The multidrug resistance (MDR)
proteins are member of the
ATP-binding cassette superfamily and are present in a majority of human
tumors. Their activity is a crucial factor leading to therapeutic failure. It is likely that compounds which inhibit the function of the MDR-efflux
proteins such as MDR1 will improve the cytotoxic action of anticancer
chemotherapy. Therefore, a search for MDR reversing compounds was conducted among three classes of
plant derived compounds such as
diterpenes,
triterpenes and
carotenoids in a hope to find inhibitors without adverse effects in these natural compounds. The inhibition of efflux activity was determined by measuring the accumulation of substrate analogues such as
rhodamine in
tumor cells in the presence of potential inhibitors. Thus we determined the effect of structurally unrelated
diterpenes,
triterpenes and
carotenoids on reversal of multidrug resistance in MDR-1 gene-transfected L1210 mouse
lymphoma cells and MDR mediated multidrug resistance of human
breast cancer cells MDA-MB-231 (HTB-26) and MCF-7. The majority of
diterpenes,
cycloartane triterpenes and
carotenoids isolated from vegetables and medicinal plants were able to enhance
rhodamine 123 accumulations of MDR-cells. Synergistic interaction was found between epirubicine and resistance modifier
terpenoids in vitro. It is supposed that these MDR modulators bind into transmembrane domains and the action of
ABC transporters is inhibited by induced conformational changes.