Effect of P-glycoprotein on flavopiridol sensitivity.
Flavopiridol is the first potent inhibitor of cyclin-dependent kinases (CDKs) to enter clinical trials. Little is known about mechanisms of resistance to this agent. In order to determine whether P-glycoprotein (Pgp) might play a role in flavopiridol resistance, we examined flavopiridol sensitivity in a pair of Chinese hamster ovary cell lines differing with respect to level of Pgp expression. The IC(50)s of flavopiridol in parental AuxB1 (lower Pgp) and colchicine-selected CH(R)C5 (higher Pgp) cells were 90.2 +/- 6.6 nM and 117 +/- 2.3 nM, respectively (P< 0.01), suggesting that Pgp might have a modest effect on flavopiridol action. Consistent with this hypothesis, pretreatment with either quinidine or verapamil (inhibitors of Pgp-mediated transport) sensitized CH(R)C5 cells to the antiproliferative effects of flavopiridol. Because of concern that colony forming assays might not accurately reflect cytotoxicity, we also examined flavopiridol-treated cells by trypan blue staining and flow cytometry. These assays confirmed that flavopiridol was less toxic to cells expressing higher levels of Pgp. Further experiments revealed that flavopiridol inhibited the binding of [3H]-azidopine to Pgp in isolated membrane vesicles, but only at high concentrations. Collectively, these results identify flavopiridol as a weak substrate for Pgp.
Boerner
S A
SA
Division of Oncology Research, Mayo Clinic, Rochester, MN, USA.
Tourne
M E
ME
Kaufmann
S H
SH
Bible
K C
KC
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity; D003078:Colchicine / Q000633:toxicity; D003114:Colony-Forming Units Assay; D006224:Cricetinae; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005419:Flavonoids / Q000633:toxicity*; D017239:Paclitaxel / Q000633:toxicity; D010880:Piperidines / Q000633:toxicity*; D011802:Quinidine / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib; D014700:Verapamil; D011802:Quinidine; D017239:Paclitaxel; D002945:Cisplatin; D003078:Colchicine