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.

Chalcones, potential anticancer agents, have shown promise in the suppression of multidrug resistance due to the inhibition of drug efflux driven by certain adenosine triphosphate (ATP)-binding cassette (ABC) transporters. The gene and protein expression of chosen ABC transporters (multidrug resistance protein 1, ABCB1; multidrug resistance-associated protein 1, ABCC1; and breast cancer resistance protein, ABCG2) in human colorectal cancer cells (COLO 205 and COLO 320, which overexpress active ABCB1) was mainly studied in this work under the influence of a novel synthetic acridine-based chalcone, 1C. While gene expression dropped just at 24 h, compound 1C selectively suppressed colorectal cancer cell growth and greatly lowered ABCB1 protein levels in COLO 320 cells at 24, 48, and 72 h. It also reduced ABCC1 protein levels after 48 h. Molecular docking and ATPase tests show that 1C probably acts as an allosteric modulator of ABCB1. It also lowered galectin-1 (GAL1) expression in COLO 205 cells at 24 h. Functional tests on COLO cells revealed ABCB1 and ABCC1/2 to be major contributors to multidrug resistance in both. Overall, 1C transiently lowered GAL1 in COLO 205 while affecting important functional ABC transporters, mostly ABCB1 and to a lesser extent ABCC1 in COLO 320 cells. COLO 320’s absence of GAL1 expression points to a possible yet unknown interaction between GAL1 and ABCB1.