Overcoming chemoresistance in prostate cancer with Chinese medicine Tripterygium wilfordii via multiple mechanisms
// Zhijun Wang 1 , Ranadheer Ravula 2 , Leming Shi 3 , Yunjie Song 3 , Steven Yeung 1 , Mandy Liu 2 , Bernard Lau 1 , Jijun Hao 4 , Jeffrey Wang 2 , Christopher Wai Kei Lam 5 , Moses Sing Sum Chow 1 , Ying Huang 2 1 Center for Advancement of Drug Research and Evaluation, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA 2 Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA 3 Center 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 4 College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA, USA 5 State 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 Correspondence to: Moses Sing Sum Chow, email: firstname.lastname@example.org Ying Huang, email: email@example.com Keywords: chemotherapy, resistance, Chinese medicine, Tripterygium wilfordii, prostate cancer Received: September 24, 2015 Accepted: July 06, 2016 Published: July 28, 2016 ABSTRACT 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 IC 50 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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