p53 prevents doxorubicin cardiotoxicity independently of its prototypical tumor suppressor activities

作者：Jie Li, Pingyuan Wang, Nathaniel Long, Jie Zhuang, Danielle Springer, Jizhong Zou, Yongshun Lin, Christopher K. E. Bleck, Jihoon Park, Ju‐Gyeong Kang, Paul M. Hwang · 发表于：Proceedings of the National Academy of Sciences · 年份：2019 · DOI：10.1073/pnas.1904979116 · 被引用次数：84 · 研究领域：Chemotherapy-induced cardiotoxicity and mitigation、Mitochondrial Function and Pathology、Electron Spin Resonance Studies

Significance Doxorubicin is a DNA-damaging agent that is highly effective against various types of cancers, but a subset of treated patients develop heart failure for unclear genetic reasons. In the current study using p53 mouse models, low-dose doxorubicin as administered in the clinics surprisingly revealed that the absence of p53 increases susceptibility to doxorubicin cardiotoxicity while a mutant of p53 that retains mitochondrial regulation is protective. Notably, promoting mitochondrial biogenesis with a simple vitamin supplement ameliorated the cardiotoxicity. Furthermore, mitochondrial blood markers observed in association with doxorubicin susceptibility could provide guidance for the safer use of this effective chemotherapy.