Letter to the editor
An updated review of Cucurbitacins and their biological and pharmacological activities
Sun Ok Chung1, Yong Joo Kim1, Sang Un Park21Department of Biosystems Machinery Engineering, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764, Korea
2Department of Crop Science, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764, Korea
EXCLI J 2015;14:Doc562
Cucurbitacins (Cus) are a class of highly oxidized tetracyclic triterpenoids that confer a bitter taste to cucurbits such as cucumber, melon, watermelon, squash, and pumpkin. To date, a large number of Cus and Cu-derived compounds have been isolated from the Cucurbitaceae family and from other species of the plant (Alghasham, 2013; Shang et al., 2014).
Cus have a range of biological and pharmacological activities that first attracted attention in the 1960s (Chen et al., 2012). Cucurbitacin B (CuB) and Cucurbitacin E (CuE) have been particularly widely studied (Lan et al., 2013). Recent reports have demonstrated that CuE has growth-inhibitory effects in the proliferation of many cancer cells such as bladder cancer, hepatocellular carcinoma, pancreatic cancer, breast cancer, and leukemia (Dong et al., 2010; Sörensen et al., 2012). CuB has been shown to have antimicrobial and anti-inflammatory activity. However, most reports on CuB focus on its anticancer activity. CuB inhibits the growth of human malignant cells, both in vitro and in vivo, and has been shown to be effective against breast cancer, head and neck squamous cell carcinoma, pancreatic cancer, hepatocellular carcinoma, osteosarcoma, and myeloid leukemia (Duangmano et al., 2010; Kausar et al., 2013; Guo et al., 2014).
Consequently, natural and semisynthetic Cus are proposed as a promising source for the development of new drugs for the prevention and treatment of various cancers. Here, we summarize key recent studies that have evaluated the biological and pharmacological activities of Cu and its derivatives (Table 1(Tab. 1)).
References in Table 1: Zhang et al., 2014; Jacquot et al., 2014; Kong et al., 2014; Guo et al., 2014; Feng et al., 2014; Hsu et al., 2014; Gupta and Srivastava, 2014; Gao et al., 2014; Yuan et al., 2014; Wang et al., 2014; Ma et al., 2014; Seo et al., 2014; Kim et al., 2013; Johnson et al., 2013; Song et al., 2013; Lan et al., 2013; Hung et al., 2013; Spear et al., 2013; He et al., 2013; Qiao et al., 2013; Kausar et al., 2013; Abbas et al., 2013; Aribi et al., 2013; Duangmano et al., 2012; Zhang et al., 2012.
This research was supported by Agriculture, Food and Rural Affairs Research Center Support Program, Ministry of Agriculture, Food and Rural Affairs.
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3. Chen X, Bao J, Guo J, Ding Q, Lu J, Huang M, et al. Biological activities and potential molecular targets of cucurbitacins: a focus on cancer. Anticancer Drugs. 2012;23:777-87.
4. Lan T, Wang L, Xu Q, Liu W, Jin H, Mao W, et al. Growth inhibitory effect of Cucurbitacin E on breast cancer cells. Int J Clin Exp Pathol. 2013;6:1799-805.
5. 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.
6. Sörensen PM, Iacob RE, Fritzsche M, Engen JR, Brieher WM, Charras G, et al. The natural product cucurbitacin E inhibits depolymerization of actin filaments. ACS Chem Biol. 2012;7:1502-8.
7. Duangmano S, Dakeng S, Jiratchariyakul W, Suksamrarn A, Smith DR, Patmasiriwat P. Antiproliferative effects of cucurbitacin B in breast cancer cells: down-regulation of the c-Myc/hTERT/telomerase pathway and obstruction of the cell cycle. Int J Mol Sci. 2010;11:5323-38.
8. Kausar H, Munagala R, Bansal SS, Aqil F, Vadhanam MV, Gupta RC. Cucurbitacin B potently suppresses non-small-cell lung cancer growth: identification of intracellular thiols as critical targets. Cancer Lett. 2013;332:35-45.
9. Guo J, Wu G, Bao J, Hao W, Lu J, Chen X. Cucurbitacin B induced ATM-mediated DNA damage causes G2/M cell cycle arrest in a ROS-dependent manner. PLoS One. 2014a;9:e88140.
10. Zhang M, Bian ZG, Zhang Y, Wang JH, Kan L, Wang X, et al. Cucurbitacin B inhibits proliferation and induces apoptosis via STAT3 pathway inhibition in A549 lung cancer cells. Mol Med Rep. 2014;10: 2905-11.
11. Jacquot C, Rousseau B, Carbonnelle D, Chinou I, Malleter M, Tomasoni C, et al. Cucurbitacin-D-induced CDK1 mRNA up-regulation causes proliferation arrest of a non-small cell lung carcinoma cell line (NSCLC-N6). Anticancer Res. 2014;34:4797-806.
12. Kong Y, Chen J, Zhou Z, Xia H, Qiu MH, Chen C. Cucurbitacin E induces cell cycle G2/M phase arrest and apoptosis in triple negative breast cancer. PLoS One. 2014;9:e103760.
