The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity

Abstract

Doxorubicin is a commonly used chemotherapeutic agent for the treatment of a range of cancers, but despite its success in improving cancer survival rates, doxorubicin is cardiotoxic and can lead to congestive heart failure. Therapeutic options for this patient group are limited to standard heart failure medications with the only drug specific for doxorubicin cardiotoxicity to reach FDA approval being dexrazoxane, an iron-chelating agent targeting oxidative stress. However, dexrazoxane has failed to live up to its expectations from preclinical studies while also bringing up concerns about its safety. Despite decades of research, the molecular mechanisms of doxorubicin cardiotoxicity are still poorly understood and oxidative stress is no longer considered to be the sole evil. Mitochondrial impairment, increased apoptosis, dysregulated autophagy and increased fibrosis have also been shown to be crucial players in doxorubicin cardiotoxicity. These cellular processes are all linked by one highly conserved intracellular kinase: adenosine monophosphate-activated protein kinase (AMPK). AMPK regulates mitochondrial biogenesis via PGC1α signalling, increases oxidative mitochondrial metabolism, decreases apoptosis through inhibition of mTOR signalling, increases autophagy through ULK1 and decreases fibrosis through inhibition of TGFβ signalling. AMPK therefore sits at the control point of many mechanisms shown to be involved in doxorubicin cardiotoxicity and cardiac AMPK signalling itself has been shown to be impaired by doxorubicin. In this review, we introduce different agents known to activate AMPK (metformin, statins, resveratrol, thiazolidinediones, AICAR, specific AMPK activators) as well as exercise and dietary restriction, and we discuss the existing evidence for their potential role in cardioprotection from doxorubicin cardiotoxicity.

Date Palm Pollen Extract Avert Doxorubicin-Induced Cardiomyopathy Fibrosis and Associated Oxidative/Nitrosative Stress, Inflammatory Cascade, and Apoptosis-Targeting Bax/Bcl-2 and Caspase-3 Signaling Pathways

“…The necrotic or apoptotic cardiomyocytes are replaced by overproduced collagen by fibroblast. However, it contributes to heart rigidity and instability [ 85 , 117 ]. DOX-induced cardiac fibrosis is based on the inflammatory and growth factors signaling paths regulated by TGF-β1.…”

Understanding the common mechanisms of heart and skeletal muscle wasting in cancer cachexia

“…Most of anti-cancer drugs enhance oxidative damage in both the skeletal and the cardiac muscle. In the former, oxidative stress can be directly linked to protein hypercatabolism and wasting 160 , 161 , while in the latter its role has been downscaled, also considering the limited success of anti-oxidants against the cardiotoxicity of drugs like doxorubicin 188 .…”

The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin

“…Interleukins 8 and 6 are also associated to cardiovascular disease, heart failure and stroke [59]. Here, empagli ozin improved cardiac, hepatic and renal microenvironment through the reduction of pro-in ammatory cytokines during treatment with DOXO.As summarized in Figure 7, empagli ozin inhibits activity of SGLT-2 thereby reducing intracellular glucose and sodium in cardiomyocytes, consequently increasing 5' AMP-activated protein kinase (AMPK) that has a key role in doxorubicin-mediated cardiomyocyte injury through SMAD, NoX and Wnt [60]. The overall picture of the study is in line with other recent work highlighting on the protective effects of SGLT2 inhibitors on DOXO induced cardiotoxicity [61,62].…”