Withaferin A Synergizes the Therapeutic Effect of Doxorubicin through ROS-Mediated Autophagy in Ovarian Cancer

被引:96
作者
Fong, Miranda Y. [1 ]
Jin, Shunying [2 ]
Rane, Madhavi [2 ]
Singh, Raj K. [3 ]
Gupta, Ramesh [4 ,5 ]
Kakar, Sham S. [1 ,5 ]
机构
[1] Univ Louisville, Dept Physiol & Biophys, Louisville, KY 40292 USA
[2] Univ Louisville, Dept Med, Louisville, KY 40292 USA
[3] Vivo Biosci Inc, Birmingham, AL USA
[4] Univ Louisville, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA
[5] Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40292 USA
基金
美国国家卫生研究院;
关键词
INDUCED CELL-DEATH; HEPATOCELLULAR-CARCINOMA; LIPOSOMAL DOXORUBICIN; PROSTATE-CANCER; DOWN-REGULATION; UP-REGULATION; APOPTOSIS; CYTOTOXICITY; DYSFUNCTION; INHIBITION;
D O I
10.1371/journal.pone.0042265
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];
摘要
Application of doxorubicin (Dox) for the treatment of cancer is restricted due to its severe side effects. We used combination strategy by combining doxorubicin (Dox) with withaferin A (WFA) to minimize the ill effects of Dox. Treatment of various epithelial ovarian cancer cell lines (A2780, A2780/CP70 and CaOV3) with combination of WFA and Dox (WFA/DOX) showed a time- and dose-dependent synergistic effect on inhibition of cell proliferation and induction of cell death, thus reducing the dosage requirement of Dox. Combination treatment resulted in a significant enhancement of ROS production resulting in immense DNA damage, induction of autophagy analyzed by transmission electron microscope and increase in expression of autophagy marker LC3B, and culminated in cell death analyzed by cleaved caspase 3. We validated combination therapy on tumor growth using an in vitro 3Dimension (3D) tumor model and the more classic in vivo xenograft model of ovarian cancer. Both tumor models showed a 70 to 80% reduction in tumor growth compared to control or animals treated with WFA or Dox alone. Immunohistochemical analysis of the tumor tissues from animals treated with WFA/Dox combination showed a significant reduction in cell proliferation and formation of microvessels accompanied by increased in LC3B level, cleaved caspase 3, and DNA damage. Taken together, our data suggest that combining WFA with Dox decreases the dosage requirement of Dox, therefore, minimizing/eliminating the severe side effects associated with high doses of DOX, suggesting the application of this combination strategy for the treatment of ovarian and other cancers with no or minimum side effects.
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页数:16
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