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

Area of Science:

• Oncology
• Pharmacology
• Cancer Therapeutics

Background:

• Triple-negative breast cancer (TNBC) presents significant clinical challenges due to its aggressiveness and lack of targeted treatments.
• Current treatment strategies require combination therapies that enhance efficacy and allow for dose reduction.
• Cisplatin and digitoxin are anticancer agents with limitations including resistance and toxicity.

Purpose of the Study:

• To investigate the synergistic interaction between digitoxin and cisplatin in TNBC cells.
• To identify the most synergistic area (MSA) for this drug combination.
• To evaluate the dose-sparing potential of digitoxin when combined with cisplatin.

Main Methods:

• Utilized checkerboard and fixed-ratio designs to profile digitoxin-cisplatin effects in MDA-MB-231 TNBC cells.
• Quantified drug interaction using Chou-Talalay combination index (CI) and dose-reduction index (DRI) via CompuSyn.
• Employed multiple matrix models (Bliss, Loewe, ZIP, HSA) in SynergyFinder to confirm synergistic effects.

Main Results:

• Chou-Talalay analysis revealed synergy across all tested ratios, with the strongest interaction at a 1:200 digitoxin/cisplatin ratio (CI = 0.30 at ED97).
• Dose-reduction analysis indicated up to a 27-fold reduction in cisplatin dosage was possible at a 1:25 ratio (ED97).
• Matrix models confirmed synergy, identifying the MSA at 31.25 nM digitoxin and 6.25 µM cisplatin.

Conclusions:

• A robust synergistic interaction exists between digitoxin and cisplatin in MDA-MB-231 TNBC cells.
• The identified dosing window maximizes cytotoxic effects while offering potential for reduced cisplatin exposure.
• This combination therapy presents a promising strategy for managing triple-negative breast cancer.