Targeting Multidrug Resistance in Cancer: Impact of Retinoids, Rexinoids, and Carotenoids on ABC Transporters

The active efflux of drugs by adenosine triphosphate (ATP)-binding cassette (ABC) trans-porters, such as multidrug resistance protein 1 (MDR1/ABCB1), multidrug resistance-associated protein 1 and 2 (MRP1/ABCC1; MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2), is a well-established mechanism contributing to multidrug resistance (MDR). Interestingly, various vitamin A-based molecules have been found to influence the expression or function of these transporters. This work investigated the current evidence on the effects of retinoids, rexinoids, and carotenoids on ABC transporters and their potential to reverse MDR. Several studies indicated that these compounds could inhibit ABC transporter activity at non-toxic concentrations, either by downregulating gene/protein expression or by directly blocking efflux function. These effects were often associated with increased chemosensitivity to several conventional anticancer agents. Overall, the degree of inhibition varied depending on several factors, including compound type and their chemical modification, dose, incubation time, treatment timing, the type of target cells, method of transporter overexpression, and coadministration with other compounds. Although particular attention was paid to elucidating the underlying mechanisms, current knowledge in this area remains limited. Moreover, extensive in vivo and clinical studies validating these findings are still lacking, emphasizing the need for further research to evaluate their translational potential.