Dataset Information

A novel preclinical strategy for identifying cardiotoxic kinase inhibitors and mechanisms of cardiotoxicity.

ABSTRACT: 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.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.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, ?-adrenergic agonist-induced activation of ERKs does not require it. Consequently, activation of ?-adrenergic signaling markedly decreases sorafenib-induced cell death. Consistent with these in vitro data, inhibition of ?-adrenergic signaling with the receptor antagonist prazosin worsens sorafenib-induced cardiomyopathy in zebrafish.Zebrafish may be a valuable preclinical tool to predict cardiotoxicity. The ?-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 ?-adrenergic activation that bypasses Raf to activate ERKs.

SUBMITTER: Cheng H

PROVIDER: S-EPMC3908774 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A novel preclinical strategy for identifying cardiotoxic kinase inhibitors and mechanisms of cardiotoxicity.

Cheng Hui H Kari Gabor G Dicker Adam P AP Rodeck Ulrich U Koch Walter J WJ Force Thomas T

Circulation research 20111013 12

<h4>Rationale</h4>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.<h4>Objectives</h4>To explore the potential use of zebrafish as a preclinical model to ...[more]

PMID: 21998323

Similar Datasets

Project description:Tyrosine kinase inhibitors (TKIs) are characterized as multi-targeted anticancer agents that lack specificity, leading to cardiovascular adverse effects. To date, there are no reliable means to predict the cardiotoxicity of TKIs under development. The present study assessed the usual variants of genes to determine the molecular targets of TKIs associated with heart failure (HF). Gene or gene products affected by TKIs were assessed using the Drug Gene Interaction Database. These genes were investigated in genome-wide association studies (GWAS) datasets associated with HF at a genome-wide significant level (P<1×10-5). Subsequently, single-nucleotide polymorphisms (SNPs) that reached the established GWAS threshold (P<5×10-8) were investigated for genome-wide significance. Based on a threshold score of 3, nine gene loci yielded associations according to their biological function using RegulomeDB. Finally, comprehensive functional analysis of SNPs was performed using bioinformatics databases to identify potential drug targets. Using rSNPBase, rs7115242, rs143160639 and rs870064 were found to interfere with proximal transcription regulation, while rs7115242, rs143160639 and rs117153772 were involved in distal regulation, and most SNPs participated in post-transcriptional RNA binding protein-mediated regulation. rs191188930 on platelet-derived growth factor receptor (PDGFR) α was associated with numerous TKI drugs, including sunitinib, pazopanib, sorafenib, dasatinib and nilotinib. Using RegulomeDB and HaploReg v4.1, rs191188930 was predicted to be located in enhancer histone markers. PhenoScanner GWAS analysis revealed that rs191188930 was associated with other diseases or phenotypes, in addition to HF. Genotype-Tissue Expression analysis indicated that the PDGFRα gene had the highest median expression in 'Cells-Transformed fibroblasts', and the Search Tool for the Retrieval of Interacting Genes/Proteins revealed the protein-protein interaction network of PDGFRα. The present findings demonstrated the overlap of TKI-induced genes and those mediating HF risk, suggesting molecular mechanisms potentially responsible for TKI-induced HF risk. Additionally, the present genetic study may be helpful to further investigate off-target drug effects.

Project description:IntroductionBile duct cancer (cholangiocarcinoma, CCA) has a poor prognosis for patients, and despite recent advances in targeted therapies for other cancer types, it is still treated with standard chemotherapy. Anaplastic lymphoma kinase (ALK) has been shown to be a primary driver of disease progression in lung cancer, and ALK inhibitors are effective therapeutics in aberrant ALK-expressing tumors. Aberrant ALK expression has been documented in CCA, but the use of ALK inhibitors has not been investigated. Using CCA cell lines and close-to-patient primary cholangiocarcinoma cells, we investigated the potential for ALK inhibitors in CCA.MethodsALK, cMET, and ROS1 expression was determined in CCA patient tissue by immunohistochemistry and digital droplet polymerase chain reaction, and that in cell lines was determined by immunoblot and immunofluorescence. The effect on cell viability and mechanism of action of ALK, cMet, and ROS1 inhibitors was determined in CCA cell lines. To determine whether ceritinib could affect primary CCA cells, tissue was taken from four patients with biliary tract cancer, without ALK rearrangement, mutation, or overexpression, and grown in three-dimensional tumor growth assays in the presence or absence of humanized mesenchymal cells.ResultsALK and cMet but not ROS were both upregulated in CCA tissues and cell lines. Cell survival was inhibited by crizotinib, a c-met/ALK/ROS inhibitor. To determine the mechanism of this effect, we tested c-Met-specific and ALK/ROS-specific inhibitors, capmatinib and ceritinib, respectively. Whereas capmatinib did not affect cell survival, ceritinib dose-dependently inhibited survival in all cell lines, with IC50 ranging from 1 to 9 µM and co-treatments with gemcitabine and cisplatin further sensitized cells, with IC50 ranging from IC50 0.60 to 2.32 µM. Ceritinib did not inhibit cMet phosphorylation but did inhibit ALK phosphorylation. ALK was not mutated in any of these cell lines. Only ceritinib inhibited 3D growth of all four patient samples below mean peak serum concentration, in the presence and absence of mesenchymal cells, whereas crizotinib and capmatinib failed to do this. Ceritinib appeared to exert its effect more through autophagy than apoptosis.DiscussionThese results indicate that ceritinib or other ALK/ROS inhibitors could be therapeutically useful in cholangiocarcinoma even in the absence of aberrant ALK/ROS1 expression.

Dataset Information

A novel preclinical strategy for identifying cardiotoxic kinase inhibitors and mechanisms of cardiotoxicity.

Publications

A novel preclinical strategy for identifying cardiotoxic kinase inhibitors and mechanisms of cardiotoxicity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets