Choi Bo Yoon, Joo Jong Cheon, Lee Yeon Kyu, Jang Ik-Soon, Park Soo Jung, Park Yoon Jung
Department of Nutritional Science and Food Management, College of Science & Industry Convergence, Ewha Womans University, Seoul, Republic of Korea.
Department of Sasang Constitutional Medicine, College of Korean Medicine, Wonkwang University, Iksan, Republic of Korea.
BMC Complement Altern Med. 2017 May 25;17(1):277. doi: 10.1186/s12906-017-1776-2.
Ovarian cancer is one of the major causes of death among females in worldwide. Cisplatin is a primary anti-cancer drug against ovarian cancer, but the recurrent tumors after treatment frequently show acquired chemoresistance. Extract of Scutellaria baicalensis (SbE) has been reported to have functional compounds including baicalin, which has anti-cancer effects. However, the anti-cancer effects of SbE in ovarian cancer and its underlying mechanisms are elusive.
We investigated that the effects of SbE and/or cisplatin on cell death in the cisplatin sensitive ovarian cancer cell line A2780 (CSC) and the counterpart cell line that has cisplatin resistance (CRC). Molecular mechanisms of the effects, focusing on apoptosis and autophagy, were examined.
Treatment of cisplatin or SbE reduced cell viability significantly in CSC and too much lesser extent in CRC. Cisplatin-induced cell death in CSC was mediated by p53-induced apoptosis acompanied by expresson of damage-regulated autophagy modulator (DRAM). In CRC, decreased DRAM expression (p < 0.01) hindered p21-mediated cell death and contributed to cisplatin resistance. Treatment of SbE also induced cell death in CSC by p53-dependent apoptosis, not in CRC. Autophagy was not induced by neither cisplatin nor SbE. Intriguingly, the combinational treatment of SbE and cisplatin significantly decreased cell viability in CRC. The cell death was mediated by autophagy with increased expression of Atg5 and Atg12 (p < 0.05), rather than p53-dependent pathway with repressed expression of p21 (p < 0.001) through HDAC1 activation.
The combined treatment of SbE with cisplatin was effective in CRC, leading to cell death via Beclin1-independent autophagy, suggesting that SbE treatment in combination with cisplatin has a potential as a chemotherapeutic agent in cisplatin-resistant ovarian cancer.
卵巢癌是全球女性主要死因之一。顺铂是治疗卵巢癌的一线抗癌药物，但治疗后复发肿瘤常表现出获得性化疗耐药。黄芩提取物（SbE）据报道含有包括黄芩苷在内的具有抗癌作用的功能性化合物。然而，SbE在卵巢癌中的抗癌作用及其潜在机制尚不清楚。
我们研究了SbE和/或顺铂对顺铂敏感的卵巢癌细胞系A2780（CSC）和具有顺铂耐药性的对应细胞系（CRC）细胞死亡的影响。研究了以细胞凋亡和自噬为重点的作用分子机制。
顺铂或SbE处理显著降低了CSC中的细胞活力，而在CRC中的降低程度则小得多。顺铂诱导CSC中的细胞死亡是由p53诱导的细胞凋亡介导的，并伴有损伤调节自噬调节剂（DRAM）的表达。在CRC中，DRAM表达降低（p<0.01）阻碍了p21介导的细胞死亡并导致顺铂耐药。SbE处理也通过p53依赖性细胞凋亡在CSC中诱导细胞死亡，但在CRC中则不然。顺铂和SbE均未诱导自噬。有趣的是，SbE与顺铂联合处理显著降低了CRC中的细胞活力。细胞死亡是由自噬介导的，Atg5和Atg12表达增加（p<0.05），而不是通过HDAC1激活导致p21表达受抑制（p<0.001）的p53依赖性途径。
SbE与顺铂联合治疗对CRC有效，通过不依赖Beclin1的自噬导致细胞死亡，表明SbE与顺铂联合治疗在顺铂耐药卵巢癌中具有作为化疗药物的潜力。
