Trihydroxylated Anthocyanins Potentiate Effects of Docetaxel in Mesenchymal Triple Negative Breast Cancer Cells

Triple negative breast cancer (TNBC) presents a significant therapeutic challenge due to its poor prognosis and limited treatment options. While anthocyanins, a group of flavonoids, exhibit promising anticancer potential, their structure-activity relationship and adjuvant properties in TNBC remain underexplored. This study evaluated the anti-proliferative effects of five structurally distinct anthocyani(di)ns-cyanidin-3-O-glucoside (C3G), delphinidin-3-O-glucoside (D3G), delphinidin-3-O-rutinoside (D3R), malvidin-3-O-glucoside (M3G), and luteolinidin (LT)-on mesenchymal TNBC cells. Combination assays of docetaxel (DT), a first-line chemotherapeutic agent, with the most potent anthocyani(di)ns were conducted with TNBC and MCF-12A non-cancerous cells. Trihydroxylated anthocyanins (D3G and D3R), particularly those with a monosaccharide at C3, demonstrated the strongest anti-proliferative effects, reducing MDA-MB-231 cell proliferation by 95% and 70%, respectively, at 400 μM (IC₅₀: 253.28 and 341.33 μM) without affecting MCF-12A cells. These were followed by 3-deoxy (LT), dihydroxylated (C3G), and O-methylated (M3G) anthocyani(di)ns. In Hs 578T mesenchymal TNBC cells, the trihydroxylated anthocyanins tested also induced strong anti-proliferative effects. Synergistic effects (combination index < 0.9) were observed for binary (D3G + DT or D3R + DT) and ternary (D3G + D3R + DT) combinations, reducing DT concentrations by up to 37-fold and anthocyanin concentrations by up to 21.9-fold to achieve similar inhibition. The ternary combination was the most effective, requiring the lowest concentrations of DT and anthocyanins. These results underscore the critical role of the ortho-trihydroxylated structure in the anti-proliferative effects of anthocyani(di)ns, highlighting trihydroxylated anthocyanins as promising adjuvants in TNBC treatment, with the potential to lower DT dosage, minimize side effects, delay resistance, and reduce treatment costs while maintaining efficacy.