Dipyridamole increases VP16 growth inhibition, accumulation and retention in parental and multidrug-resistant CHO cells.
Dipyridamole (DP) has been shown to reverse multidrug resistance (MDR) via interactions with P-glycoprotein (P-gp). The effect of DP on VP16 growth inhibition was investigated in parental (CHO-K1) and MDR (CHO-Adr(r)) Chinese hamster ovary cells. CHO-Adr(r) cells were 18-fold resistant to VP16 and intracellular accumulation was 28% less than in CHO-K1 cells. DP reduced the resistance of CHO-Adr(r) to VP16 by a factor of 2-3 and caused a similar potentiation of VP16 growth inhibition in the parental cells. A time-dependent increase in intracellular VP16 accumulation, which was similar in both cell lines, was caused by DP. The intracellular retention of VP16 was increased 2- to 3-fold by DP in both cell lines. The magnitude of the effect of DP on all three parameters measured was similar (2- to 4-fold), suggesting that the increased growth inhibition was related to increased intracellular exposure to VP16 owing to the inhibition of the efflux of VP16 by DP. However, since the effect of DP was similar in both parental and P-gp-overexpressing cells it is unlikely that the potentiation of VP16 by DP is mediated via an interaction with P-gp.
Turner
R N
RN
Cancer Research Unit, Medical School, University of Newcastle upon Tyne, UK.
Curtin
N J
NJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004176:Dipyridamole / Q000494:pharmacology*; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D005047:Etoposide / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D004176:Dipyridamole; D005047:Etoposide; D004317:Doxorubicin