Reversal of P-glycoprotein-mediated multidrug resistance by 5,6,7,3',4'-pentamethoxyflavone (Sinensetin).
Multidrug resistance (MDR) cells can be sensitized to anticancer drugs when treated concomitantly with chemosensitizers. In this study, chemosensitizing effects of 5,6,7,3',4'-pentamethoxyflavone (sinensetin) and its analogs were investigated with respect to in vitro efficacy and structure-activity relationship. Sinensetin reversed the resistance of P-glycoprotein (Pgp)-overexpressing AML-2/D100 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 Pgp. Flow cytometry showed 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 Pgp 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.
Kolon Central Research Park, Yongin-City, Republic of Korea. chchoi@mail.chosun.ac.kr
Cheol Hee
CH
Choi
Kyung Hoon
KH
Sun
Chun San
CS
An
Jin Cheol
JC
Yoo
Kyung Soo
KS
Hahm
In Hwa
IH
Lee
Jae Kyung
JK
Sohng
Youn Chul
YC
Kim
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D005419:Flavonoids / Q000494:pharmacology*; D006461:Hemolysis; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011794:Quercetin / Q000494:pharmacology; D020112:Rhodamine 123 / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005419:Flavonoids; D020112:Rhodamine 123; C059295:sinensetin; D011794:Quercetin