Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, U.S.A.;
Department of Pharmaceutical Sciences, College of Pharmacy, Marshall B. Ketchum University, Fullerton, CA, U.S.A.
In Vivo. 2022 Sep-Oct;36(5):2020-2031. doi: 10.21873/invivo.12928.
BACKGROUND/AIM: Prostate cancer is currently the second most common cancer in men and chemotherapy is the main treatment for metastatic castrate-resistant prostate cancers (mCRPC). However, chemoresistance leading to treatment failure is inevitable. Thus, therapeutic approaches that can overcome chemoresistance are important areas of research for cancer chemotherapy.
In the present study, six components of tripterygium wilfordii including celastrol, triptolide, pristimerin, triptonide, demethylzeylasteral, and wilforlide A were screened for their chemosensitizing effect on drug-resistant prostate cancer cell lines PC3 and DU145. The most active compound was further investigated on its potential mechanism of action and in vivo efficacy using a SCID mouse model.
Among the six components only wilforlide A significantly enhanced sensitivity to docetaxel (by reducing the IC in resistant prostate cancer cell lines). Wilforlide A inhibited P-glycoprotein efflux transporter and downregulated cyclin E2 splice variant 1 mRNA, both have been known as mechanisms of resistance. The chemosensitizing effect was further verified using a xenograft mouse model. In the high-dose treatment group, the combination of wilforlide A and docetaxel significantly retarded tumor growth of resistant prostate cancer, although neither docetaxel nor wilforlide A monotreatment groups showed any effect.
Wilforlide A was found to enhance the chemosensitizing effect of docetaxel both in vitro and in vivo. Further studies are warranted to verify wilforlide A as a new drug candidate to overcome docetaxel resistance in prostate cancer.
背景/目的：前列腺癌是目前男性中第二常见的癌症，化疗是治疗转移性去势抵抗性前列腺癌（mCRPC）的主要方法。然而，导致治疗失败的化疗耐药性是不可避免的。因此，能够克服化疗耐药性的治疗方法是癌症化疗的重要研究领域。
在本研究中，筛选了雷公藤的 6 种成分（包括雷公藤红素、雷公藤内酯甲、白瑞香素、雷公藤丙素、去甲基泽拉木醛和雷公藤内酯 A），以研究它们对耐药前列腺癌细胞系 PC3 和 DU145 的化疗增敏作用。对最有效的化合物进行了进一步研究，以确定其在 SCID 小鼠模型中的潜在作用机制和体内疗效。
在这 6 种成分中，只有雷公藤内酯 A 能显著增强多西他赛对耐药前列腺癌细胞系的敏感性（通过降低 IC 值）。雷公藤内酯 A 抑制了 P-糖蛋白外排转运体，并下调了细胞周期蛋白 E2 剪接变体 1 mRNA，这两者都被认为是耐药的机制。该增敏作用在异种移植小鼠模型中得到了进一步验证。在高剂量治疗组中，雷公藤内酯 A 与多西他赛联合使用显著抑制了耐药前列腺癌的肿瘤生长，尽管多西他赛和雷公藤内酯 A 单药治疗组均无效果。
发现雷公藤内酯 A 能增强多西他赛在体内外的化疗增敏作用。需要进一步的研究来验证雷公藤内酯 A 作为一种克服前列腺癌多西他赛耐药的新药候选物。
