Multidrug resistance (MDR) cells can be sensitized to anticancer drugs A hen treated concomitantly with chemosensitizers. In this study. chemosensitizing effects of 5,6,7.3'.4'-pentamethoxyflavone (sinensetin) and its analogs ere investigated kith respect to in vitro efficacy and structure-activity relationship. Sinensetin reversed the resistance of P-glycoprotein (P-p)-overexpressing AML-2/ 13100 to vincristine in a concentration-dependent manner. Chemosensitizing effect of sinensetin was 10- and 18-fold higher than those of 5,7.3',4'-tetramethoxyflavone and 3,7-dihydroxy-3'.4'-dimethoxyflavone, respectively. Sinensetin cytotoxicity in AML-2/ D100 was not changed by the complete inhibition of Pgp. suggesting that it is not a substrate for Pap. Flow, cytometry shocked that sinensetin increased drug accumulation in the AML-2/D100 in a concentration-dependent manner, Unlike verapamil and cyclosporin A, the maximum non-cytotoxic concentrations of sinensetin were found to decrease the P-p levels. Azidopine-binding assay showed that cyclosporin A or verapamil inhibited azidopine binding on Pgp partially but sinensetin did not, Taken together, these results suggest that sinensetin has a chemosensitizing effect in reversing Pgp-mediated MDR by increasing the intracellular accumulation of drugs without competition in a binding site of azidopine. Thus. sinensetin is anticipated as a novel and highly potent second-generation flavonoid chemosensitizer, since sinensetin has significant advantages of having a high therapeutic index. of being a non-transportable inhibitor, and of effecting no induction of Pgp. (C) 2002 Elsevier Science (USA). All rights reserved.