The Study Of Effects Of Anti-diabetic Drugs On P-glycoprotein And Chemotherapeutic Sensitivity Of Breast Cancer Cells

Objective Both diabetes mellitus and anti-diabetic drugs have been reported to affect breast cancer, while the specific mechanisms are still unclear. In the present study, we aimed to detect the effects of various anti-diabetic drugs on the expression and function of P-glycoprotein(P-gp) and chemosensitivity of multidrug resistant breast cancer cell line MCF-7/ADR, and provide the basis for making antidiabetic regimen for diabetic breast cancer patients treated with chemotherapy.Methods We incubated cells with different concentration anti-diabetic drugs including metformin(0, 1, 2, 5, 10 m M), glucagon-like peptide-1 analogues liraglutide(0, 50, 100, 200, 300 n M), glimepiride(0, 0.5, 1, 2, 5, 10 μM) and insulin( 0, 0.001, 0.005, 0.01, 0.05, 0.1 μM). P-gp expressions in gene and protein levels of the intervened cells were examined by real-time PCR and Western blot, respectively.The efflux function of P-gp was determined by rhodamine-123 accumulation assays.The viability and chemosensitivity of the cells were determined by MTT assays.Results(1) Compared with MCF-7/ADR cells, metformin and liraglutide significantly inhibited the viability of MCF-7 cells(P < 0.05), while similar change was not observed in glimepiride and insulin treated cells. In addition, compared with untreated MCF-7/ADR cells, metformin and liraglutide significantly inhibited viability of MCF-7/ADR cells(P < 0.05), while insulin significantly enhanced viability of MCF-7/ADR(P < 0.05).(2) Metformin and liraglutide significantly decreased the expression of P-gp both in gene and protein level of MCF-7/ADR cells(P < 0.05). Insulin increased the expression of P-gp both in gene and protein level in MCF-7/ADR cells(P < 0.05). Glimepiride had no impact on the expression of P-gp.(3) Metformin, liraglutide and glimepiride reduced the efflux function of P-gp of MCF-7/ADR cells(P < 0.05). However, insulin enhanced the efflux function of P-gp(P < 0.05).(4) Metformin and liraglutide significantly enhanced the cytotoxicity of epirubicin to MCF-7/ADR cells(P < 0.05), while insulin reduced cytotoxicity of epirubicin to MCF-7/ADR cells(P < 0.05). Glimepiride did not significantly affect chemotherapeutic sensitivity of MCF-7/ADR cells.(5) Compared with vehicle control, metformin or liraglutide monotherapy, combination of metformin with liraglutide significantly increased the chemotherapeutic sensitivity of MCF-7/ADR cells. Both metformin combined with glimepiride and metformin combined with insulin could significantly increase the cytotoxicity of epirubicin to MCF-7/ADR cells contrasted to vehicle control cells.Conclusion Anti-diabetic drugs can affect the expression and function of P-gp and change chemotherapeutic sensitivity of breast cancer cells. Metformin and liraglutide can downregulate the expression and function of P-gp, while insulin can enhance the expression and function of of P-gp. Glimepiride does not affect the expression of P-gp, but could inhibit the drug efflux function of P-gp. Metformin and liraglutide may enhance chemotherapeutic sensitivity of breast cancer; insulin may weaken the chemotherapeutic sensitivity of breast cancer; metformin and liraglutide combination chemotherapy can display an overlaying effect on chemotherapeutic sensitivity of MCF-7/ADR cells compared to metformin or liraglutide monotherapy. The P-gp may be one of the pathways that antidiabetic drugs affect breast cancer chemotherapy sensitivity. However, the specific mechanism remains to be further studied.