Reserpine inhibits DNA repair, cell proliferation, invasion and induces apoptosis in oral carcinogenesis via modulation of TGF-β signaling

Abstract

Reserpine is a natural indole alkaloid isolated from Rauwolfia serpentina and has potent antioxidant, antimicrobial, and anti-mutagenic properties. Accordingly, this study aimed to investigate the effect of reserpine on DNA repair, cell proliferation, invasion and apoptosis in 7,12-dimethylbenz[a]anthracene(DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Transforming growth factor-β (TGF-β) was found to induce Smad2, 3 and 4 phosphorylation triggering Smad3/Snail mediated DNA repair proteins and Smad2/4 nuclear translocation. In contrast, reserpine inhibits TGF-β dependent Smad2/3/4 phosphorylation, thereby blockage Smad3/Snail activation and Smad2/4 nuclear translocation. Interruption of these oncogenic signaling pathways leads to downregulating ERCC1, XPF, Ku70, DNA-PKcs, PCNA, cyclin D1, HIF-1α, IL-6, Mcl-1 and stimulates Bax, cytochrome C, Apaf-1, caspase-9, caspase-3 and PARP protein expressions. This study provides therapeutic potential of reserpine in inhibiting DNA repair, cell proliferation, and invasion while simultaneously inducing apoptosis via modulation TGF-β signals.