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

Andrew  K. Kwegyir-Afful; Senthilmurugan Ramalingam; Vidya  P. Ramamurthy; Puranik Purushottamachar; Francis  N. Murigi; Tadas  S. Vasaitis; Weiliang Huang; Maureen  A. Kane; Yuji Zhang; Nicholas Ambulos; Sudhir Tiwari; Pratima Srivastava; Ivo  P. Nnane; Arif Hussain; Yun Qiu; David  J. Weber; Vincent  C. O. Njar

doi:10.3390/cancers11111637

Cancers (Oct 2019)

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

Andrew K. Kwegyir-Afful,
Senthilmurugan Ramalingam,
Vidya P. Ramamurthy,
Puranik Purushottamachar,
Francis N. Murigi,
Tadas S. Vasaitis,
Weiliang Huang,
Maureen A. Kane,
Yuji Zhang,
Nicholas Ambulos,
Sudhir Tiwari,
Pratima Srivastava,
Ivo P. Nnane,
Arif Hussain,
Yun Qiu,
David J. Weber,
Vincent C. O. Njar

Affiliations

Andrew K. Kwegyir-Afful: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA
Senthilmurugan Ramalingam: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA
Vidya P. Ramamurthy: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA
Puranik Purushottamachar: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA
Francis N. Murigi: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA
Tadas S. Vasaitis: Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, 207 Somerset Hall, Princess Anne, MD 21853, USA
Weiliang Huang: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA
Maureen A. Kane: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA
Yuji Zhang: Division of Biostatistics and Bioinformatics, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
Nicholas Ambulos: Department of Microbiology and Immunology and University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
Sudhir Tiwari: DMPK (Biology Division), GVK BIO, Nacharam, Hyderabad 500076, India
Pratima Srivastava: DMPK (Biology Division), GVK BIO, Nacharam, Hyderabad 500076, India
Ivo P. Nnane: Janssen Research & Development, Spring House, PA 19477, USA
Arif Hussain: Veterans Affairs Medical Center, Baltimore, MD 21201, USA
Yun Qiu: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA
David J. Weber: Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA
Vincent C. O. Njar: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA

DOI: https://doi.org/10.3390/cancers11111637
Journal volume & issue: Vol. 11, no. 11
p. 1637

Abstract

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These 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.

Published in Cancers

ISSN: 2072-6694 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.mdpi.com/journal/cancers/

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