Cardio-Oncology: Mechanisms, Drug Combinations, and Reverse Cardio-Oncology

Figures

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  Figure 1. ANTs cause cardiotoxicity through multiple mechanisms. ANTs induce ROS production: a large number of ROS causes mitochondrial swelling, opens the mPTP, and activates endogenous apoptotic pathways. ANTs cause mitochondrial lipid peroxidation by downregulating GPx4 expression. ANTs cause dysregulation of macroautophagy and mitophagy and affect autophagy-lysosomal acidity. ANTs targeting Top2 leads to DNA damage. ANTs induce Ca2+ leakage in the sarcoplasmic reticulum. ANTs induce changes in ncRNA expression. ROS, reactive oxygen species;mTOR, mammalian target of rapamycin; Bcl-2, B-cell lymphoma 2; Ulk1, unc-51-like autophagy activating kinase 1; SR, sarcoplasmic reticulum; Top2, topoisomerase 2. Created with BioRender.com.

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  Figure 2. Mechanisms of non-anthracycline-based chemotherapeutic cardiotoxicity. The mechanisms of cisplatin toxicity to the heart include oxidative stress, inflammation, endoplasmic reticulum stress, and activation of ERK1/2 and p38 MAPK pathways. Cyclophosphamide causes myocardial injury mainly by inducing oxidative stress, nitrative stress, and inhibiting the PI3K/AKT/mTOR pathway. MTX activates proinflammatory pathways, inhibits Bcl2 expression, and induces cardiomyocyte apoptosis. 5-FU activates mitophagy and blocks the TCA cycle, thereby causing mitochondrial dysfunction. CYCL, cyclophosphamide; PLA, platinum; vWF, von Willebrand factor; t-PA, tissue plasminogen activator; hs-CRP, high-sensitivity C-reactive protein, PAI-1, plasminogen activator inhibitor; NF-κB, nuclear factor kappa B; eNOS, endothelial nitric oxide synthase; Keap1, Kelch-like ECH-associated protein 1; Nrf2, nuclear factor erythroid 2-related factor 2. Created with BioRender.com.

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  Figure 3. Mechanisms of radiotherapy-induced cardiotoxicity. Radiotherapy stimulates Ca2+ release from the ER, causing Ca2+ overload in mitochondria. Radiation-produced ROS leads to mitochondrial dysfunction and activation of endogenous apoptotic pathways. ROS can induce an inflammatory response. Radiation causes increased expression of TGF/β, which induces myocardial hypertrophy by targeting ERK1/2 and AKT signaling pathways. Radiotherapy increases the risk of thrombosis by upregulating expression of vWF and proinflammatory adhesion factors, as well as causing endothelial damage. RT, radiotherapy; Bax2, bcl-2-associated X protein; Apaf-1, apoptotic protease activating factor-1; PUMA, polyunsaturated fatty acid; Cyto c, cytochrome c. Created with BioRender.com.

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  Figure 4. Mechanisms of cardiotoxicity induced by monoclonal antibodies/small molecule tyrosine kinase inhibitors. Inhibition of intracellular signaling by interference with downstream signaling pathways induces oxidative stress, ER stress, and apoptosis, ultimately causing cardiac injury. EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; VEGFR, vascular endothelial growth factor receptor. Created with BioRender.com.

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  Figure 5. Mechanisms of immunotherapy-induced cardiotoxicity. Inhibition of CELA-4 expression leads to the proliferation and infiltration of CD8+ T cells in the heart. Chimeric antigen receptor T-cell therapy drives CRS to an inflammatory response. APC, antigen-presenting cells; MHC, major histocompatibility complex; TCR, T-cell receptor; CTLA-4, cytotoxic T-lymphocyte-associated antigen-4; PD-1, programmed cell death protein 1; PD-L1, programmed cell death 1 ligand 1; CRS, cytokine release syndrome. Created with BioRender.com.

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  Figure 6. Mechanisms of reverse cardiac oncology (schematic). Secreted factors from the damaged heart promote the growth and metastasis of tumor cells through the circulation. Created with BioRender.com.