BACKGROUND AND PURPOSE: Doxorubicin anti-cancer therapy is associated with cardiotoxicity, resulting from DNA damage

 

Abstract

BACKGROUND AND PURPOSE: Doxorubicin anti-cancer therapy is associated with cardiotoxicity, resulting from DNA damage response (DDR). Hepatocyte growth factor (HGF) protects cardiomyocytes from injury, but its administration is hampered by low biodistribution. In this study we investigated whether the activation of the HGF receptor - encoded by the Met gene - by an agonist monoclonal antibody (mAb) protects from doxorubicin-induced cardiotoxicity.

EXPERIMENTAL APPROACH: MAb (5 mg/kg) was injected in vivo into C57BL/6J mice prior to doxorubicin (three doses of 7 mg/kg). The cardiac functions were evaluated through magnetic resonance imaging (MRI) after treatment termination. Heart histological staining and mRNA levels of genes associated with heart failure (Acta1, Nppa), inflammation (IL-6) and fibrosis (Ctgf, Col1a2, Timp1, and Mmp9) were assessed. MAb (100 nM) was administered in vitro to H9c2 cardiomyoblasts before addition of doxorubicin (25 μM). DDR and apoptosis markers were evaluated by quantitative western blotting, flow cytometry and immunofluorescence. Stattic was used for pharmacological inactivation of signal transducer and activation of transcription 3 (Stat3).

KEY RESULTS: In vivo, administration of mAb alleviated doxorubicin-induced cardiac dysfunction and fibrosis. In vitro, mAb mimicked the response to HGF by (i) inhibiting histone H2AX phosphorylation at S139, (ii) quenching the expression of the DNA repair enzyme poly (ADP-ribose) polymerase 1, and (iii) reducing the proteolytic activation of caspase 3. The Met-driven cardioprotection involved, at least in vitro, the phosphorylation of Stat3.

CONCLUSION AND IMPLICATIONS: This paper shows that Met agonist mAb provides a new tool for cardioprotection against anthracycline cardiotoxicity.

PMID: 32133617 [PubMed - as supplied by publisher]

20:50

pubmed: ctoall&ca or conall

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