Intrinsic or acquired resistance of
tumor cells to multiple cytotoxic drugs (multidrug resistance MDR) is a major cause of failure of
cancer chemotherapy. MDR is often caused by elevated expression of
drug transporters such as
P-glycoprotein (P-gp) or multidrug resistance
protein (MRP). A number of compounds, termed chemosensitizers, have little or no cytotoxic action of their own, but inhibit (P-gp) or MRP-mediated
drug export and are capable of sensitizing MDR cells to the cytotoxic effects of chemotherapeutic drugs. Here we examined the ability of steroidal
alkaloids of plant origin, namely the Veratrum sp.
alkaloid cyclopamine and the Lycopersicon sp.
alkaloid tomatidine, to act as potent and effective chemosensitizers in multidrug resistant
tumor cells.
Drug uptake was determined by measuring accumulation of
tetramethylrosamine in multidrug resistant NCI AdrR human
adenocarcinoma cells. Resistance to
adriamycin and
vinblastine was determined by utilizing the MTT cell survival assay.
Cyclopamine and
tomatidine elevate
tetramethylrosamine uptake by NCI AdrR cells and sensitize the cells to the cytotoxic action of
adriamycin and
vinblastine. In both cases these agents are comparable in patency and efficacy to
verapamil, a reversal agent commonly used in MDR research. It is concluded that steroidal
alkaloids of plant origin act as inhibitors of P-gp-mediated
drug transport and multidrug resistance and therefore may serve as chemosensitizers in
combination chemotherapy with conventional cytotoxic drugs for treating multidrug resistant
cancer.