Development of cardiac hypertrophy by sunitinib in vivo and in vitro rat cardiomyocytes is influenced by the aryl hydrocarbon receptor signaling pathway

Maayah, Zaid H.; Ansari, Mushtaq A.; Gendy, Mohamed A.M. El; Al-Arifi, Mohammed N.; Korashy, Hesham M.

doi:10.1007/s00204-013-1159-5

Cited by 36 publications

(42 citation statements)

References 59 publications

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“…In this context, we have recently shown that development of cardiac hypertrophy by SUN in vivo and in vitro rat cardiomyocytes is influenced by the aryl hydrocarbon receptor signaling pathway [33]. In addition, previous mechanistic studies have reported that SUN elicits harmful cardiac effects through inhibiting AMPK and RSK and damaging the mitochondrial [34] and increased autophagic flux [35].…”

Section: Discussionmentioning

confidence: 93%

Mitogen-Activated Protein Kinases Pathways Mediate the Sunitinib-Induced Hypertrophy in Rat Cardiomyocyte H9c2 Cells

et al. 2014

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Sunitinib (SUN) is a multi-targeted tyrosine kinase inhibitor used for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Cardiotoxicity has been reported as a significant side effect associated with the SUN treatment, yet the mechanism is poorly understood. The main purpose of this study was to investigate the potential effects of SUN on cardiac hypertrophic genes and the role of mitogen-activated protein kinases (MAPKs) signaling pathway in rat cardiomyocyte H9c2 cell line. In the present study, real-time quantitative polymerase chain reaction showed that the treatment of H9c2 cells with increasing concentrations of SUN (0, 1, 2.5, and 5 µM) significantly induced hypertrophic gene markers, such as brain natriuretic peptides (BNP) and myosin heavy chain (β-MHC and α-MHC) in concentration- and time-dependent manners. The onset of mRNA induction was observed as early as 9 h and remained elevated for at least 18 h after treatment with SUN 5 µM. At the protein level, Western blot analysis showed that SUN increased BNP and β-MHC, while it inhibited α-MHC protein levels in a concentration-dependent manner. These SUN-mediated effects were associated with increase in cell size and hypertrophy by approximately 70 % at the highest concentration, 5 µM. Importantly, inhibition of the MAPK signaling pathway using SB203580 (p38 MAPK inhibitor), U0126 (extracellular signal-regulated kinase inhibitor), and SP600125 (c-Jun NH2-terminal kinase inhibitor) significantly potentiated the SUN-induced BNP and β-MHC mRNA levels, but did alter the α-MHC level. Whereas at the protein level, MAPK inhibitors generally decreased the SUN-induced BNP, whereas only SB and U0 increased β-MHC protein levels with no effect on α-MHC, which were associated with a significant decrease in cell size. Together, these results indicate that SUN induced hypertrophic gene expression through MAPK-dependent mechanisms.

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Section: Discussionmentioning

confidence: 93%

Mitogen-Activated Protein Kinases Pathways Mediate the Sunitinib-Induced Hypertrophy in Rat Cardiomyocyte H9c2 Cells

et al. 2014

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“…Callero et al reported that activating AHR with an agonist inhibited cell growth in a dose-dependent manner in RCC cell lines (24 ). It was also found that sunitinib, a tyrosine kinase inhibitor used for metastatic ccRCC, induced CYP1A1 expression through AHR in breast cancer (25 ). Aminoflavone, which has an antiproliferative effect on human breast cancer cells mediated by AHR, is also applied in clinical trials as a new anticancer drug.…”

Section: Discussionmentioning

confidence: 99%

Integrative Bioinformatics Analysis Reveals New Prognostic Biomarkers of Clear Cell Renal Cell Carcinoma

