugs 2010; 21: 389-400.
Duncan KL, Duncan MD, Alley MC, Sausville EA. Cucurbitacin E-induced disruption of the actin and vimentin cytoskeleton in prostate carcinoma cells. Biochem Pharmacol 1996; 52: 1553-60.
Sun C, Zhang M, Shan X, Zhou X, Yang J, Wang Y, et al. Inhibitory effect of cucurbitacin E on pancreatic cancer cells growth via STAT3 signaling. J Cancer Res Clin Oncol 2010; 136: 603-10.
Attard E, Brincat MP, Cuschieri A. Immunomodulatory activity of cucurbitacin E isolated from Ecballium elaterium. Fitoterapia 2005; 76: 439-41.
Dong Y, Lu B, Zhang X, Zhang J, Lai L, Li D, et al. Cucurbitacin E, a tetracyclic triterpenes compound from Chinese medicine, inhibits tumor angiogenesis through VEGFR2-mediated Jak2-STAT3 signaling pathway. Carcinogenesis 2010; 31: 2097-104.
Huang WW, Yang JS, Lin MW, Chen PY, Chiou SM, Chueh FS, et al. Induces G(2)/M phase arrest through STAT3/p53/p21 signaling and provokes apoptosis via Fas/CD95 and mitochondria-dependent pathways in human bladder cancer T24 Cells. Evid Based Complement Alternat Med 2012; 1-11.
Shan XL, Zhou XY, Yang J, Wang YL, Deng YH, Zhang MX. Inhibitory effect of cucurbitacin E on the proliferation of ovarian cancer cells and its mechanism. Chin J Cancer 2010; 29: 20-4.
Yang Y, Zhang P, Luo Q, Deng Y, Ma E, Jing Y. Inhibitory effect of cucurbitacin E on the prolifferation of hepatoma cells through induction of G2/M phase arrest. J Shenyang Pharm Univ 2010; 27: 388-91.
Lui VW, Yau DM, Wong EY, Ng YK, Lau CP, Ho Y, et al. Cucurbitacin I elicits anoikis sensitization, inhibits cellular invasion and in vivo tumor formation ability of nasopharyngeal carcinoma cells. Carcinogenesis 2009; 30: 2085-94.
Shi X, Franko B, Frantz C, Amin HM, Lai R. JSI-124 (cucurbitacin I) inhibits Janus kinase-3/signal transducer and activator of transcription-3 signalling, downregulates nucleophosmin-anaplastic lymphoma kinase (ALK), and induces apoptosis in ALK- positive anaplastic large cell lymphoma cells. Br J Haematol 2006; 135: 26-32.
Su Y, Li G, Zhang X, et al. JSI-124 inhibits glioblastoma multiforme cell proliferation through G(2)/M cell cycle arrest and apoptosis augment. Cancer Biol Ther 2008; 7: 1243-9.
Escandell JM, Kaler P, Recio MC, Sasazuki T, Shirasawa S, Augenlicht L, et al. Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: the role of p53 and p21. Biochem Pharmacol 2008; 76: 198-207.
Rıos JL, Giner RM, Jime’nez MJ, Wickman G, Hancke JL. A study on the anti-inflammatory activity of Cayaponia tayuya root. Fitoterapia 1990; 61: 275-8.
Tan MJ, Ye JM, Turner N, Hohen Behrens C, Ke CQ, Tang CP, et al. Antidiabetic activities of triterpenoids isolated from bitter melon associated with activation of the AMPK Pathway. Chem Biol 2008; 15: 263-73.
Harinantenaina L, Tanaka M, Takaoka S, Oda M, Mogami O, Uchida M, et al. Momordica charantia constituents and antidiabetic screening of the isolated major compounds. Chem Pharm Bull (Tokyo) 2006; 54: 1017-21.
Zhu ZJ, Zhong ZC, Luo ZY, Xiao ZY. Studies on the active constituents of Momordica charantia. Acta Pharm Sinica 1990; 25: 898-903.
Jianchao C, Renrong T, Qiu M, Lu L, Yongtang Z, Zhang Z. Trinorcucurbitane and cucurbitane triterpenoids from the roots of Momordica charantia. Phytochemistry 2008; 69: 1043-8.
Jose´ GA, Omar MC, Fernando B, Robert B, Jose´ PC, Andre’s N, et al. Antidiabetic properties of selected Mexican copalchis of the Rubiaceae family. Phytochemistry 2007; 68: 2087-95.
Edery H, Schatzberg-Porath G, Gitter S. (1961). Pharmacodynamic activity of Elatericin (Cucurbitacin D). Arch. lnr. Pharmacodyn. Ther 1961; 30: 315-35.
Hu R, Peng Y, Chen B, Chen Y, Hou X. Study on Tian Gua Di (Cucumis melo L.), an antihepatitis Chinese medicine. Preparation and assay of Gua Di Su and cucurbitacins B and E. Zhongcaoyao 1982; 13: 445-7.
Shohat B, Beemer AM, Gitter S, Lavie D. Antifertility activity of dihydroelatericin A in the female mouse. Experientia 1972; 28: 1203-5.
Albert O, Djetcha T, Lagrange E. Etude experimentale de Iactivite anthelmintique de quelques cucurbitacins. Chim Ther 1970; 5: 205-10.
Guha J, Pen SP. Antigibbellerins of the Cucurbitaceae. Nat New Biol 1973; 244: 223-4.
Bar-Nun N, Mayer AM. Cucurbitacins-repressors of induction of lactase formation. Phytochemistry 1989; 28: 1369-71.
