Targeting Wnt/β-catenin signaling pathway in triple-negative breast cancer by benzylic organotrisulfides: Contribution of the released hydrogen sulfide towards potent anti-cancer activity.

The potent anti-cancer activity of naturally occurring organopolysulfides has attracted wide research attention over the last two decades. Sustained donation of hydrogen sulfide (HS) from organopolysulfides is found to be beneficial for the treatment of several organ-specific cancers. In the present study, for the first time, the mechanism of action for the potent anti-cancer activity of bis(3,5-dimethoxybenzyl) trisulfide 4 against highly aggressive triple-negative breast cancer cells (MDA-MB-231) is described. Preliminary in vitro studies revealed potent anti-proliferative activity of the trisulfide 4 against triple-negative breast cancer cells with an IC value of 1.0 μM. Mechanistic studies reveal that the compound exhibited anti-cancer activity, primarily by targeting and suppressing the Wnt/β-catenin signaling pathway. The inactivation of the β-catenin level was associated with the cell cycle arrest in the G2/M phase and the significant down-regulation of downstream signaling genes such as Cyclin D1 and c-Myc expression. Several control experiments with analogous organosulfur compounds and the key enzyme inhibitors reveal that the presence of a trisulfide unit in the compound is crucial for the desired inactivation of β-catenin expression, which is promoted by GSK-3β-induced phosphorylation of β-catenin and its proteasomal degradation. Moreover, the trisulfide unit or the released HS induced down-regulation of the p53 expression with the possible S-sulfhydration process led to p53-independent up-regulation of p21 expression. Therefore, the key results of this study highlighting the potency of synthetic benzylic organotrisulfide and the released HS towards the growth inhibition of triple-negative breast cancer via Wnt/β-catenin signaling pathway would certainly be helpful for further studies and developing small-molecule anti-cancer therapeutics in future.