Next Article in Journal
Clinical Significance of Various Drug-Sensitivity Markers in Patients with Surgically Resected Pulmonary Pleomorphic Carcinoma
Next Article in Special Issue
Therapeutic Inducers of Apoptosis in Ovarian Cancer
Previous Article in Journal
SLUG Directs the Precursor State of Human Brain Tumor Stem Cells
Previous Article in Special Issue
Understanding and Targeting Apoptotic Pathways in Ovarian Cancer
Article

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

1
Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA
2
Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA
3
Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, 207 Somerset Hall, Princess Anne, MD 21853, USA
4
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA
5
Division of Biostatistics and Bioinformatics, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
6
Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA
7
Department of Microbiology and Immunology and University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
8
DMPK (Biology Division), GVK BIO, Nacharam, Hyderabad 500076, India
9
Janssen Research & Development, Spring House, PA 19477, USA
10
Veterans Affairs Medical Center, Baltimore, MD 21201, USA
11
Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA
12
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
*
Author to whom correspondence should be addressed.
Current Address: Toxicology Team (HFV-153), Division of food Safety, Office of Veterinary Medicine, U.S. Food and Drug Administration, Laurel, MD 20708, USA.
Current Address: Division of Hematologic Malignancies, Cellular Therapy, Duke Cancer Institute DUMC 3961, 2400 Pratt St, Durham, NC 27710, USA.
Cancers 2019, 11(11), 1637; https://doi.org/10.3390/cancers11111637
Received: 2 September 2019 / Revised: 3 October 2019 / Accepted: 18 October 2019 / Published: 24 October 2019
(This article belongs to the Special Issue Apoptosis in Cancer)
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. View Full-Text
Keywords: prostate cancer; castration-/drug-resistant PC cell; galeterone (Gal); NGGAs; VNPP433-3β AR/AR-V7; Mnk1/2 degraders; Mnk-eIF4E/mTORC1 signaling pathways; apoptosis prostate cancer; castration-/drug-resistant PC cell; galeterone (Gal); NGGAs; VNPP433-3β AR/AR-V7; Mnk1/2 degraders; Mnk-eIF4E/mTORC1 signaling pathways; apoptosis
Show Figures

Graphical abstract

MDPI and ACS Style

Kwegyir-Afful, A.K.; Ramalingam, S.; Ramamurthy, V.P.; Purushottamachar, P.; Murigi, F.N.; Vasaitis, T.S.; Huang, W.; Kane, M.A.; Zhang, Y.; Ambulos, N.; Tiwari, S.; Srivastava, P.; Nnane, I.P.; Hussain, A.; Qiu, Y.; Weber, D.J.; Njar, V.C.O. 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. Cancers 2019, 11, 1637. https://doi.org/10.3390/cancers11111637

AMA Style

Kwegyir-Afful AK, Ramalingam S, Ramamurthy VP, Purushottamachar P, Murigi FN, Vasaitis TS, Huang W, Kane MA, Zhang Y, Ambulos N, Tiwari S, Srivastava P, Nnane IP, Hussain A, Qiu Y, Weber DJ, Njar VCO. 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. Cancers. 2019; 11(11):1637. https://doi.org/10.3390/cancers11111637

Chicago/Turabian Style

Kwegyir-Afful, Andrew K., 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, and Vincent C.O. Njar 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" Cancers 11, no. 11: 1637. https://doi.org/10.3390/cancers11111637

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop