Galeterone and the next generation galeterone analogs, VNPP414 and VNPP433-3β exert potent therapeutic effects in castration-/drug-resistant prostate cancer preclinical models in vitro and in vivo
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AbstractThese studies compared the efficacies of our clinical agent galeterone (Gal) and the FDA-approved prostate cancer drug, enzalutamide (ENZ) with two lead next generation galeterone analogs (NGGAs), VNPP414 and VNPP433-3β, using prostate cancer (PC) in vitro and in vivo models. Antitumor activities of orally administered agents were also assessed in CWR22Rv1 tumor-bearing mice. We demonstrated that Gal and NGGAs degraded AR/AR-V7 and Mnk1/2; blocked cell cycle progression and proliferation of human PC cells; induced apoptosis; inhibited cell migration, invasion, and putative stem cell markers; and reversed the expression of epithelial-to-mesenchymal transition (EMT). In addition, Gal/NGGAs (alone or in combination) also inhibited the growth of ENZ-, docetaxel-, and mitoxantrone-resistant human PC cell lines. The NGGAs exhibited improved pharmacokinetic profiles over Gal in mice. Importantly, in vivo testing showed that VNPP433-3β (at 7.53-fold lower equimolar dose than Gal) markedly suppressed (84% vs. Gal, 47%; p < 0.01) the growth of castration-resistant PC (CRPC) CWR22Rv1 xenograft tumors, with no apparent host toxicity. ENZ was ineffective in this CRPC xenograft model. In summary, our findings show that targeting AR/AR-V7 and Mnk1/2 for degradation represents an effective therapeutic strategy for PC/CRPC treatment and supports further development of VNPP433-3β towards clinical investigation. Copyright 2019 by the authors.
SponsorsThis work was supported in part by a grant from the National Institutes of Health (NIH) and the National Cancer Institute (NCI) (R01CA224696), start-up funds from University of Maryland School of Medicine (UMSOM) and the Center for Biomolecular Therapeutics (CBT), Baltimore, MD, USA to V.C.O.N., Merit Review Award (101 BX000545) Medical Research Service, Department of Veterans Affairs to A.H., NIH (R01CA106504) and VA (I01 BX004160/BX/BLRD) to Y.Q. and Marlene and Stewart Greenebaum Comprehensive Cancer Center (MSGCCC; Philanthropic Funds), Baltimore, MD, USA to A.H., Y.Q. and V.C.O.N.
Castration-/drug-resistant PC cell
Mnk-eIF4E/mTORC1 Signaling pathways
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85074236077&doi=10.3390%2fcancers11111637&partnerID=40&md5=d6d56eec5f73a53010597c442932d471; http://hdl.handle.net/10713/11404