title: Overcoming chemoresistance in prostate cancer with Chinese medicine Tripterygium wilfordii via multiple mechanisms.
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 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.
authors.affiliation: Center for Advancement of Drug Research and Evaluation, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA.
authors.forename: Ranadheer
authors.initials: R
authors.lastname: Ravula
authors.affiliation: 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.
authors.forename: Leming
authors.initials: L
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Song
authors.affiliation: Center for Advancement of Drug Research and Evaluation, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Yeung
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA.
authors.forename: Mandy
authors.initials: M
authors.lastname: Liu
authors.affiliation: Center for Advancement of Drug Research and Evaluation, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Lau
authors.affiliation: College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA, USA.
authors.forename: Jijun
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Christopher Wai Kei
authors.initials: CW
authors.lastname: Lam
authors.affiliation: Center for Advancement of Drug Research and Evaluation, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA.
authors.forename: Moses Sing Sum
authors.initials: MS
authors.lastname: Chow
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D018938:Caco-2 Cells; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D003630:Daunorubicin / Q000737:chemistry; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010936:Plant Extracts / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology; D029757:Tripterygium / Q000737:chemistry*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004365:Drugs, Chinese Herbal; D010936:Plant Extracts; D043823:Taxoids; D000077143:Docetaxel; D003630:Daunorubicin
keywords: Chinese medicine; chemotherapy; prostate cancer; resistance; Tripterygium wilfordii