Rahmania Yusi Luluk, Renta Person Pesona, Bima Damar Nurwahyu, Lin Yu-Shan, Nguyen Ngoc Thang, Wang Pin-Yu, Suzery Meiny, Chiu Wen-Tai
Department of Biomedical Engineering, National Cheng Kung University, Tainan, 701, Taiwan.
Department of Marine Science, Faculty of Agriculture, University of Bengkulu, Bengkulu, 38371, Indonesia.
J Ovarian Res. 2025 Jun 12;18(1):129. doi: 10.1186/s13048-025-01712-4.
Ovarian cancer is a highly prevalent cancer among women with a high risk for relapse and drug resistance. Seventy eight percent of women diagnosed with ovarian cancer live for at least one year after diagnosis. Hyptolide, a natural compound, has been shown to act as an anti-inflammatory and antibacterial agent, and latest research shows that it acts as an anticancer agent. These properties indicate that hyptolide may be a potential treatment option for ovarian cancer, including chemoresistant cases; however, its effects in chemoresistant ovarian cancer have not yet been demonstrated, and the mechanisms underlying its induction of cell death remain unclear.
We found that hyptolide inhibited cell viability in ovarian cancer cell lines, regardless of their chemoresistance, and these effects were mediated by ER stress and the activation of GRP78 and ATF6. Combined treatment of cisplatin-resistant cell lines with hyptolide and cisplatin demonstrated a synergistic effect, enhancing apoptosis. Additionally, the reversal of chemoresistance with hyptolide treatment was mediated by β-catenin cytoplasm translocation leading to E-cadherin expression, ultimately promoting mesenchymal-epithelial transition.
Our findings suggest that hyptolide induces ER stress-mediated cell death and overcomes cisplatin chemoresistance in ovarian cancer cells, supporting its potential use as a chemotherapeutic agent.
卵巢癌是女性中一种高度常见的癌症，复发和耐药风险很高。78%被诊断为卵巢癌的女性在诊断后存活至少一年。Hyptolide是一种天然化合物，已被证明具有抗炎和抗菌作用，最新研究表明它还具有抗癌作用。这些特性表明Hyptolide可能是卵巢癌（包括耐药病例）的一种潜在治疗选择；然而，其在耐药性卵巢癌中的作用尚未得到证实，其诱导细胞死亡的机制仍不清楚。
我们发现Hyptolide抑制卵巢癌细胞系的细胞活力，无论其是否具有耐药性，这些作用是由内质网应激以及GRP78和ATF6的激活介导的。用Hyptolide和顺铂联合处理顺铂耐药细胞系显示出协同作用，增强了细胞凋亡。此外，Hyptolide处理导致的耐药逆转是由β-连环蛋白细胞质易位介导的，从而导致E-钙黏蛋白表达，最终促进间质-上皮转化。
我们的研究结果表明，Hyptolide诱导内质网应激介导的细胞死亡，并克服卵巢癌细胞中的顺铂耐药性，支持其作为化疗药物的潜在用途。
