Effects of xanthine derivatives on the influx and efflux of doxorubicin in P388 and DOX-resistant P388 leukemia cells

Abstract

It was reported that xanthine derivatives (caffeine and 1-methyl-3-propyl-7-butylxanthine) enhanced the antitumor activity of doxorubicin (DOX) with increasing DOX concentrations in tumors in vivo in our previous papers. In addition, these actions were found to be related to the inhibitory activity toward DOX efflux from tumor cells in vitro. In this study, we searched for novel biochemical modulators of DOX among 3- n-propylxanthines with functional groups at the 1- or 7-position by using an assay system for their inhibitory effect on DOX efflux from P388 leukemia and DOX resistant P388 leukemia (P388/DOX) cells. 1-Substituted xanthines facilitated the DOX efflux from P388 cells. In contrast, among 7-substituted xanthines, XT-141 and XT-139 significantly inhibited the DOX efflux from P388 cells. In addition, XT-141 inhibited the DOX efflux from P388/DOX cells, and P-glycoprotein (P-gp) inhibitor facilitated DOX influx and inhibited DOX efflux from P388/DOX cells in a dose-dependent manner. These results indicated that the resistance of P388/DOX might depend on the over-expression of P-gp, and that XT-141 inhibited DOX efflux through its interaction with P-gp. We suspect that XT-141 is a useful biochemical modulator of DOX in DOX-resistant tumors with over-expression of P-gp in addition in DOX-sensitive tumors.