Sulfonylated Goniothalamin and Piplartine Derivatives Exhibit Selective Antiproliferative Activity on Breast Cancer Cells via Oxidative Stress-Mediated Mechanisms.

Breast cancer is a highly heterogeneous and treatment-resistant malignancy, underscoring the urgent need for novel therapeutic strategies. In this study, we investigated the antitumor potential of sulfonylated derivatives of goniothalamin (compound 3) and piplartine (compound 6) using the MCF-7 human breast cancer cell line as a study model. Both compounds significantly reduced cell viability of MCF-7 cells, with half-maximal inhibitory concentrations (IC50) of 20 μM (compound 3) and 7 μM (compound 6). These compounds were highly selective toward tumor cells (MCF-7) compared with nontumor cells (primary fibroblasts). Investigation of the mechanism of action revealed that both compounds exhibit pro-oxidant activity on tumor cells, contributing to DNA damage and cell cycle arrest. Key cell-cycle regulators, such as cyclins B and D, p21, and MYC, were modulated by the treatments. Interestingly, compound 3 induced cellular senescence, whereas compound 6 primarily triggered apoptosis. The expression profile of pro-apoptotic BAX and antiapoptotic BCL2 genes was also modulated by compound 6. These findings suggest that the antitumor effects of compounds 3 and 6 are mediated by oxidative stress-induced DNA damage, leading to activation of senescence or apoptotic pathways. These results support further in vivo studies to validate the antitumor potential of sulfonylated derivatives of GNT and PPT in breast cancer.