Effect of P-glycoprotein on flavopiridol sensitivity

Abstract

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 [ 3 H]-azidopine to Pgp in isolated membrane vesicles, but only at high concentrations. Collectively, these results identify flavopiridol as a weak substrate for Pgp.

Combined treatment with the checkpoint abrogator UCN-01 and MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and -resistant myeloma cells through an IL-6–independent mechanism

“…27 Although enhanced expression of Pgp has been shown to reduce, albeit weakly, uptake of small molecule inhibitors such as flavopiridol, 47 it has been found to be somewhat more effective in diminishing the toxicity of UCN-01 in MCF-7 breast cancer cells. 48 However, the finding that Dox40 MM cells were fully sensitive to UCN-01/PD184352 toxicity argues that Pgp-related mechanisms do not play a major role in determining the response of MM cells to either of these agents.…”

Disposition of orally administered a promising chemotherapeutic agent flavopiridol in the intestine

“…The symbol "*" indicates that the difference due to the concentration change is significant (p < 0.05, independent sample t-test). 24 . FLAP at the high dose of 12 mg/kg may be over-dose to the P-gp efflux, resulting in the increase of Cmax due to the saturated P-gp efflux.…”

Flavopiridol Sensitivity of Cancer Cells Isolated from Ascites and Pleural Fluids

“…These cells also showed increased resistance to other anticancer agents, suggesting the involvement of a multidrug resistant protein. Because overexpression of MDR-1 has modest effects on flavopiridol resistance (19), the most likely candidate may be ABCG2, a member of the ATP-binding cassette transporter family that was found to enhance flavopiridol resistance in MCF-7 breast cancer cell line (20 -22). Increased efflux has also been suggested as the cause of flavopiridol resistance in an ovarian cancer cell line although the protein responsible has not been identified (23).…”