AMPK activation by agents such as metformin, statins, and resveratrol shows potential for cardioprotection against doxorubicin-induced cardiotoxicity in preclinical models.
Do AMPK-activating agents prevent doxorubicin-induced cardiotoxicity in patients and preclinical models receiving doxorubicin?
AMPK activation is a promising molecular target for cardioprotection against doxorubicin-induced cardiotoxicity, warranting further clinical investigation.
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.
Timm et al. (2020) conducted a review in Doxorubicin-Induced Cardiotoxicity. AMPK activators (e.g., metformin, statins, resveratrol, AICAR) was evaluated. AMPK activation by agents such as metformin, statins, and resveratrol shows potential for cardioprotection against doxorubicin-induced cardiotoxicity in preclinical models.