Deinoxanthin Overcomes P‐Glycoprotein‐Mediated Multidrug Resistance in Breast Cancer Cells

Multidrug resistance (MDR) remains a critical barrier in effective cancer chemotherapy which is largely attributed to the overexpression of ATP-binding cassette (ABC) transporters. P-glycoprotein (P-gp) is the major ABC transporter which actively effluxes chemotherapeutic agents from cancer cells. In the present study, we investigated the effect of deinoxanthin (DNX), a carotenoid isolated from Deinococcus radiodurans, as a reversal agent of P-gp-mediated drug resistance. The structure of isolated DNX was confirmed using HPLC, spectroscopic analyses, and HRMS. Molecular docking studies revealed a favorable binding interaction between DNX and human P-gp. Further, functional assays demonstrated that DNX significantly enhanced intracellular accumulation of Calcein-AM in doxorubicin-resistant MCF-7 (MCF-7/DOX) cells in a concentration-dependent manner. We observed that doxorubicin (DOX) alone treatment exhibited limited cytotoxicity in P-gp overexpressing MDR cells. However, its combination with DNX markedly restored drug sensitivity, as evidenced by synergistic effects in combination index (CI) analysis. Additionally, DNX enhanced intracellular retention of DOX in the P-gp overexpressing MDR cells. The DNX-DOX combination also significantly reduced the migratory potential of MCF-7/DOX cells compared to DOX alone treatment. It has also been noticed that DNX treatment attenuated P-gp overexpression in the MDR cells. Further, DNX treatment suppressed interleukin-6 (IL-6) expression and modulates PI3K/AKT/NF-κB signaling pathway MDR cells. In conclusion, DNX significantly inhibits P-gp drug efflux activity and indirectly suppress its expression most probably, through PI3K/AKT/NF-κB signaling modulation. These findings suggest that DNX as a P-gp reversal candidate warranting further preclinical evaluation, including pharmacokinetic and in vivo studies, for the reversal of P-gp-mediated multidrug resistance in cancer.