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
Abstract
:1. Introduction
2. Results
2.1. Unlike Enzalutamide, Galeterone and the Lead NGGAs Show Strong In Vitro Anti-Prostate Cancer Activities in Drug-Naïve and Drug-Resistant Prostate Cancer Cell Lines
2.2. Gal and VNPP433-3β Synergize with Docetaxel (DOC) and Enzalutamide (ENZ)
2.3. Gal and NGGAs Target AR/AR-V7 and Mnk1/2-eIF4E Signaling Pathways in Drug-Naïve and Drug-Resistant Prostate Cancer Cell Lines
2.4. VNPP414 and VNPP433-3β Reverse EMT Activity, Deplete Stem Cell Like Factors and Inhibit Prostate Cancer Cells Migration and Invasion
2.5. Pharmacokinetic Parameters of VNPP414 and VNPP433-3β in Mouse are Superior to Those of Galeterone
2.6. Galeterone and the NGGAs Are More Effective Than Enzalutamide (ENZ) in Castration-Resistant Prostate Cancer CWR22Rv1 Xenograft Model
3. Discussion
4. Materials and Methods
4.1. Reagents, Compounds and Antibodies
4.2. Cell Culture
4.3. Western Blot Analysis
4.4. Cell Viability Assays MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium Bromide, Colorimetric Assay)
4.5. Combination Studies to Assess Synergy, Additivity or Antagonism
4.6. RNA Isolation and Real-Time Polymerase Chain Reaction Analysis
4.7. Cell Motility and Invasion Assay
4.8. Colony Formation Assay
4.9. Animal Study Approval
4.9.1. Pharmacokinetic Studies
4.9.2. In Vivo Anti-Tumor Studies in CWR22Rv1 CRPC Xenograft Model.
4.10. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Compounds | Dosing | AUC (0–∞) (ng.h/mL) | Cmax (ng/mL) | T1/2 (h) | F (%) |
---|---|---|---|---|---|
Galeterone | IV (1 mg/kg) | 57.90 | - | 0.17 | - |
IP (10 mg/kg) | 111.29 | 506.59 | 1.24 | 168.81 | |
PO (10 mg/kg) | 969.07 | 32.8 | 1.26 | 18.44 | |
VNPP414 | IV (1 mg/kg) | 547.43 | - | 7.48 | - |
IP (10 mg/kg) | 8601.34 | 2174.37 | 6.25 | 157.12 | |
PO (10 mg/kg) | 1030.00 | 175.40 | 4.30 | 19.35 | |
VNPP433-3β | IV (1 mg/kg) | 3469.23 | - | 14.26 | - |
IP (10 mg/kg) | 57290.45 | 2294.19 | 22.38 | 123.20 | |
PO (10 mg/kg) | 31755.01 | 706.27 | 31.19 | 49.45 |
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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.; et al. 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
Kwegyir-Afful AK, Ramalingam S, Ramamurthy VP, Purushottamachar P, Murigi FN, Vasaitis TS, Huang W, Kane MA, Zhang Y, Ambulos N, et al. 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 StyleKwegyir-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, and et al. 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