Targeting Drug Resistance in Cancer: Dimethoxycurcumin as a Functional Antioxidant Targeting ABCC3

The development of new anticancer therapies remains challenging due to tumor heterogeneity and the frequent emergence of multidrug resistance (MDR). Natural products have garnered increasing attention as alternative or complementary therapeutic agents due to their bioactivity and reduced toxicity. Polyphenols, particularly curcumin and its derivatives, have shown potential in modulating signaling pathways, enhancing chemosensitivity, and overcoming drug resistance. In this study, we discovered the anticancer potential of Dimethoxycurcumin, a synthetic curcumin analog identified through consensus fingerprint similarity screening. Focusing on the ATP-binding cassette (ABC) transporter family—key mediators of drug efflux—we examined the impact of Dimethoxycurcumin on ABCC3 (MRP3), a transporter implicated in tumor cell survival and resistance. Our in vitro experiments demonstrated that Dimethoxycurcumin significantly reduced cell viability and colony formation, indicating a strong inhibitory effect on ABCC3 function. These results suggest that Dimethoxycurcumin may sensitize cancer cells to chemotherapy by targeting resistance pathways. This study supports the therapeutic value of plant-derived compounds and their derivatives in oncology and contributes to a better understanding of how functional antioxidants may interact with MDR-related transporters. Targeting ABC transporters with natural compound derivatives may offer a promising strategy for developing more effective and less toxic anticancer therapies.