Pediatric doxorubicin exposure induces persistent pathological changes in mice

Over 50 % of pediatric cancer patients undergo treatment with chemotherapy regimens containing anthracyclines, such as doxorubicin (DOX). However, the long-term effects of childhood DOX exposure remain poorly understood, and protective strategies are limited. To establish a mouse model that recapitulates the chronic health conditions in adult survivors of childhood cancer, 14-day-old C57BL/6N mice received DOX (2.5 mg/kg, twice weekly for 2 weeks, i.p.) and were monitored for 32 weeks. Pediatric DOX injection induced late cardiotoxicity including systolic and diastolic dysfunction, cardiac fibrosis and cardiomyocyte atrophy, which were alleviated by treatment with the CDK7/12/13 inhibitor THZ1. Pediatric DOX also reduced heart, liver and spleen weight, while sparing the lung and kidney. Mechanistically, DOX induced persistent activation of p38 in the heart and diminished physiological cardiomyocyte hypertrophy. Pediatric DOX caused slow body weight gain and late mortality, which were surprisingly exacerbated by THZ1. Notably, pediatric THZ1 exposure also hindered body weight gain and reduced heart and liver weight. In conclusion, pediatric DOX exposure resulted in chronic cardiac dysfunction, underweight and premature death during adulthood in mice. Pharmacologic inhibition of CDK7/12/13 with THZ1 partially protected against pediatric DOX-induced cardiotoxicity, but aggravated growth delay and accelerated mortality.