Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity

被引：593

作者：

Burridge, Paul W. ^{[1
,2
,3
,4
,5
]}

Li, Yong Fuga ^{[6
,7
]}

Matsa, Elena ^{[1
,2
,3
]}

Wu, Haodi ^{[1
,2
,3
]}

Ong, Sang-Ging ^{[1
,2
,3
]}

Sharma, Arun ^{[1
,2
,3
]}

Holmstrom, Alexandra ^{[1
,2
,3
]}

Chang, Alex C. ^{[1
,2
,8
]}

Coronado, Michael J. ^{[9
]}

Ebert, Antje D. ^{[1
,2
,3
]}

Knowles, Joshua W. ^{[1
,3
]}

Telli, Melinda L. ^{[10
]}

Witteles, Ronald M. ^{[1
,3
]}

Blau, Helen M. ^{[1
,2
,8
]}

Bernstein, Daniel ^{[1
,9
]}

Altman, Russ B. ^{[7
,11
]}

Wu, Joseph C. ^{[1
,2
,3
]}

机构：

[1] Stanford Univ, Sch Med, Stanford Cardiovasc Inst, Stanford, CA 94305 USA

[2] Stanford Univ, Sch Med, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA

[3] Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA 94305 USA

[4] Northwestern Univ, Feinberg Sch Med, Dept Pharmacol, Chicago, IL 60611 USA

[5] Northwestern Univ, Feinberg Sch Med, Ctr Pharmacogen, Chicago, IL 60611 USA

[6] Stanford Univ, Sch Med, Stanford Genome Technol Ctr, Stanford, CA 94305 USA

[7] Stanford Univ, Sch Med, Dept Bioengn, Stanford, CA 94305 USA

[8] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA

[9] Stanford Univ, Sch Med, Div Cardiol, Dept Pediat, Stanford, CA 94305 USA

[10] Stanford Univ, Dept Med, Div Oncol, Sch Med, Stanford, CA 94305 USA

[11] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA

来源：

NATURE MEDICINE | 2016年 / 22卷 / 05期

基金：

美国国家卫生研究院;

关键词：

ANTHRACYCLINE-INDUCED CARDIOTOXICITY; MUSCLE GENE-EXPRESSION; INDUCED CARDIOMYOPATHY; OXIDATIVE STRESS; RISK-FACTORS; HEART; DEXRAZOXANE; INHIBITION; MATURATION; SURVIVORS;

D O I：

10.1038/nm.4087

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but it causes a dose-related cardiotoxicity that can lead to heart failure in a subset of patients. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). Here we demonstrate that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate the predilection to DIC of individual patients at the cellular level. hiPSC-CMs derived from individuals with breast cancer who experienced DIC were consistently more sensitive to doxorubicin toxicity than hiPSC-CMs from patients who did not experience DIC, with decreased cell viability, impaired mitochondria! and metabolic function, impaired calcium handling, decreased antioxidant pathway activity, and increased reactive oxygen species production. Taken together, our data indicate that hiPSC-CMs are a suitable platform to identify and characterize the genetic basis and molecular mechanisms of DIC.

引用

页码：547 / 556

页数：10

共 60 条

[1]

A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer [J].