Mad-Adam Nadeeya, Rattanaburee Thidarath, Tanawattanasuntorn Tanotnon, Graidist Potchanapond
Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand.
Oncol Lett. 2022 Feb;23(2):59. doi: 10.3892/ol.2021.13177. Epub 2021 Dec 22.
Ovarian cancer ranks eighth in cancer incidence and mortality among women worldwide. Cisplatin-based chemotherapy is commonly used for patients with ovarian cancer. However, the clinical efficacy of cisplatin is limited due to the occurrence of adverse side effects and development of cancer chemoresistance during treatment. Trans-(±)-kusunokinin has been previously reported to inhibit cell proliferation and induce cell apoptosis in various cancer cell types, including breast, colon and cholangiocarcinoma. However, the potential effects of (±)-kusunokinin on ovarian cancer remains unknown. In the present study, chemosensitive ovarian cancer cell line A2780 and chemoresistant ovarian cancer cell lines A2780cis, SKOV-3 and OVCAR-3 were treated with trans-(±)-kusunokinin to investigate its potential effects. MTT, colony formation, apoptosis and multi-caspase assays were used to determine cytotoxicity, the ability of single cells to form colonies, induction of apoptosis and multi-caspase activity, respectively. Moreover, western blot analysis was performed to determine the proteins level of topoisomerase II, cyclin D1, CDK1, Bax and p53-upregulated modulator of apoptosis (PUMA). The results demonstrated that trans-(±)-kusunokinin exhibited the strongest cytotoxicity against A2780cis cells with an IC value of 3.4 µM whilst also reducing the colony formation of A2780 and A2780cis cells. Trans-(±)-kusunokinin also induced the cells to undergo apoptosis and increased multi-caspase activity in A2780 and A2780cis cells. This compound significantly downregulated topoisomerase II, cyclin D1 and CDK1 expression, but upregulated Bax and PUMA expression in both A2780 and A2780cis cells. In conclusion, trans-(±)-kusunokinin suppressed ovarian cancer cells through the inhibition of colony formation, cell proliferation and the induction of apoptosis. This pure compound could be a potential targeted therapy for ovarian cancer treatment in the future. However, studies in an animal model and clinical trial need to be performed to support the efficacy and safety of this new treatment.
卵巢癌在全球女性癌症发病率和死亡率中排名第八。基于顺铂的化疗常用于卵巢癌患者。然而，由于治疗期间出现副作用和癌症化疗耐药性，顺铂的临床疗效有限。先前有报道称反式-(±)-kusunokinin可抑制多种癌细胞类型（包括乳腺癌、结肠癌和胆管癌）的细胞增殖并诱导细胞凋亡。然而，(±)-kusunokinin对卵巢癌的潜在作用仍不清楚。在本研究中，用反式-(±)-kusunokinin处理化疗敏感的卵巢癌细胞系A2780和化疗耐药的卵巢癌细胞系A2780cis、SKOV-3和OVCAR-3，以研究其潜在作用。MTT法、集落形成实验、凋亡实验和多 caspase 检测分别用于测定细胞毒性、单细胞形成集落的能力、凋亡诱导和多 caspase 活性。此外，进行蛋白质印迹分析以确定拓扑异构酶II、细胞周期蛋白D1、细胞周期蛋白依赖性激酶1（CDK1）、 Bax和p53上调凋亡调节因子（PUMA）的蛋白质水平。结果表明，反式-(±)-kusunokinin对A2780cis细胞表现出最强的细胞毒性，IC值为3.4μM，同时也减少了A2780和A2780cis细胞的集落形成。反式-(±)-kusunokinin还诱导A2780和A2780cis细胞发生凋亡并增加多 caspase 活性。该化合物显著下调A2780和A2780cis细胞中拓扑异构酶II、细胞周期蛋白D1和CDK1的表达，但上调Bax和PUMA的表达。总之，反式-(±)-kusunokinin通过抑制集落形成、细胞增殖和诱导凋亡来抑制卵巢癌细胞。这种纯化合物可能是未来卵巢癌治疗的潜在靶向疗法。然而，需要在动物模型和临床试验中进行研究以支持这种新疗法的疗效和安全性。