et al. 2014

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BACKGROUND The outcome of clear cell renal cell carcinoma (ccRCC) is still unpredictable. Even with new targeted therapies, the average progression-free survival is dismal. Markers for early detection and progression could improve disease outcome. METHODS To identify efficient and hitherto unrecognized pathogenic factors of the disease, we performed a uniquely comprehensive pathway analysis and built a gene interaction network based on large publicly available data sets assembled from 28 publications, comprising a 3-prong approach with high-throughput mRNA, microRNA, and protein expression profiles of 593 ccRCC and 389 normal kidney samples. We validated our results on 2 different data sets of 882 ccRCC and 152 normal tissues. Functional analyses were done by proliferation, migration, and invasion assays following siRNA (small interfering RNA) knockdown. RESULTS After integration of multilevel data, we identified aryl-hydrocarbon receptor (AHR), grainyhead-like-2 (GRHL2), and KIAA0101 as new pathogenic factors. GRHL2 expression was associated with higher chances for disease relapse and retained prognostic utility after controlling for grade and stage [hazard ratio (HR), 3.47, P = 0.012]. Patients with KIAA0101-positive expression suffered worse disease-free survival (HR, 3.64, P < 0.001), and in multivariate analysis KIAA0101 retained its independent prognostic significance. Survival analysis showed that GRHL2- and KIAA0101-positive patients had significantly lower disease-free survival (P = 0.002 and P < 0.001). We also found that KIAA0101 silencing decreased kidney cancer cell migration and invasion in vitro. CONCLUSIONS Using an integrative system biology approach, we identified 3 novel factors as potential biomarkers (AHR, GRHL2 and KIAA0101) involved in ccRCC pathogenesis and not linked to kidney cancer before.

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“…The protection against cisplatin and arsenic trioxide-induced cardiotoxicity has been attributed to the increase in the endogenous anti-oxidant enzymes activity namely, SOD, catalase, and glutathione peroxidase [270,277], in addition to activation of the anti-oxidant NRF2-heme oxygenase-1 pathway [276], suggesting the importance of the anti-oxidant properties of resveratrol in these models as well. Recently, an in vitro study has reported that resveratrol protects against sunitinib-induced hypertrophy in H9c2 cells [278]. The authors of that study proposed that resveratrol prevents hypertrophy by antagonizing the aryl hydrocarbon receptor (AhR) and inhibiting CYP1A1 enzyme [278], suggesting that resveratrol may also protect against chemotherapy-induced cardiomyopathy through its AhR-antagonistic properties.…”

Section: Chemotherapy-induced Cardiotoxicitymentioning

confidence: 99%

Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases

Zordoky

Robertson

Dyck

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

278

217

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Cardiovascular disease is the leading cause of death worldwide. Despite advancements in diagnosis and treatment of cardiovascular disease, the incidence of cardiovascular disease is still rising. Therefore, new lines of medications are needed to treat the growing population of patients with cardiovascular disease. Although the majority of the existing pharmacotherapies for cardiovascular disease are synthesized molecules, natural compounds, such as resveratrol, are also being tested. Resveratrol is a non-flavonoid polyphenolic compound, which has several biological effects. Preclinical studies have provided convincing evidence that resveratrol has beneficial effects in animal models of hypertension, atherosclerosis, stroke, ischemic heart disease, arrhythmia, chemotherapy-induced cardiotoxicity, diabetic cardiomyopathy, and heart failure. Although not fully delineated, some of the beneficial cardiovascular effects of resveratrol are mediated through activation of silent information regulator 1 (SIRT1), AMP-activated protein kinase (AMPK), and endogenous anti-oxidant enzymes. In addition to these pathways, the anti-inflammatory, anti-platelet, insulin-sensitizing, and lipid-lowering properties of resveratrol contribute to its beneficial cardiovascular effects. Despite the promise of resveratrol as a treatment for numerous cardiovascular diseases, the clinical studies for resveratrol are still limited. In addition, several conflicting results from trials have been reported, which demonstrates the challenges that face the translation of the exciting preclinical findings to humans. Herein, we will review much of the preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular disease and provide information about the physiological and molecular signaling mechanisms involved. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.

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Development of cardiac hypertrophy by sunitinib in vivo and in vitro rat cardiomyocytes is influenced by the aryl hydrocarbon receptor signaling pathway

Cited by 36 publications

References 59 publications

Mitogen-Activated Protein Kinases Pathways Mediate the Sunitinib-Induced Hypertrophy in Rat Cardiomyocyte H9c2 Cells

Mitogen-Activated Protein Kinases Pathways Mediate the Sunitinib-Induced Hypertrophy in Rat Cardiomyocyte H9c2 Cells

Integrative Bioinformatics Analysis Reveals New Prognostic Biomarkers of Clear Cell Renal Cell Carcinoma

Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases

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