A Novel Preclinical Strategy for Identifying Cardiotoxic Kinase Inhibitors and Mechanisms of Cardiotoxicity
- Authors
- Cheng, H., Kari, G., Dicker, A.P., Rodeck, U., Koch, W.J., and Force, T.
- ID
- ZDB-PUB-111027-13
- Date
- 2011
- Source
- Circulation research 109(12): 1401-9 (Journal)
- Registered Authors
- Dicker, Adam P.
- Keywords
- zebrafish, kinase inhibitors, cancer, cardiotoxicity, ERK
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Apoptosis/drug effects*
- Benzenesulfonates/pharmacology*
- Cardiotoxins/pharmacology*
- Cell Survival/drug effects
- Cells, Cultured
- Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors
- Female
- Indoles/pharmacology*
- Male
- Models, Animal
- Myocytes, Cardiac/cytology
- Myocytes, Cardiac/drug effects*
- Niacinamide/analogs & derivatives
- Phenylurea Compounds
- Protein Kinase Inhibitors/pharmacology*
- Proto-Oncogene Proteins B-raf/antagonists & inhibitors
- Proto-Oncogene Proteins c-raf/antagonists & inhibitors
- Pyridines/pharmacology*
- Pyrroles/pharmacology*
- Quinazolines/pharmacology*
- Rats
- Rats, Sprague-Dawley
- Signal Transduction/drug effects
- Zebrafish
- PubMed
- 21998323 Full text @ Circ. Res.
Rationale: Despite intense interest in strategies to predict which kinase inhibitor (KI) cancer therapeutics may be associated with cardiotoxicity, current approaches are inadequate. Sorafenib is a KI of concern because it inhibits growth factor receptors and Raf-1/B-Raf, kinases that are upstream of extracellular signal-regulated kinases (ERKs) and signal cardiomyocyte survival in the setting of stress.
Objectives: To explore the potential use of zebrafish as a preclinical model to predict cardiotoxicity and to determine whether sorafenib has associated cardiotoxicity, and, if so, define the mechanisms.
Methods and Results: We find that the zebrafish model is readily able to discriminate a KI with little or no cardiotoxicity (gefitinib) from one with demonstrated cardiotoxicity (sunitinib). Sorafenib, like sunitinib, leads to cardiomyocyte apoptosis, a reduction in total myocyte number per heart, contractile dysfunction, and ventricular dilatation in zebrafish. In cultured rat cardiomyocytes, sorafenib induces cell death. This can be rescued by adenovirus-mediated gene transfer of constitutively active MEK1, which restores ERK activity even in the presence of sorafenib. Whereas growth factor–induced activation of ERKs requires Raf, α-adrenergic agonist-induced activation of ERKs does not require it. Consequently, activation of α-adrenergic signaling markedly decreases sorafenib-induced cell death. Consistent with these in vitro data, inhibition of α-adrenergic signaling with the receptor antagonist prazosin worsens sorafenib-induced cardiomyopathy in zebrafish.
Conclusions: Zebrafish may be a valuable preclinical tool to predict cardiotoxicity. The α-adrenergic signaling pathway is an important modulator of sorafenib cardiotoxicity in vitro and in vivo and appears to act through a here-to-fore unrecognized signaling pathway downstream of α-adrenergic activation that bypasses Raf to activate ERKs.