Digitoxin as a novel synergistic partner of cisplatin in triple-negative breast cancer (TNBC) cells.

BackgroundTriple-negative breast cancer (TNBC) remains clinically challenging due to its aggressive nature, high recurrence rate, and lack of targeted therapies. To address these limitations, combination chemotherapies that synergistically enhance antitumor efficacy while permitting dose reduction and supporting dose-sparing strategies are urgently needed. Cisplatin has a broad spectrum of anticancer activity. However, its resistance and dose-limiting toxicities constrain clinical benefit. Digitoxin is a cardiac glycoside that has anticancer activity.ObjectiveWe aimed to assess the nature of interaction between digitoxin and cisplatin in TNBC cells, define the most synergistic area (MSA), and estimate dose-sparing potential.MethodsWe profiled digitoxin-cisplatin effects in MDA-MB-231 TNBC cell line by checkerboard and fixed-ratio designs, quantifying interaction with Chou-Talalay combination index/dose-reduction index by CompuSyn, and multiple matrix models by SynergyFinder.ResultsThe CI analysis demonstrated synergy across all tested ratios, with the strongest synergistic interaction at a digitoxin/cisplatin ratio of 1:200 (CI = 0.30 at ED97). Dose-reduction analysis showed up to 27-fold cisplatin sparing (ratio 1:25, ED97). Matrix-based models confirmed synergy (Bliss 6.9, Loewe 18.6, ZIP 7.1, and HSA 14), converging on MSA at 31.25 nM digitoxin and 6.25 µM cisplatin.ConclusionOur results highlight a robust synergistic interaction between digitoxin and cisplatin in MDA-MB-231 cells with a dosing window that maximizes cytotoxic effect while potentially reducing cisplatin exposure.