Pediatric Anthracycline‐Induced Cardiotoxicity: Mechanisms, Pharmacogenomics, and Pluripotent Stem‐Cell Modeling

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  Figure 1. Chemical structures of clinically approved anthracyclines.

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  Figure 2. Summary of proposed mechanisms for identified genetic variants associated with anthracycline‐induced cardiotoxicity (ACT) in children. 1. The retinoic acid receptor‐gamma (RARG) variant decreases repression of topoisomerase (TOP)2B such that its levels increase enabling greater amounts of doxorubicin to stabilize its complex with double‐stranded DNA breaks. This leads to increased DNA damage and signals for apoptosis. 2. Carbonyl reductase (CBR)3 variants with increased catalytic activity result in accumulation of toxic C‐13 alcohol metabolites. 3. Decreased anthracycline uptake into cardiomyocytes due to a variant in transporter solute carrier (SLC)28A3 is protective against ACT. 4. The UDP‐glucuronosyltransferase (UGT)1A6 variant increases glucuronidation of anthracyclines resulting in higher levels of toxic metabolites, which predispose patients to ACT. 5. Decreased anthracycline efflux due to polymorphisms in ABC transporters leads to an accumulation of anthracyclines in cardiomyocytes sensitizing them to ACT. 6. Sulfotransferase (SULT)2B1 variant increases sulfonation and therefore renal excretion of anthracyclines and are thus protective against ACT. 7. Mutations in the…

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  Figure 3. Superoxide anion conversion pathway to hydroxyl radical and catalase defense pathway.

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  Figure 4. Disease modeling anthracycline‐induced cardiotoxicity (ACT) with patient‐specific human‐induced pluripotent stem cells‐derived cardiomyocytes (hiPSC‐CMs).