Y. Lavie et al., Inhibitory effect of steroidal alkaloids on drug transport and multidrug resistance in human cancer cells, ANTICANC R, 21(2A), 2001, pp. 1189-1194
Intrinsic or acquired resistance of rumor cells to multiple cytotoxic drugs
(multidrug resistance. MDR) is a major cause of failure of cancer chemothe
rapy. 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 o
f sensitizing MDR cells to the cytotoxic effects of chemotherapeutic drugs.
Here we examined the ability of steroidal alkaloids of plant origin, namel
y the Veratrum sp. alkaloid cyclopamine and the Lycopersicon sp. alkaloid t
omatidine, to act as potent and effective chemosensitizers in multidrug res
istant tumor cells. Drug uptake was determined by measuring accumulation of
tetramethylrosamine in multidrug resistant NCI AdrR human adenocarcinoma c
ells. Resistance to adriamycin and vinblastine was determined by utilizing
the MTT cell survival assay. Cyclopamine and tomatidine elevate tetramethyl
rosamine uptake by NCI AdrR cells and sensitize the cells to the cytotoxic
action of adriamycin and vinblastine. In both cases these agents are compar
able in patency and efficacy to verapamil, a reversal agent commonly used i
n MDR research. It is concluded that steroidal alkaloids of plant origin ac
t as inhibitors of P-gp-mediated drug transport and multidrug resistance an
d therefore may serve as chemosensitizers in combination chemotherapy with
conventional cytotoxic drugs for treating multidrug resistant cancer.