Pterostilbene Combined with Histone Deacetylase Inhibitor Attenuates Prostate Cancer Progression In Vitro and In Vivo

• Main Author: Butt, Nasir A
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01.01.2017
• Subjects: Alternative Medicine; Cancer; Oncology; Pharmacology; Therapy
• ISBN: 9780355819052; 0355819058

Metastasis-associated protein 1(MTA1) is a cancer progression-related epigenetic regulator, which is overexpressed in hormone-refractory and metastatic prostate cancer (PCa). MTA1 is a part of the multi-protein nucleosome remodeling and deacetylation (NuRD) complex. In previous studies, MTA1 expression was reported to be significantly increased in a prostate-specific Pten -null model, and that potent natural analog of resveratrol, pterostilbene (Pter), exerts its antitumorigenic effects by blocking MTA1-associated inactivation (deacetylation) of tumor suppressors. SAHA (suberoylanilide hydroxamine) is a clinically approved histone deacetylase (HDAC) inhibitor that has been shown to be effective in repressing tumor cell growth. Hypothesis: We hypothesize that targeting the MTA1/HDAC unit of the NuRD complex using Pter in combination with SAHA will block prostate tumor progression with higher efficacy and lower toxicity than either drug alone. Methods: Twenty-seven prostate-specific luciferase expressing Pten knockout (Pten f/f., Rosa26 Luc/+; Pb-Cre4) male mice were randomized into four groups: Vehicle control (10% DMSO); Pter (10 mg/kg bodyweight [bw]), SAHA (50 mg/kg bw), and Pter + SAHA. Compounds were injected daily intraperitoneally (ip), starting at 8 weeks of age. Prostate-specific luciferase expression allowed non-invasive monitoring of prostate tumor growth in these animals. Mice were sacrificed at week 18. LNCaP and PC3M prostate cancer cells were used for in vitro functional assays. Results: Histopathological (H&E, SMA, CK-8) and immunohistochemical (Ki-67, cleaved caspase-3, CD31) evaluation of prostate tissues showed a 90% (p<0.0001) reduction in proliferation, an 80% (p<0.0001) reduction in angiogenesis, and a 10-fold (p<0.0001) increase in apoptosis when comparing combination therapy to the control group. Molecular analysis (MTA1, HIF-lα, p27, and AcH3) via western blotting and qPCR also showed combination treatment to be more effective than single therapy in our animal model. Similar effects were observed in PCa cell lines with combination therapy showing a significant inhibition of cell viability (p<0.0001) compared to control. Molecular analysis in vitro also validated the effectiveness of combination therapy over vehicle or single treatments. Conclusion: Our findings support future studies of phytochemicals in combination with standard treatments to assess the effects of these approaches on tumor initiation and progression.