P-glycoprotein expression by cancer cells affects cell cytotoxicity and cell-cycle perturbations induced by six chemotherapeutic drugs.
BACKGROUND
P-glycoprotein (P-gp)-mediated chemoresistance plays an important role in drug resistance.


METHODS
We investigated if P-gp expression by cancer cells affects cell cytotoxicity and cell-cycle perturbations induced by six commonly used chemotherapeutic agents (doxorubicin, daunorubicin, mitoxantrone, vinblastine, paclitaxel, and colchicine). For this purpose, we used KB cell lines as a model and flow cytometric cell viability and drug-induced cell-cycle perturbation-based methods. We continuously cultured KB cell lines, in the presence of various anticancer agents and measured the cell-cycle kinetics and percentage of cell viability by flow cytometry at different time intervals.


RESULTS
The highly resistant cell line KB V-1 was significantly less susceptible to drug cytotoxicity than the sensitive cell line KB 3-1. KB V-1 cells cultured with different chemotherapy agents continued cell-cycle progression without any significant perturbation of cell compartment distribution. Addition of verapamil, by inhibiting P-gp, reversed resistance thereby increasing drug cytotoxicity and allowing the appearance of drug induced cell-cycle perturbations.


CONCLUSIONS
We conclude that P-gp interferes with cell cytotoxicity and cell-cycle perturbations induced by anticancer agents. Flow cytometry can be used to conveniently detect P-gp-mediated chemoresistance by cancer cells as it allows the analysis of cell cytotoxicity and cell-cycle modifications after exposure to specific chemotherapeutic and reversal agents.
Galmarini
Carlos M
CM
Division Medicina-Hospital Municipal de Oncologia Maria Curie, Buenos Aires, Argentina. felipe.galmarini@mail.roche.com.ar
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D008942:Mitoxantrone / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D014747:Vinblastine; D004317:Doxorubicin; D008942:Mitoxantrone; D017239:Paclitaxel; D003078:Colchicine; D003630:Daunorubicin