Inhibition of Wnt/beta-catenin Signaling Induces Greater Susceptibility to Therapies in Castration Resistant Prostate Cancer
Introduction: Castration resistant prostate cancer is a progression of prostate cancer that results when cancer cells develop mechanisms that enable them to stimulate their own androgen receptors.1 It is estimated about 10-20% of prostate cancers will progress to CRPC and the estimated mean survival of CRPC patients is between 9 to 36 months.2 Right now, the gold standard of care for prostate cancer is androgen deprivation therapy.3 The resumed expression of multiple androgen receptor-regulated genes in CRPC allows continued tumor growth and survival thus rendering androgen deprivation therapy useless.1 The main treatment for CRPC patients is Enzalutamide which competitively inhibits androgens and prevents them from binding to the androgen receptor in cancer cells.4 However, over time resistance has become prevalent to it and therefore has greatly diminished its therapeutic efficacy. Methods: One study had MR49F and C4-2R prostate cancer cells with elevated Wnt/b-catenin levels and Enzalutamide resistance were treated with ICG001 (Wnt/b-catenin pathway inhibitor) and/or Enzalutamide to determine efficacy of combined treatment. Another study had mice induced with resistant prostate cancer and divided into groups receiving Enzalutamide, ICG001, or combined therapy for 3 weeks. A third study treated one group of prostate cancer stem cells with capsaicin (inhibit Wnt/b-catenin pathway) against another group of prostate cancer stem cells treated with LiCl (activate Wnt/b-catenin pathway). Results: Cell viability and colony formation showed a greater decrease in cancer cell growth with combination therapy of Enzalutamide and ICG001 compared to Enzalutamide or the inhibitor alone.1 Tumor volume in Enzalutamide treatment alone showed no statistical difference from control group due to conferred resistance, while combination treatment resulted in synergistic decreased tumor volume.1 Results of Western blot data in the third study show that inhibition of Wnt/b-catenin pathway yields lower viability of prostate cancer stem cells compared to prostate cancer stem cells that had an active Wnt/b-catenin pathway.8 Conclusions: Studies showed that activation of the Wnt/b-catenin pathway in Enzalutamide sensitive cells leads to drug resistance, however, combination of b-catenin inhibitor with Enzalutamide resensitized resistant prostate cancer cells to the therapeutic effects of Enzalutamide.
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