title: Reversal of doxorubicin resistance in multidrug resistant melanoma cells in vitro and in vivo by dipyridamole.
abstract: The occurrence of multidrug resistance (MDR) decreases the clinical utility of several anticancer agents, including doxorubicin (DOX). A transmembrane efflux pump, P-glycoprotein (P-gp), is frequently implicated in the development of MDR in tumor cells. Dipyridamole (DP), a clinically used antiplatelet drug, enhances the cytotoxicity of the anticancer drugs affected by MDR. Although this aspect has been studied extensively in cell culture models, the effectiveness of DP to overcome multidrug resistance has not been investigated using in vivo models of multidrug-resistant solid tumors. Therefore, the objective of this study was to evaluate the role of DP in the reversal of resistance to DOX in tumor-bearing mice in the context of its anti-MDR activity in vitro. For this purpose, drug-sensitive murine melanoma cells (B16V) and their DOX-selected MDR variant, B16VDXR cells, were used. In vitro, the reversal of DOX resistance of B16VDXR cells by DP was determined using clonogenic assays, and the influence of DP on the transport of DOX was evaluated by measurement of steady-state accumulation as well as efflux of DOX in B16VDXR cells. Antitumor activity of different treatments was assessed by monitoring tumor growth. Pharmacokinetics of DOX, with or without DP, were evaluated in C57BL/6 mice bearing B16V or B16VDXR tumors. DP produced a 6.4-fold reversal of resistance to DOX in vitro; this was accompanied by an increase (3.6-fold) in the steady-state intracellular accumulation of DOX and a marked reduction in the efflux of DOX from B16VDXR cells. Furthermore, a linear correlation was observed between the EC50 values and the steady-state intracellular levels of DOX in the multidrug-resistant cells. In the in vivo experiments, similar growth patterns were seen for the DOX alone and the DOX+DP groups for B16V tumors. The results with B16VDXR tumors were in sharp contrast. The DOX+DP treatment caused a significant delay in the growth of B16VDXR tumors compared to treatment with DOX alone or controls. DP did not alter the plasma pharmacokinetics of DOX in C57BL/6 mice but resulted in a significant increase in the intratumoral accumulation of DOX.
authors.affiliation: Department of Medicinal Chemistry and Pharmaceutics, Northeast Louisiana University, Monroe, USA.
authors.forename: P B
authors.initials: PB
authors.lastname: Desai
authors.forename: J
authors.initials: J
authors.lastname: Duan
authors.forename: R
authors.initials: R
authors.lastname: Sridhar
authors.forename: B D
authors.initials: BD
authors.lastname: Damle
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D004176:Dipyridamole / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000493:pharmacokinetics*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D066298:In Vitro Techniques; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology
chemical_list: D000903:Antibiotics, Antineoplastic; D010975:Platelet Aggregation Inhibitors; D004176:Dipyridamole; D004317:Doxorubicin