Zhijun Wang1,2, Steven Yeung3, Shanchao Yang4, Ying Huang3, Moses Sing Sum Chow5. 1. Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, U.S.A.; zwang@ketchum.edu mchow@westernu.edu. 2. Department of Pharmaceutical Sciences, College of Pharmacy, Marshall B. Ketchum University, Fullerton, CA, U.S.A. 3. Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, U.S.A. 4. Department of Pharmacy Practice and Administration, College of Pharmacy, Western University of Health Sciences, Pomona, CA, U.S.A. 5. Department of Pharmacy Practice and Administration, College of Pharmacy, Western University of Health Sciences, Pomona, CA, U.S.A. zwang@ketchum.edu mchow@westernu.edu.
Abstract
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. MATERIALS AND METHODS: 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. RESULTS: Among the six components only wilforlide A significantly enhanced sensitivity to docetaxel (by reducing the IC50 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. CONCLUSION: 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.
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. MATERIALS AND METHODS: 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. RESULTS: Among the six components only wilforlide A significantly enhanced sensitivity to docetaxel (by reducing the IC50 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. CONCLUSION: 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.
Authors: James L Mohler; Emmanuel S Antonarakis; Andrew J Armstrong; Anthony V D'Amico; Brian J Davis; Tanya Dorff; James A Eastham; Charles A Enke; Thomas A Farrington; Celestia S Higano; Eric Mark Horwitz; Michael Hurwitz; Joseph E Ippolito; Christopher J Kane; Michael R Kuettel; Joshua M Lang; Jesse McKenney; George Netto; David F Penson; Elizabeth R Plimack; Julio M Pow-Sang; Thomas J Pugh; Sylvia Richey; Mack Roach; Stan Rosenfeld; Edward Schaeffer; Ahmad Shabsigh; Eric J Small; Daniel E Spratt; Sandy Srinivas; Jonathan Tward; Dorothy A Shead; Deborah A Freedman-Cass Journal: J Natl Compr Canc Netw Date: 2019-05-01 Impact factor: 11.908
Authors: William Lopez; Nhu Nguyen; Jessica Cao; Christine Eddow; K Kirk Shung; Nan Sook Lee; Mosses S S Chow Journal: Technol Cancer Res Treat Date: 2021 Jan-Dec