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.

Keywords: AICAR; AMPK; Cardiotoxicity; Doxorubicin; Metformin.

Fig. 1

Molecular mechanisms of doxorubicin-induced cardiotoxicity. Doxorubicin (DOX) preferentially binds to cardiolipin in the inner mitochondrial membrane. Through its proximity to mitochondrial membrane proteins, DOX interferes with the electron transport chain (ETC), which is thought to contribute to reactive oxygen species (ROS) generation and mitochondrial dysfunction. DOX also inhibits uptake of free fatty acids (FFAs) into mitochondria by inhibiting the carnitine acyl-carnitine translocase. ROS can furthermore be directly produced by DOX through redox cycling on the quinone moiety and by Fenton reaction with molecular iron. ROS inhibits several enzymes in the tricarboxylic acid (TCA) cycle and may damage mitochondrial DNA. DOX furthermore inhibits mitophagy and autophagy and induces apoptosis. In the nucleus, DOX inhibits topoisomerase IIβ, which may lead to DNA damage. In fibroblasts (inset), DOX triggers TGFβ signalling, which induces fibrosis. ATP syn, ATP synthase; CoA-SH, coenzyme A; CPT-1/2, carnitine palmitoyltransferase; FAT, fatty acid transporter; GLUT, glucose transporter

Fig. 2

AMPK activation and downstream effects in the heart. AMPK is activated by phosphorylation on its α subunit (Thr172) via calcium/calmodulin-dependent protein kinase kinase II (CAMKK2) and liver kinase B1 (LKB1). AMP acts as an allosteric regulator on the γ subunit, preventing dephosphorylation of AMPK. This occurs when the ATP to AMP ratio is low, signalling a low-energy state. A low ATP to AMP ratio is also present during exercise and dietary restriction and can be pharmacologically achieved with thiazolidinediones and potentially with metformin and resveratrol. 5-aminoimidazole-4-carboxamide riboside (AICAR) is an AMPK mimetic and thus does not rely on the ATP to AMP ratio for AMPK activation. LKB1 can be activated through sirtuin 1-mediated deacetylation by statins and potentially with metformin and resveratrol. Downstream targets of phosphorylated AMPK overall promote catabolic processes such as glucose uptake and glycolysis, fatty acid uptake, mitochondrial biogenesis and autophagy and inhibit anabolic processes such as protein synthesis (and fibrosis). ACC, acetyl-CoA carboxylase; CD36, fatty acid transporter; eEF2k, eukaryotic elongation factor 2 kinase; GLUT4, glucose transporter 4; LPL, lipoprotein lipase; mTOR, mammalian target of rapamycin; PFK2, phosphofructokinase 2; PGC1α, peroxisome proliferator–activated receptor-gamma coactivator 1α; TGFβ, transforming growth factor β; ULK1, Unc-51 like autophagy activating kinase