2. Academic Validation
  3. Chrysophanol protects against doxorubicin-induced cardiotoxicity by suppressing cellular PARylation

Chrysophanol protects against doxorubicin-induced cardiotoxicity by suppressing cellular PARylation

  • Acta Pharm Sin B. 2019 Jul;9(4):782-793. doi: 10.1016/j.apsb.2018.10.008.
Jing Lu 1,  Jingyan Li 1,  Yuehuai Hu 1,  Zhen Guo 1,  Duanping Sun 2,  Panxia Wang 1,  Kaiteng Guo 1,  Dayue Darrel Duan 3,  Si Gao 4,  Jianmin Jiang 1,  Junjian Wang 1,  Peiqing Liu 1
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 2 Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, China.
  • 3 Laboratory of Cardiovascular Phenomics, Department of Pharmacology, University of Nevada Reno School of Medicine, Reno, NV 89557, USA.
  • 4 School of Medicine, Guangxi University of Science and Technology, Liuzhou 545005, China.
PMID: 31384538 DOI: 10.1016/j.apsb.2018.10.008
Abstract

The clinical application of doxorubicin (DOX) in Cancer chemotherapy is limited by its life-threatening cardiotoxic effects. Chrysophanol (CHR), an anthraquinone compound isolated from the rhizome of Rheum palmatum L., is considered to play a broad role in a variety of biological processes. However, the effects of CHR׳s cardioprotection in DOX-induced cardiomyopathy is poorly understood. In this study, we found that the cardiac Apoptosis, mitochondrial injury and cellular PARylation levels were significantly increased in H9C2 cells treated by Dox, while these effects were suppressed by CHR. Similar results were observed when PARP1 activity was suppressed by its inhibitors 3-aminobenzamide (3AB) and ABT888. Ectopic expression of PARP1 effectively blocked this CHR׳s cardioprotection against DOX-induced cardiomyocyte injury in H9C2 cells. Furthermore, pre-administration with both CHR and 3AB relieved DOX-induced cardiac Apoptosis, mitochondrial impairment and heart dysfunction in Sprague-Dawley rat model. These results revealed that CHR protects against DOX-induced cardiotoxicity by suppressing cellular PARylation and provided critical evidence that PARylation may be a novel target for DOX-induced cardiomyopathy.

Keywords

3AB, 3-aminobenzamide; ADR, adriamycin; ANOVA, one-way analysis of variance; Apoptosis; CHR, chrysophanol; CMC-Na, sodium carboxymethyl; CO, cardiac output; Cardiotoxicity; Chrysophanol; Cyt c, Cytochrome c; DOX, doxorubicin; Doxorubicin; EF, ejection fraction; FBS, fetal bovine serum; FS, fractional shortening; HE, hematoxylin-eosin; HR, heart rate; IVSd, end-diastolic interventricular septum; IVSs, end-systolic interventricular septum; LV, end-systolic volume; LVEDV, LV end-diastolic volume; LVIDd, LV end-diastolic internal diameter; LVIDs, LV end-systolic internal diameter; LVPWd, LV end-diastolic posterior wall thickness; LVPWs, LV end-systolic posterior wall thickness; Mitochondria; NS, normal saline; PAR, polymers of ADP-ribose; PARP1, poly(ADP-ribose) polymerase 1; PARylated, poly(ADP-ribosyl)ated; PARylation; PARylation, poly(ADP-ribosyl)ation; PBS, phosphate-buffered saline; RCR, respiratory control ratio; ROS, reactive oxygen species; Rh123, rhodamine 123; SD, Sprague–Dawley; TUNEL, TdT-mediated dUTP nick end labeling; VDAC1, voltage dependent anion channel 1.

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