Cardiotoxicity of anti-cancer drugs: cellular mechanisms and clinical implications

Figures

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  Figure 1. Mechanisms of doxorubicin-induced myocardial dysfunction. Doxorubicin inhibits DNA replication by intercalating with DNA and stabilising Topoisomerase 2 cleavage complex, triggering its degradation and intrinsic apoptosis. Doxorubicin's quinone structure is prone to free radical generation leading to increased generation of reactive oxygen species. Proteins of the electron transport chain in the mitochondria undergo conformational changes that result in loss of mitochondrial membrane potential, loss of ATP production, and activation of casepase-3 mediated apoptosis. Various cell death receptors in cardiomyocytes have been shown to be upregulated including proteins pivotal in apoptosis, such as autophagy, RIPK1/3-dependent necroptosis, ferroptosis, and pyroptosis. The net effect is decreased cardiomyocyte contractility and cell death, resulting in fibrosis and continuous compensatory hypertrophic remodelling of remaining cardiomyocytes. The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

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  Figure 2. Trastuzumab inhibits HER2 receptor activation Overexpression of human epidermal growth factor receptor 2 (HER2) in malignant cells result in uncontrolled downstream activating effects of three major growth signalling pathways of phosphoinositide 3-kinases (PI3K), Akt, mitogen-activating kinase (MAPK), and Focal Adhesion Kinases (FAK) that regulate cell proliferation, differentiation, and survival. Neuregulin-1 is a growth factor released from myocardial cells that stimulate HER2, promoting cell survival. Trastuzumab binds to HER2 and inhibit uncontrolled cell growth by HER2 receptor downregulation and cell death. The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

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  Figure 3. Overall summary of molecular mechanisms of cardiotoxicity for commonly-used agent classes. 5-FU, 5-Flurouracil; AMPK, adenosine monophosphate-activated protein kinase; CAR-T, chimeric antigen receptor T-cell therapy; Erk, extracellular signal-regulated kinase; HER2, human epidermal growth factor receptor 2; ICAM1, Intercellular adhesion molecule-1; mTORC1, mammalian target of rapamycin complex 1; NO, nitric oxide; PP2A, Protein phosphatase 2A; Top2, Topoisomerase-2; VEGF, vascular endothelial growth factor; vCAM1, vascular cell adhesion molecule-1; vWF, von Willebrand factor. Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.