Wei J, Yang Q, Lin L, Zhu C, Wei J
Department of Cardiology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
Nan Fang Yi Ke Da Xue Xue Bao. 2023 Oct 20;43(10):1682-1688. doi: 10.12122/j.issn.1673-4254.2023.10.05.
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 (<0.05). In the test group, CK-MB, LDH and BNP levels were significantly lowered after the combined treatment (<0.05), while EF and FS did not undergo obvious changes (>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 (<0.05). Doxorubicin treatment reduced FS in both wild-type and AKO mice, but the reduction was less obvious in AKO group (<0.05). The combined treatment restored FS in wild-type mice (<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 (<0.05); The combined treatment with metformin reduced doxorubicin-induced elevation of LDH and cTnI levels in the wild-type mice (<0.05) but not in AKO group (>0.05). Doxorubicin increased myocardial cell apoptosis in both mice (<0.01) but less strongly in AKO mice (<0.05).
Chemotherapy with doxorubicin causes cardiotoxicity, which can be mitigated by combined treatment with metformin possibly through a mechanism involving the AMPK pathway.
探讨二甲双胍是否通过AMPK途径降低阿霉素的心脏毒性。
我们分析了123例接受阿霉素分阶段化疗的髓系白血病、非霍奇金淋巴瘤或乳腺癌患者的数据，其中43例接受二甲双胍联合治疗（试验组），80例未接受二甲双胍治疗（对照组）。观察患者血浆CK-MB、LDH和BNP水平的变化，以及左心室射血分数（EF）和左心室缩短分数（FS）。在AMPKα2基因敲除（AKO）的C57BL/6小鼠中，还观察了单独或联合使用二甲双胍和阿霉素治疗对心肌损伤、心脏功能和心肌细胞凋亡的影响。
化疗后对照组CK-MB、LDH和BNP水平升高，EF和FS显著降低（P<0.05）。试验组联合治疗后CK-MB、LDH和BNP水平显著降低（P<0.05），而EF和FS无明显变化（P>0.05）。治疗后试验组CK-MB、LDH和BNP水平低于对照组，EF和FS高于对照组（P<0.05）。阿霉素治疗使野生型和AKO小鼠的FS降低，但AKO组降低不明显（P<0.05）。联合治疗使野生型小鼠的FS恢复（P<0.05），但AKO小鼠未恢复。阿霉素使野生型和AKO小鼠的LDH和cTnI水平显著升高，但后者升高幅度较小（P<0.05）；二甲双胍联合治疗降低了野生型小鼠阿霉素诱导的LDH和cTnI水平升高（P<0.05），但AKO组未降低（P>0.05）。阿霉素使两种小鼠的心肌细胞凋亡增加（P<0.01），但AKO小鼠增加程度较小（P<0.05）。
阿霉素化疗可导致心脏毒性，二甲双胍联合治疗可能通过涉及AMPK途径的机制减轻这种毒性。
