Effects of various methoxyflavones on vincristine uptake and multidrug resistance to vincristine in P-gp-overexpressing K562/ADM cells.

PURPOSE

Some methoxyflavones (MFs) are known to inhibit the function of P-glycoprotein. The aim of this study is to characterize the reversal of multidrug resistance (MDR) by MFs.

METHODS

The effects of 19 MFs, including 3,5,6,7,8,3',4'-heptamethoxyflavone, nobiletin, and tangeretin, and flavone on the uptake of [3H]vincristine into an adriamycin-resistant variant of human chronic myelogenous leukemia (K562/ADM) cells were investigated. Potentiation of vincristine-induced growth inhibition by these MFs was also tested in K562/ADM cells by means of WST-1 [2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium] assay.

RESULTS

All MFs (20 microM) tested increased the uptake of [3H]vincristine. 3,5,6,7,8,3',4'-heptamethoxyflavone, nobiletin, tangeretin, quercetagetin and quercetin pentamethylether showed especially potent effects. The increase in the uptake of [3H]vincristine was proportional to the number of methoxyl moieties. While substitution with a methoxyl moiety at the C3 position was the most influential, methoxyl substitution at both the C3' and C5' positions resulted in a decrease in the potentiation of uptake. Furthermore, there was a significant correlation between the potencies for increasing [3H]vincristine uptake and for growth inhibition assessed by WST-1 assay.

CONCLUSIONS

MFs increased the uptake of [3H]vincristine into MDR cells and exhibited MDR-reversing effects. Their potencies were influenced by the number and positions of the methoxyl moieties.