13. Guo J, Zhao W, Hao W, Ren G, Lu J, Chen X. Cucurbitacin B induces DNA damage, G2/M phase arrest, and apoptosis mediated by reactive oxygen species (ROS) in leukemia K562 cells. Anticancer Agents Med Chem. 2014b;14:1146-53.
14. Feng H, Zang L, Zhao ZX, Kan QC. Cucurbitacin-E inhibits multiple cancer cells proliferation through attenuation of Wnt/β-catenin signaling. Cancer Biother Radiopharm. 2014;29:210-4.
15. Hsu YC, Huang TY, Chen MJ. Therapeutic ROS targeting of GADD45γ in the induction of G2/M arrest in primary human colorectal cancer cell lines by cucurbitacin E. Cell Death Dis. 2014;5:e1198.
16. Gupta P, Srivastava SK. Inhibition of Integrin-HER2 signaling by Cucurbitacin B leads to in vitro and in vivo breast tumor growth suppression. Oncotarget. 2014;5:1812-28.
17. Gao Y, Islam MS, Tian J, Lui VW, Xiao D. Inactivation of ATP citrate lyase by Cucurbitacin B: A bioactive compound from cucumber, inhibits prostate cancer growth. Cancer Lett. 2014;349:15-25.
18. Yuan G, Yan SF, Xue H, Zhang P, Sun JT, Li G. Cucurbitacin I induces protective autophagy in glioblastoma in vitro and in vivo. J Biol Chem. 2014;289:10607-19.
19. Wang Y, Zhao GX, Xu LH, Liu KP, Pan H, He J, et al. Cucurbitacin IIb exhibits anti-inflammatory activity through modulating multiple cellular behaviors of mouse lymphocytes. PLoS One. 2014;9:e89751.
20. Ma J, Zi Jiang Y, Shi H, Mi C, Li J, Xing Nan J, et al. Cucurbitacin B inhibits the translational expression of hypoxia-inducible factor-1α. Eur J Pharmacol. 2014;723:46-54.
21. Seo CR, Yang DK, Song NJ, Yun UJ, Gwon AR, Jo DG, et al. Cucurbitacin B and cucurbitacin I suppress adipocyte differentiation through inhibition of STAT3 signaling. Food Chem Toxicol. 2014;64:217-24.
22. Kim SR, Seo HS, Choi HS, Cho SG, Kim YK, Hong EH, et al. Trichosanthes kirilowii ethanol extract and cucurbitacin d inhibit cell growth and induce apoptosis through inhibition of stat3 activity in breast cancer cells. Evid Based Complement Alternat Med. 2013;2013:975350.
23. Johnson MD, O'Connell MJ, Walter K. Cucurbitacin I blocks cerebrospinal fluid and platelet derived growth factor-BB stimulation of leptomeningeal and meningioma DNA synthesis. BMC Complement Altern Med. 2013;13:303.
24. Song Y, Ding N, Kanazawa T, Yamashita U, Yoshida Y. Cucurbitacin D is a new inflammasome activator in macrophages. Int Immunopharmacol. 2013;17:1044-50.
25. Hung CM, Chang CC, Lin CW, Ko SY, Hsu YC. Cucurbitacin E as inducer of cell death and apoptosis in human oral squamous cell carcinoma cell line SAS. Int J Mol Sci. 2013;14:17147-56.
26. Spear SA, Burns SS, Oblinger JL, Ren Y, Pan L, Kinghorn AD, et al. Natural compounds as potential treatments of NF2-deficient schwannoma andmeningioma: cucurbitacin D and goyazensolide. Otol Neurotol. 2013;34:1519-27.
27. He J, Wang Y, Xu LH, Qiao J, Ouyang DY, He XH. Cucurbitacin IIa induces caspase-3-dependent apoptosis and enhances autophagy in lipopolysaccharide-stimulated RAW 264.7 macrophages. Int Immunopharmacol. 2013;16:27-34.
28. Qiao J, Xu LH, He J, Ouyang DY, He XH. Cucurbitacin E exhibits anti-inflammatory effect in RAW 264.7 cells via suppression of NF-κB nuclear translocation. Inflamm Res. 2013;62:461-9.
29. Abbas S, Vincourt JB, Habib L, Netter P, Greige-Gerges H, Magdalou J. The cucurbitacins E, D and I: investigation of their cytotoxicity toward human chondrosarcoma SW 1353 cell line and their biotransformation in man liver. Toxicol Lett. 2013;216:189-99.
30. Aribi A, Gery S, Lee DH, Thoennissen NH, Thoennissen GB, Alvarez R, et al. The triterpenoid cucurbitacin B augments the antiproliferative activity of chemotherapy in human breast cancer. Int J Cancer. 2013;132:2730-7.
31. Duangmano S, Sae-Lim P, Suksamrarn A, Domann FE, Patmasiriwat P. Cucurbitacin B inhibits human breast cancer cell proliferation through disruption of microtubule polymerization and nucleophosmin/B23 translocation. BMC Complement Altern Med. 2012;12:185.
32. Zhang T, Li J, Dong Y, Zhai D, Lai L, Dai F, et al. Cucurbitacin E inhibits breast tumor metastasis by suppressing cell migration and invasion. Breast Cancer Res Treat. 2012;135:445-58.
Table 1: Recent studies on Cus and their biological and pharmacological activities