Dipyridamole reverses the resistance to topoisomerase II inhibitors but not to antimicrotubule agents in multidrug-resistant melanoma cells.
The influence of dipyridamole (DP) on the cytotoxicity and cellular disposition of several DNA topoisomerase II (topo II) inhibitors and antimitotic agents in multidrug-resistant B16VDXR cells was examined. B16VDXR cells, derived from parental B16V cells by step-wise treatment with doxorubicin (DOX), overexpress a 170 kDa P-glycoprotein (P-gp). Additionally, the resistance to DOX in B16VDXR cells is associated with decreased frequency of DNA strand breaks compared to that in the drug-sensitive B16V cells. DP (10 microM) significantly (P < 0.01) potentiated the cytotoxicity of DOX (6.4-fold), mitoxantrone (2.3-fold), and etoposide (14-fold) in the drug-resistant B16VDXR cells. This was accompanied by a 3.7-fold and 4.2-fold increase in the total intracellular and nuclear levels of DOX, respectively. Surprisingly, no significant change in the intracellular and nuclear levels or the efflux of etoposide was observed in B16VDXR cells. Combination index (CI) analysis, however, indicated that DP interacted synergistically with DOX as well as etoposide. Further, it was intriguing to observe that DP (10 microM) failed to modulate the resistance to vincristine, vinblastine, and taxol. This was despite a significant increase in the accumulation of vinblastine (3.3-fold) and taxol (3.9-fold) in B16VDXR cells in the presence of DP (10 microM). The observed pattern of chemosensitization suggests that in addition to interaction with P-gp, the multidrug-resistance modulating activity of DP may involve P-gp independent mechanism(s). The possibilities include that (i) DP interacts with topo II or (ii) DP promotes the formation and/or obstructs the repair of DNA strand breaks caused by topo II inhibitors.
Damle
B
B
Division of Medicinal Chemistry and Pharmaceutics, School of Pharmacy, Northeast Louisiana University, Monroe 71209.
Desai
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004176:Dipyridamole / Q000494:pharmacology*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D005047:Etoposide / Q000097:blood / Q000493:pharmacokinetics; D007424:Intracellular Fluid / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; D004176:Dipyridamole; D005047:Etoposide