Approach for chemosensitization of cisplatin-resistant ovarian cancer by cucurbitacin B
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Ovarian cancer is the most deadly gynecological cancer. The first line in treatment is platinum-based drugs. However, most patients suffer from tumor recurrence, characterized by resistance to cisplatin. A plausible approach to address the tumor resistance is to co-administer the chemotherapeutic agents along with natural products to offer a synergistic effect and optimize the dosage regimen. Cucurbitacin B is a natural product and displays antitumor activity against a wide array of cancer cell lines. The aim of this work is to determine the antitumor activity against ovarian cancer cell line (A2780) and possible sensitization activity on cisplatin-resistant cell line (A2780CP) in 2D and 3D culture model. 3D spheroids were generated from A2780CP cell line. A2780, A2780CP, and the spheroids were treated with cucurbitacin B, cisplatin alone, or pretreated with cucurbitacin B followed by cisplatin. The viability, cell cycle, and apoptosis were analyzed. Level of ROS and total glutathione was measured. In this study, cucurbitacin B showed cytotoxicity against the ovarian cancer cell lines, and pretreatment of A2780CP cells leads to a significant increase in the cytotoxicity of cisplatin. The mechanism behind the sensitization effect was dependent in part on the depletion of the total glutathione, an increase in ROS through a decrease in the level of dual-specificity tyrosine-regulated kinase (Dyrk1B), decrease in pERK1/2 and pSTAT3 level. The viability of spheroids treated with a combination of cisplatin and cucurbitacin B were significantly decreased. The resulting data shows that cucurbitacin B is a promising chemosensitizer for the cisplatin-resistant ovarian cancer.
KeywordsOvarian cancer Chemotherapy resistance Cisplatin Cucurbitacin B Dyrk1B
We would like to thank Lucas Kopel and Mahmoud Salama (Chemistry and Biochemistry Department, South Dakota State University, Brookings, SD, USA). This work was supported by the Egyptian government via the Egyptian Ministry of Higher Education and Scientific Research.
Conflict of interest
FE helped in the design of the study, carried out the research, and drafted the manuscript. FB, AE, and FH participated in the design and conceive of the study. SC helped in the design and revision of the draft. All authors read and approved the final manuscript.
- 15.Kim KY, Choi KC, Park SH, Auersperg N, Leung PC. Extracellular signal-regulated protein kinase, but not c-Jun N-terminal kinase, is activated by type II gonadotropin-releasing hormone involved in the inhibition of ovarian cancer cell proliferation. J Clin Endocrinol Metab. 2005;90(3):1670–7. doi: 10.1210/jc.2004-1636.CrossRefPubMedGoogle Scholar
- 16.Hayakawa J, Ohmichi M, Kurachi H, Ikegami H, Kimura A, Matsuoka T, et al. Inhibition of extracellular signal-regulated protein kinase or c-Jun N-terminal protein kinase cascade, differentially activated by cisplatin, sensitizes human ovarian cancer cell line. J Biol Chem. 1999;274(44):31648–54.CrossRefPubMedGoogle Scholar
- 33.Chou TC, Martin N. CompuSyn for drug combinations: PC software and user’s guide: a computer program for quantitation of synergism and antagonism in drug combinations, and the determination of IC50 and ED50 and LD50 Values, ComboSyn Inc, Paramus, (NJ), 2005.Google Scholar
- 43.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(1):118–24. doi: 10.1016/j.canlet.2010.01.029.CrossRefPubMedGoogle Scholar
- 49.Godoy H, Mhawech-Fauceglia P, Beck A, Miller A, Lele S, Odunsi K. Expression of poly (adenosine diphosphate-ribose) polymerase and p53 in epithelial ovarian cancer and their role in prognosis and disease outcome. Int J Gynecol Pathol: Off J Int Soc Gynecol Pathol. 2011;30(2):139–44. doi: 10.1097/PGP.0b013e3181fa5a64.CrossRefGoogle Scholar
- 55.Burleson K, Hansen L, Skubitz A. Ovarian carcinoma spheroids disseminate on type I collagen and invade live human mesothelial cell monolayers. Clin Exp Metastasis. 2005;21:685-697.Google Scholar