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
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 acti...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-10-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/11/11/1637 |
| id |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 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 prostate cancer castration-/drug-resistant pc cell galeterone (gal) nggas vnpp433-3β ar/ar-v7 mnk1/2 degraders mnk-eif4e/mtorc1 signaling pathways apoptosis |
| author_facet |
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 |
| author_sort |
Andrew K. Kwegyir-Afful |
| title |
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 |
| title_short |
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 |
| title_full |
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 |
| title_fullStr |
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 |
| title_full_unstemmed |
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 |
| title_sort |
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 |
| publisher |
MDPI AG |
| series |
Cancers |
| issn |
2072-6694 |
| publishDate |
2019-10-01 |
| description |
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%; <i>p</i> < 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. |
| topic |
prostate cancer castration-/drug-resistant pc cell galeterone (gal) nggas vnpp433-3β ar/ar-v7 mnk1/2 degraders mnk-eif4e/mtorc1 signaling pathways apoptosis |
| url |
https://www.mdpi.com/2072-6694/11/11/1637 |
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doaj-c13656acfccc406388a6e15ccc3065742020-11-25T02:36:18ZengMDPI AGCancers2072-66942019-10-011111163710.3390/cancers11111637cancers11111637Galeterone 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 VivoAndrew K. Kwegyir-Afful0Senthilmurugan Ramalingam1Vidya P. Ramamurthy2Puranik Purushottamachar3Francis N. Murigi4Tadas S. Vasaitis5Weiliang Huang6Maureen A. Kane7Yuji Zhang8Nicholas Ambulos9Sudhir Tiwari10Pratima Srivastava11Ivo P. Nnane12Arif Hussain13Yun Qiu14David J. Weber15Vincent C. O. Njar16Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USADepartment of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USADepartment of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USADepartment of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USADepartment of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USADepartment of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, 207 Somerset Hall, Princess Anne, MD 21853, USADepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USADepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USADivision of Biostatistics and Bioinformatics, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USADepartment of Microbiology and Immunology and University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USADMPK (Biology Division), GVK BIO, Nacharam, Hyderabad 500076, IndiaDMPK (Biology Division), GVK BIO, Nacharam, Hyderabad 500076, IndiaJanssen Research & Development, Spring House, PA 19477, USAVeterans Affairs Medical Center, Baltimore, MD 21201, USADepartment of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USACenter for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USADepartment of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USAThese 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%; <i>p</i> < 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.https://www.mdpi.com/2072-6694/11/11/1637prostate cancercastration-/drug-resistant pc cellgaleterone (gal)nggasvnpp433-3β ar/ar-v7mnk1/2 degradersmnk-eif4e/mtorc1 signaling pathwaysapoptosis |