Back to Search
Start Over
Carbidopa enhances antitumoral activity of bicalutamide on the androgen receptor-axis in castration-resistant prostate tumors.
- Source :
-
The Prostate [Prostate] 2012 Jun 01; Vol. 72 (8), pp. 875-85. Date of Electronic Publication: 2011 Oct 05. - Publication Year :
- 2012
-
Abstract
- Background: Response to bicalutamide after castration failure is not durable and treatment options at this stage are limited. Carbidopa, an L-dopa decarboxylase (AR-coactivator) inhibitor, has been shown to retard prostate tumor growth/PSA production in xenografts. Here, we hypothesize that pharmacological targeting of the AR-axis by combination treatment with bicalutamide plus carbidopa significantly enhances antitumoral activity in vitro and in vivo compared to monotherapy with either drug.<br />Methods: Carbidopa was tested for its ability to enhance the effects of bicalutamide on cell viability, apoptosis and PSA transactivation in LNCaP and C4-2 cells. The castration-resistant prostate cancer (CRPC) LNCaP xenograft tumor model was used in vivo. After CRPC progression, mice were treated with carbidopa (50 mg/kg) and bicalutamide (50 mg/kg) as monotherapy or in combination. Tumor volume and serum PSA were evaluated weekly.<br />Results: Combination treatment of carbidopa plus bicalutamide significantly inhibited cell viability in both cell lines and induced apoptosis. The combination treatment also decreased androgen-induced PSA transactivation by 62.6% in LNCaP cells and by 55.6% in C4-2 cells compared to control, while bicalutamide monotherapy reduced PSA levels by 27.5% and 29.1% in LNCaP and C4-2 cells. In vivo, bicalutamide monotherapy delayed LNCaP CRPC tumor growth rate by 72.2%, while combination treatment reduced tumor growth by 84.4% compared to control. Serum PSA was also reduced 70.6% with bicalutamide monotherapy, while combination therapy reduced PSA levels by 76.7% compared to control.<br />Conclusions: This study demonstrates preclinical proof-of-principle that pharmacological targeting of prostate tumors by combination treatment of bicalutamide plus carbidopa significantly reduces AR activity, and thereby delays CRPC tumor progression in vivo.<br /> (Copyright © 2011 Wiley Periodicals, Inc.)
- Subjects :
- Adenocarcinoma drug therapy
Adenocarcinoma metabolism
Anilides therapeutic use
Animals
Antineoplastic Agents therapeutic use
Apoptosis drug effects
Carbidopa therapeutic use
Cell Line, Tumor
Cell Survival drug effects
Disease Progression
Dopamine Agents pharmacology
Dopamine Agents therapeutic use
Drug Synergism
Drug Therapy, Combination
Humans
In Vitro Techniques
Male
Mice
Mice, Nude
Nitriles therapeutic use
Prostate-Specific Antigen blood
Prostatic Neoplasms drug therapy
Prostatic Neoplasms metabolism
Receptors, Androgen metabolism
Tosyl Compounds therapeutic use
Treatment Outcome
Xenograft Model Antitumor Assays
Adenocarcinoma pathology
Anilides pharmacology
Antineoplastic Agents pharmacology
Carbidopa pharmacology
Nitriles pharmacology
Orchiectomy
Prostatic Neoplasms pathology
Receptors, Androgen drug effects
Tosyl Compounds pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0045
- Volume :
- 72
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The Prostate
- Publication Type :
- Academic Journal
- Accession number :
- 22072572
- Full Text :
- https://doi.org/10.1002/pros.21490