Nes WD, Patterson GW. Effects of tetracyclic and pentacyclic triterpenoids on growth of Phytophtora cactorum. J Nat Prod 1981; 44: 215-20.
Xie WD, Li K, Liu ESL, Chu KH. Cucurbitacin B and uses thereof. US20090247495 (2009).
Yang B, Zhang Y, Du Z, et al. Application of cucurbitacin for preparing anticancer drugs. CN103877101 (2014).
Huang R. Application of cucurbitacin B and its analogs in preparing drugs for treating endometrial carcinoma. CN103599110 (2014).
Bai X, Liu S, Liu Y. Cucurbitacin B nano liposome and preparation thereof. CN106137966 (2016).
Liu Y, Guo Y, Zhang L, Liu X, Duan C, Huang Q. Application of cucurbitacin B in preparation of protein phosphatase 2A Inhibitors of cancer inhibitory factor. CN106074567 (2016).
Lee DH, Thoennissen NH, Koeffler HP. Combination of cucurbitacin with methotrexate for treatment of human osteosarcoma. WO2011066545 (2011).
Feng Z, Liu X. Antitumor natural medicines coupled with nitric oxide donors and pharmaceutical uses thereof. WO2011026401 (2011).
Ma E, Li Y. Application of cucurbitacins such as cucurbitacin B, cucurbitacin E and other cucurbitacin analogues or mixture thereof in preparing medicine for treating acute and chronic leukemia. CN101455672 (2009).
Sayers TJ, Booth NL, Henrich CJ, Brooks AD, Gustafson KR, Erickson KL. Method of sensitizing cancer cells to the cytotoxic effects of death receptor ligands in cancer treatment. US9238069 (2016).
Sayers TJ, Booth NL, Henrich CJ, Brooks AD, Gustafson KR, Erickson KL. Method of sensitizing cancer cells to the cytotoxic effects of death receptor ligands in cancer treatment. WO2011084623 (2011).
Sebti SM, Jove R. Materials and methods for treatment of cancer and identification of anti-cancer compounds. US7998947 (2011).
Huang S, Zhou Y, Zeng J, Shang Y, Ma Y. Preparation and application of cucurbitacin C and analogs thereof. CN104892713 (2015).
Halaweish FT, Bartalis J. Cucurbitacin compounds. US20070099852 (2007).
Halaweish FT, Bartalis J. Cucurbitacin derivatives for use as anti-proliferative or hepatoprotective agents. US20070049538 (2007).
Zhang N, Zhong R, Tan G. Preparation of Cucurbitacin B and E derivatives as antitumor, antiviral, antiinflammatory, and liver protection agents. CN102659888 (2012).
Tannin T, Grossman S, Bergman M, Dovrat S. Cucurbitacin glucosides and use thereof in treating cancer. WO2007116404 (2007).
Zhang R, Cheng H, Fan X. Method for extracting anticancer drug cucurbitacin from Hemsleya. CN101074255 (2007).
Geissman TA. New substances of plant origin. Annu Rev Pharmacol 1964; 4: 305-16.
Metcalf RL. Coevolutionary adaptations of rootworm beetles (Coleoptera: Chrysomelidae) to cucurbitacins. J Chem Ecol 1986; 12: 1109-24.
Raikhlin-Eisenkraft B, Bentur Y. Ecballium elaterium (squirting cucumber)-remedy or poison? Clin Toxicol 2000; 38: 305-8.
Shoemaker RH. The NCI60 human tumor cell line anticancer drug screen. Nat Rev Cancer 2006; 10: 813-23.
Lang KL, Silva IT, Zimmermann LA, Machado VR, Teixeira MR, Lapuh MI, et al. Synthesis and cytotoxic activity evaluation of dihydrocucurbitacin B and cucurbitacin B derivatives. Bioorg Med Chem 2012; 20: 3016-30.
Morotti ALM, Lang KL, Carvalho I, Schenkel EP, Bernardes SC. Semi-synthesis of new glycosidic triazole derivatives of dihydrocucurbitacin B. Tetrahedron Lett 2015; 56: 303-7.
Ge W, Chen X, Han F, Liu Z, Wang T, Wang M, et al. Synthesis of cucurbitacin B derivatives as potential anti-hepatocellular carcinoma agents. Molecules 2018; 23: 3345-68.
Silva IT, Geller FC, Persich L, Dudek SE, Lang KL, Caro MCB, et al. Cytotoxic effects of natural and semisynthetic cucurbitacins on lung cancer cell line A549. Invest New Drugs 2016; 34: 139-48.
Silva IT, Carvalho A, Lang KL, Dudek SE, Masemann D, Durán FJ, et al. In vitro and in vivo antitumor activity of a novel semisynthetic derivative of cucurbitacin B. PLoS One 2015; 10e0117794
Yao HK, Liu L, Wang J, Yin JT, Zhong Y. General research situation of cucurbitacins. Shangdong. Pharm Ind 2005; 24: 737-9.
Liu T, Zhang M, Zhang H, Sun C, Yang X, Deng Y, et al. Combined antitumor activity of cucurbitacin B and docetaxel in laryngeal cancer. Eur J Pharmacol 2008; 587: 78-84.
Sadzuka Y, Hatakeyama H, Daimon T, Sonobe T. Screening of biochemical modulator by tumor cell permeability of doxorubicin. Int J Pharm 2008; 354: 63-9.

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Year: 2019
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DOI: 10.2174/1574892813666181119123035
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