Demystifying the Relationship Between Metformin, AMPK, and Doxorubicin Cardiotoxicity

Abstract

Doxorubicin (DOX) is an extremely effective and wide-spectrum anticancer drug, but its long-term use can lead to heart failure, which presents a serious problem to millions of cancer survivors who have been treated with DOX. Thus, identifying agents that can reduce DOX cardiotoxicity and concurrently enhance its antitumor efficacy would be of great clinical value. In this respect, the classical antidiabetic drug metformin (MET) has stood out, appearing to have both antitumor and cardioprotective properties. MET is proposed to achieve these beneficial effects through the activation of AMP-activated protein kinase (AMPK), an essential regulator of mitochondrial homeostasis and energy metabolism. AMPK itself has been shown to protect the heart and modulate tumor growth under certain conditions. However, the role and mechanism of the hypothesized MET-AMPK axis in DOX cardiotoxicity and antitumor efficacy remain to be firmly established by in vivo studies using tumor-bearing animal models and large-scale prospective clinical trials. This review summarizes currently available literature for or against a role of AMPK in MET-mediated protection against DOX cardiotoxicity. It also highlights the emerging evidence suggesting distinct roles of the AMPK subunit isoforms in mediating the functions of unique AMPK holoenzymes composed of different combinations of isoforms. Moreover, the review provides a perspective regarding future studies that may help fully elucidate the relationship between MET, AMPK and DOX cardiotoxicity.

Growth differentiation factor‐15 and the effect of empagliflozin in heart failure: Findings from the EMPEROR program

“…17 This relationship is noteworthy, since metformin acts (in part) as an activator of AMPK. 25 Like GDF-15, AMPK exerts cardioprotective effects and acts to promote catabolism (including lipolysis and fatty acid oxidation). [26][27][28] AMPK and GDF-15 act to reinforce each other as part of a positive feedback loop, 11,15 and GDF-15 appears to mediate the effects of metformin on body weight and energy balance.…”

“…Metformin interacts directly with the promoter that regulates GDF‐15 expression, and thus, GDF‐15 has been proposed as a biomarker of metformin use 17 . This relationship is noteworthy, since metformin acts (in part) as an activator of AMPK 25 . Like GDF‐15, AMPK exerts cardioprotective effects and acts to promote catabolism (including lipolysis and fatty acid oxidation) 26–28 .…”

“…The trials enrolled patients with New York Heart Association class II–IV heart failure with elevated circulating levels of natriuretic peptides across a broad range of ejection fractions. The design and results of the EMPEROR trials have been published previously 25,26 . The ethics committees of each of the participating institutions approved the protocol, and all patients gave written informed consent.…”

“…The design and results of the EMPEROR trials have been published previously. 25,26 The ethics committees of each of the participating institutions approved the protocol, and all patients gave written informed consent.…”

“…A total of 1124 patients had baseline GDF-15 measurements available, with an overall median (percentile 25 Compared to patients with the lowest baseline GDF-15 levels (<T1), those with higher GDF-15 levels (>T2) were older, more likely to have worse heart failure symptoms and have been recently hospitalized for heart failure, had higher levels of NT-proBNP and hs-cTnT, and worse kidney function. Patients with higher GDF-15 levels were more likely to be treated with loop diuretics.…”