The true colors of autophagy in doxorubicin-induced cardiotoxicity

Abstract

Patients with cancer receiving doxorubicin-based chemotherapy often have to stop taking the drug due to its cardiotoxicity and therefore lose out on the beneficial effects of its potent antitumor activity. Doxorubicin has been demonstrated to damage cardiomyocytes via various mechanisms, including accumulation of reactive oxygen species (ROS), DNA damage and autophagy dysfunction. The present review focuses on autophagy, describing the general process of autophagy and the controversy surrounding its role in doxorubicin-induced cardiotoxicity. In addition, the associations between autophagy and apoptosis, ROS, DNA damage and inflammatory processes are discussed. In the future, it will be useful to further elucidate the process of autophagy and reveal its association with various pathological processes to develop effective strategies of preventing doxorubicin-induced cardiotoxicity.

Keywords: autophagy; cardiotoxicity; doxorubicin.

Figure 1.

Five core steps of autophagy: Initiation, nucleation, elongation, maturation and degradation. This process is induced by various stress stimuli, including inhibition of mTOR. In initiation, the organelles to be degraded are gradually wrapped. Subsequently, an autophagosome is formed and cytosolic components are sequestered and characterized by a LC3-II-positive double membrane structure. In the final step, cytosolic components are degraded in an autolysosome. ATG, autophagy related gene; LC3, light chain 3; mTOR, mammalian target of rapamycin; ULK1, serine-threonine kinase Unc-51-line kinase-1; Vsp, vacuolar protein sorting; FIP200, focal adhesion kinase family interacting protein of 200 kD.

Figure 2.

PI3K-AKT signal path diagram: Intracellular and extracellular factors activate the receptor of PI3K, which in turn catalyzes the conversion of PIP2 to PIP3, a catalytic reaction that is reversed by PTEN. PIP3 further activates Akt with the cooperation of PDK1/2. Activated Akt increases the activity of Rheb, which in turn upregulates mTOR activity, which inhibits autophagy initiation by promoting ULK1 phosphorylation. PI3K, phosphoinositide-3-kinase; PIP2, phosphatidylinositol 4,5-biphosphate; PIP3, phosphatidylinositol 3,4,5,-triphosphate; PTEN, phosphatase and tensin homolog; PDK1, phosphoinositide-dependent kinase 1 and 2; TSC, tuberous sclerosis 1; Rheb, Ras homolog enriched in brain; Rags, recombination-activating genes; mTOR, mammalian target of rapamycin; ATG, autophagy related gene; ULK, serine-threonine kinase Unc-51-line kinase; FIP200, focal adhesion kinase family interacting protein of 200 kD; P, phosphorylated.

Figure 3.

Influence of ROS and its association with autophagy. Damaged mitochondria represented by the green box produce excessive ROS that cause DNA damage, lipid peroxidation, endoplasmic reticulum stress, antioxidant depletion (shown in the gray box) and autophagy (shown in the blue box). This in turn promotes the phagocytosis of damaged mitochondria, reducing ROS levels from the source, indicated by the curved arrow. However, overwhelming levels of ROS can also trigger autophagic cell death (shown in the gray box). ROS, reactive oxygen species.

Figure 4.

Antioxidant mechanism of autophagy substrates. p62, which bound to ubiquitylated protein aggregates, can undergo phosphorylation and leases KEAP1 from Nrf2 and Nrf2 transfers to the nucleus as a transcription factor instead of being degraded. Ultimately, Nrf2 transactivates the transcription and expression of antioxidant genes in the nucleus, and p62 is degraded by the autophagosome with KEAP1. KEAP1, Kelch-like ECH-associated protein 1; Nrf2, nuclear factor-like 2.