Metformin mitigates doxorubicin-induced cardiotoxicity via the AMPK pathway

Abstract

To explore whether metformin reduces cardiotoxicity of doxorubicin through the AMPK pathway. We analyzed the data of 123 patients with myeloid leukemia, non-Hodgkin's lymphoma, or breast cancer receiving doxorubicin for phased chemotherapy, including 43 patients receiving combined treatment with metformin (test group) and 80 without metformin treatment (control group). The changes in plasma levels of CK-MB, LDH, and BNP, left ventricular ejection fraction (EF) and left ventricular fractional shortening (FS) of the patients were observed. The effect of treatments with metformin and doxorubicin, alone or in combination, on myocardial damage, cardiac function and myocardial cell apoptosis were also observed in C57BL/6 mice with AMPKα2 gene knockout (AKO). CK-MB, LDH and BNP levels increased and EF and FS decreased significantly in the control group after chemotherapy (P<0.05). In the test group, CK-MB, LDH and BNP levels were significantly lowered after the combined treatment (P<0.05), while EF and FS did not undergo obvious changes (P>0.05). CK-MB, LDH and BNP levels were lower and EF and FS were higher significantly in the test group than in the control group after the treatment (P<0.05). Doxorubicin treatment reduced FS in both wild-type and AKO mice, but the reduction was less obvious in AKO group (P<0.05). The combined treatment restored FS in wild-type mice (P<0.05) but not in AKO mice. Doxorubicin significantly increased LDH and cTnI levels in both wild-type and AKO mice, but with smaller increments in the latter (P<0.05); The combined treatment with metformin reduced doxorubicin-induced elevation of LDH and cTnI levels in the wild-type mice (P<0.05) but not in AKO group (P>0.05). Doxorubicin increased myocardial cell apoptosis in both mice (P<0.01) but less strongly in AKO mice (P<0.05). Chemotherapy with doxorubicin causes cardiotoxicity, which can be mitigated by combined treatment with metformin possibly through a mechanism involving the AMPK pathway.