Linh N K Tran1,2, Ganessan Kichenadasse3, Katherine L Morel3, Tina C Lavranos4, Sonja Klebe5, Karen M Lower6, Rebecca J Ormsby3, David J Elliot7, Pamela J Sykes3. 1. Flinders Centre for Innovation in Cancer, Flinders University and Medical Centre, Adelaide, South Australia khaclinh@gmail.com linh.tran@flinders.edu.au khaclinh@ump.edu.vn. 2. University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh, Vietnam. 3. Flinders Centre for Innovation in Cancer, Flinders University and Medical Centre, Adelaide, South Australia. 4. Bionomics Ltd, Thebarton, South Australia. 5. Department of Anatomical Pathology, Flinders University and Medical Centre, Adelaide, South Australia. 6. Molecular Medicine and Pathology, Flinders University and Medical Centre, Adelaide, South Australia. 7. Clinical Pharmacology, Flinders University and Medical Centre, Bedford Park, Adelaide, South Australia.
Abstract
BACKGROUND/AIM: The hypoglycemic drug metformin (MET) and the anti-epileptic drug valproic acid (VPA) have individually shown anti-tumor effects in prostate cancer in vitro. The present study intended to investigate the efficacy of the combination of MET and VPA in prostate cancer treatment in a pre-clinical xenograft model. MATERIALS AND METHODS: Prostate cancer cell lines (LNCaP and PC-3) were inoculated under the skin of BALB/c nude mice. The mice were treated with 200 μl/ml MET and/or 0.4% (w/v) VPA diluted in drinking water, or with vehicle control, and were monitored until the tumor volume reached 2,000 mm3 Evaluation of toxicity of the drug combination was determined in liver and kidney by histology. RESULTS: In both LNCaP and PC-3 xenografts, MET combined with VPA significantly reduced tumor growth during the first 4 weeks following treatment, and delayed the time-to-tumor volume of 2,000 mm3 by 90 days, as compared to MET or to VPA alone, and to vehicle control. There was no significant difference in total mouse weight, liver or kidney morphology in response to combination treatment (MET+VPA) compared to MET or VPA alone and vehicle control. CONCLUSION: The combination treatment of MET with VPA is more effective at slowing prostate tumor growth in vivo compared to either drug alone, in mouse xenografts. These pre-clinical results support previous in vitro data and also demonstrate the low toxicity of the combination of these drugs, suggesting that this may be a potential new therapy to be investigated in clinical trials for prostate cancer. Copyright
BACKGROUND/AIM: The hypoglycemic drug metformin (MET) and the anti-epileptic drug valproic acid (VPA) have individually shown anti-tumor effects in prostate cancer in vitro. The present study intended to investigate the efficacy of the combination of MET and VPA in prostate cancer treatment in a pre-clinical xenograft model. MATERIALS AND METHODS:Prostate cancer cell lines (LNCaP and PC-3) were inoculated under the skin of BALB/c nude mice. The mice were treated with 200 μl/ml MET and/or 0.4% (w/v) VPA diluted in drinking water, or with vehicle control, and were monitored until the tumor volume reached 2,000 mm3 Evaluation of toxicity of the drug combination was determined in liver and kidney by histology. RESULTS: In both LNCaP and PC-3 xenografts, MET combined with VPA significantly reduced tumor growth during the first 4 weeks following treatment, and delayed the time-to-tumor volume of 2,000 mm3 by 90 days, as compared to MET or to VPA alone, and to vehicle control. There was no significant difference in total mouse weight, liver or kidney morphology in response to combination treatment (MET+VPA) compared to MET or VPA alone and vehicle control. CONCLUSION: The combination treatment of MET with VPA is more effective at slowing prostate tumor growth in vivo compared to either drug alone, in mouse xenografts. These pre-clinical results support previous in vitro data and also demonstrate the low toxicity of the combination of these drugs, suggesting that this may be a potential new therapy to be investigated in clinical trials for prostate cancer. Copyright