Dulcitol Selectively Inhibits Proliferation and Metastasis Related Markers in Triple‐Negative Breast Cancer: Uncovering an Unforeseen Activity

Breast cancer remains the most commonly diagnosed cancer and a leading cause of cancer-related mortality among women worldwide. Despite advancements in treatment, resistance and toxicity issues highlight the urgent need for novel, effective, and safer therapeutic agents. Natural compounds are increasingly explored as promising sources of anticancer candidates due to their structural diversity and bioactivity. Among these, polyols, a class of sugar alcohols, have been reported to influence cancer cell behaviour by modulating oxidative stress, metabolic pathways and apoptosis, though their precise mechanisms and therapeutic potential remain underexplored. In this study, the anticancer potential of dulcitol, a naturally occurring polyol, was investigated in breast cancer cell lines with different molecular profiles. The cytotoxic effects of dulcitol were assessed using the MTT assay in MCF-7 (ER-positive), MDA-MB-231 (triple-negative), and MCF-10A (non-tumorigenic) breast cell lines. Mechanistic studies including flow cytometry-based cell cycle analysis, apoptosis detection (Annexin V-FITC), mitochondrial membrane potential assessment, caspase activation, and DNA damage analysis were performed on MDA-MB-231 cells. The expression levels of MMP-2 and MMP-9 genes were also evaluated using qRT-PCR. Dulcitol exhibited selective cytotoxicity against MDA-MB-231 cells at concentrations ≥ 7.5 mmol/L, while showing no significant effects on MCF-7 and MCF-10A cells. In MDA-MB-231 cells, dulcitol induced G0/G1 phase cell cycle arrest and promoted apoptosis in a dose-dependent manner. Additionally, increased caspase activity and mitochondrial depolarization were observed, indicating activation of the intrinsic apoptotic pathway. No significant DNA damage was detected; however, a significant downregulation of MMP-2 and MMP-9 expression suggested potential antimetastatic activity. Although the effective in vitro concentrations were relatively high, it should be noted that such levels are commonly required to reveal mechanistic effects in cell-based systems, and pharmacokinetic data on dulcitol are currently unavailable. Therefore, the present findings should be regarded as exploratory and hypothesis-generating, emphasizing the need for in vivo pharmacokinetic and efficacy studies to evaluate translational feasibility. In conclusion, our findings demonstrate that dulcitol selectively targets triple-negative breast cancer cells without affecting normal or ER-positive breast cells. Its ability to induce apoptosis and suppress metastatic gene expression highlights its promise as a potential natural therapeutic candidate for aggressive breast cancer subtypes.