The tell-tale heart: molecular and cellular responses to childhood anthracycline exposure

Abstract

Since the modern era of cancer chemotherapy that began in the mid-1940s, survival rates for children afflicted with cancer have steadily improved from 10% to current rates that approach 80% (60). Unfortunately, many long-term survivors of pediatric cancer develop chemotherapy-related health effects; 25% are afflicted with a severe or life-threatening medical condition, with cardiovascular disease being a primary risk (96). Childhood cancer survivors have markedly elevated incidences of stroke, congestive heart failure (CHF), coronary artery disease, and valvular disease (96). Their cardiac mortality is 8.2 times higher than expected (93). Anthracyclines are a key component of most curative chemotherapeutic regimens used in pediatric cancer, and approximately half of all childhood cancer patients are exposed to them (78). Numerous epidemiologic and observational studies have linked childhood anthracycline exposure to an increased risk of developing cardiomyopathy and CHF, often decades after treatment. The acute toxic effects of anthracyclines on cardiomyocytes are well described; however, myocardial tissue is comprised of additional resident cell types, and events occurring in the cardiomyocyte do not fully explain the pathological processes leading to late cardiomyopathy and CHF. This review will summarize the current literature regarding the cellular and molecular responses to anthracyclines, with an important emphasis on nonmyocyte cardiac cell types as well as those that mediate the myocardial injury response.

Keywords: anthracyclines; cardiomyocytes; cardiomyopathy; congestive heart failure; extracellular matrix; fibroblast.

Fig. 1.

Analysis of Surveillance Epidemiology and End Results (SEER) database to estimate death from cardiac causes in pediatric cancer survivors. A: standardized mortality ratio (SMR) for cardiac causes in pediatric cancer survivors compared with the general U.S. population. B: absolute death number from cardiac causes in pediatric cancer survivors compared with the general U.S. population.

Fig. 2.

Summary of myocardial cellular effects and the injury response induced by anthracyclines. Blue, absence abrogates cardiac dysfunction or protects from apoptosis; green, downregulation of mRNA and pathway inhibition; yellow, mediates apoptotic response; red, expression increases or enhances cardiac dysfunction; orange, absence enhances cardiac dysfunction. Anthracycline exposure increases p53, and global knockout abrogates the cardiotoxic response. HSF11, heat shock factor 11; Nox2, cofactor for NADPH oxidase; TopIIβ, topoisomerase II-β; HSP27, heat shock protein 27; PARP, poly(ADP-ribose)polymerase; HSP90, heat shock protein 90; GATA4, transcription factor; NFAT5, nuclear factor of activated T cells; mTOR, mammalian target of rapamycin; p38-MAPK, p38 mitogen-activated protein kinase; p-p300/CBP, phosphorylated p300/CREB binding protein; BRCA2, breast cancer susceptibility gene 2; Bcl2:Bax ratio, ratio of B-cell lymphoma 2 to bcl2-like protein 4; miR-146a, microRNA 146a; ROS, reactive oxygen species; CCPK-II, calcium calmodulin-dependent protein kinase II; Nrdp1, E3 ubiquitin ligase; Ub-proteasome, ubiquitinated proteasome; Casp3, caspase 3; Bax, bl2-like protein 4; Fas, ligand for Fas receptor; NF-κB, nuclear factor-κ light chain enhancer of activated B cells; MMPs, matrix metalloproteinases; TLR4, Toll-like receptor 4.