Overcoming chemoresistance in prostate cancer with Chinese medicine Tripterygium wilfordii via multiple mechanisms
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Zhijun Wang1, Ranadheer Ravula2, Leming Shi3, Yunjie Song3, Steven Yeung1, Mandy Liu2, Bernard Lau1, Jijun Hao4, Jeffrey Wang2, Christopher Wai Kei Lam5, Moses Sing Sum Chow1, Ying Huang2
1Center for Advancement of Drug Research and Evaluation, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA
2Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA
3Center for Pharmacogenomics, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Schools of Life Sciences and Pharmacy, Fudan University, Shanghai, China
4College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA, USA
5State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau
Moses Sing Sum Chow, email: [email protected]
Ying Huang, email: [email protected]
Keywords: chemotherapy, resistance, Chinese medicine, Tripterygium wilfordii, prostate cancer
Received: September 24, 2015 Accepted: July 06, 2016 Published: July 28, 2016
A leading cause of cancer chemotherapy failure is chemoresistance, which often involves multiple mechanisms. Chinese medicines (CM) usually contain multiple components which could potentially target many mechanisms simultaneously and may offer an advantage over single compounds that target one mechanism at a time. The purpose of this study was to investigate the chemosensitizing effect (CE) of a specific CM, Tripterygium wilfordii (TW), on prostate cancer cells resistant to docetaxel (Dtx) and identify the potential mechanisms. The CE of TW (in combination with Dtx) was evaluated in two Dtx resistant prostate cancer cell lines (PC3-TxR and DU145-TxR) and the efficacy of the combination for resistant PC3-TxR tumor was investigated using a xenograft mouse model. For mechanistic study, the inhibitory effect of TW on P-glycoprotein activity was assessed. In addition, novel gene targets of TW were identified using DNA microarray and quantitative PCR. Results showed that TW induced a CE of 8 and >38 folds in PC3-TxR and DU145-TxR cells, respectively with Dtx IC50 reversed back to that of the sensitive parent cells. An optimum dose of TW+Dtx significantly retarded tumor growth in mice compared to TW or Dtx alone. TW inhibited P-glycoprotein activity and induced a significant gene expression changes in genes related to angiogenesis, cell cycle regulation and differentiation. Our in vitro and in vivo studies demonstrate that TW in combination with Dtx was able to overcome the chemoresistance and suppress resistant prostate tumor growth via multi-mechanisms.
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