Benzquinamide inhibits P-glycoprotein mediated drug efflux and potentiates anticancer agent cytotoxicity in multidrug resistant cells

We have previously shown that efflux of cytotoxic drugs from multidrug resistant (MDR) cell lines can be quantitated at the single cell level using a sensitive fluorescence microscopy technique. Based on the structure of compounds which inhibited the efflux of Rhodamine-123 (Rho-123) using this meth...

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Bibliographic Details
Published inOncology research Vol. 4; no. 8-9; p. 359
Main Authors Mazzanti, R, Croop, J M, Gatmaitan, Z, Budding, M, Steiglitz, K, Arceci, R, Arias, I M
Format Journal Article
LanguageEnglish
Published United States 1992
Subjects
Affinity Labels
Animals
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
ATP-Binding Cassette, Sub-Family B, Member 1
Cell Survival - drug effects
Cricetinae
Drug Resistance
Drug Synergism
Humans
Membrane Glycoproteins - antagonists & inhibitors
Membrane Glycoproteins - metabolism
Mice
Microscopy, Fluorescence
Neoplasm Proteins - antagonists & inhibitors
Phenotype
Protein Binding - drug effects
Quinolizines - pharmacology
Rhodamine 123
Rhodamines - pharmacokinetics
Tumor Cells, Cultured
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Summary:We have previously shown that efflux of cytotoxic drugs from multidrug resistant (MDR) cell lines can be quantitated at the single cell level using a sensitive fluorescence microscopy technique. Based on the structure of compounds which inhibited the efflux of Rhodamine-123 (Rho-123) using this methodology, we hypothesized that the antiemetic, antihistaminic agent benzquinamide (BZQ) would interfere with P-glycoprotein (P-gp) mediated drug transport and potentiate the effects of anticancer agents in MDR cell lines. We show that BZQ interferes with P-gp mediated drug efflux and increases drug accumulation in MDR cells using Rho-123 as a fluorescent probe. BZQ increases the cytotoxicity of chemotherapeutic agents to both human and hamster MDR cell lines in vitro. A slight increase in cytotoxicity to chemotherapeutic agents is also observed in the parental cell lines with BZQ. BZQ increases [3H]daunorubicin accumulation and inhibits the binding of [125I]iodoaryl azidoprazosin to the P-gp in MDR cells. BZQ is a new agent to increase the cytotoxic effects of anticancer agents in MDR cells and may ultimately prove useful as an adjunct in cancer chemotherapy.
ISSN:0965-0407