HDAC inhibitors in models of inflammation-related tumorigenesis

Glauben, Rainer; Sonnenberg, Elena; Zeitz, Martin; Siegmund, Britta

doi:10.1016/j.canlet.2008.11.019

Cited by 68 publications

(45 citation statements)

References 50 publications

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“…For instance, antiinflammatory drugs or agents such as histone deacetylator inhibitor, naturally occurring phytoceuticals, and other synthetic chemicals could provide chemopreventive effects in models of inflammation-related tumorigenesis (21). In the current study, we added novel evidence that omeprazole, administered at longer time periods, could reverse the progression of inflammation-initiated or promoted carcinogenic step.…”

Section: Discussionmentioning

confidence: 66%

Novel Application of Proton Pump Inhibitor for the Prevention of Colitis-Induced Colorectal Carcinogenesis beyond Acid Suppression

Kim

Lee

Hong

et al. 2010

Cancer Prevention Research

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Colitis-associated cancers arise in the setting of chronic inflammation wherein an "inflammationdysplasia-carcinoma" sequence prevails. Based on our previous findings in which the proton pump inhibitor could impose significant levels of anti-inflammatory, antiangiogenic, and selective apoptosis induction beyond gastric acid suppression, we investigated whether omeprazole could prevent the development of colitis-associated cancer in a mouse model induced by repeated bouts of colitis. Omeprazole, 10 mg/kg, was given i.p. all through the experimental periods for colitis-associated carcinogenesis. Molecular changes regarding inflammation and carcinogenesis were compared between control groups and colitis-associated cancer groups treated with omeprazole in addition to chemopreventive outcome. Nine of 12 (75.0%) mice in the control group developed multiple colorectal tumors, whereas tumors were noted in only 3 of 12 (25.0%) mice treated with daily injections of omeprazole. The cancer-preventive results of omeprazole treatment was based on significant decreases in the levels of nitric oxide, thiobarbituric acid-reactive substance, and interleukin-6 accompanied with attenuated expressions of tumor necrosis factor-α, inducible nitric oxide synthase, and cyclooxygenase-2. The expressions of matrix metalloproteinase (MMP)-9, MMP-11, and MT1-MMMP were significantly decreased in mice treated with omeprazole in accordance with significant decreases in the number of β-catenin-accumulated crypts. A significant induction of apoptosis was observed in tumor tissue treated with omeprazole. Omeprazole could block the trophic effect of gastrin in colon epithelial cells. The significant anti-inflammatory, antioxidative, and antimutagenic activities of omeprazole played a cancer-preventive role against colitisinduced carcinogenesis, and our novel in vivo evidence is suggestive of chemopreventive action independent of gastric acid suppression. Cancer Prev Res; 3(8); 963-74. ©2010 AACR.

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Section: Discussionmentioning

confidence: 66%

Novel Application of Proton Pump Inhibitor for the Prevention of Colitis-Induced Colorectal Carcinogenesis beyond Acid Suppression

Kim

Lee

Hong

et al. 2010

Cancer Prevention Research

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“…However, epigenetic priming agents, such as HDACis and hypomethylating molecules will most likely be more effective as part of a combined therapeutic approach in leukemia and cancer [45][46][47]. HDACis are associated with several modes of antitumor activity including modulation of the immune response [48], cell cycle arrest, promotion of differentiation, senescence, and apoptosis [46]. Harnessing the beneficial properties of such compounds while limiting cytotoxic effects will improve their future use particularly in combination therapy.…”

Section: Discussionmentioning

confidence: 99%

Entinostat Prevents Leukemia Maintenance in a Collaborating Oncogene-Dependent Model of Cytogenetically Normal Acute Myeloid Leukemia

et al. 2013

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The incidence of refractory acute myeloid leukemia (AML) is on the increase due in part to an aging population that fails to respond to traditional therapies. High throughput genomic analysis promises better diagnosis, prognosis, and therapeutic intervention based on improved patient stratification. Relevant preclinical models are urgently required to advance drug development in this area. The collaborating oncogenes, HOXA9 and MEIS1, are frequently co-overexpressed in cytogenetically normal AML (CN-AML), and a conditional transplantation mouse model was developed that demonstrated oncogene dependency and expression levels comparable to CN-AML patients. Integration of gene signatures obtained from the mouse model and a cohort of CN-AML patients using statistically significant connectivity map analysis identified Entinostat as a drug with the potential to alter the leukemic condition toward the normal state. Ex vivo treatment of leukemic cells, but not age-matched normal bone marrow controls, with Entinostat validated the gene signature and resulted in reduced viability in liquid culture, impaired colony formation, and loss of the leukemia initiating cell. Furthermore, in vivo treatment with Entinostat resulted in prolonged survival of leukemic mice. This study demonstrates that the HDAC inhibitor Entinostat inhibits disease maintenance and prolongs survival in a clinically relevant murine model of cytogenetically normal

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“…89,91 HDACis have received significant attention as novel agents for rheumatoid arthritis, 96 capable of reducing inflammation, synovial fibroblast proliferation, joint swelling and bone and cartilage destruction in rodent models of rheumatoid arthritis. [97][98][99][100][101][102] Preclinical efficacy has also been observed in models of inflammatory bowel disease 95,103,104 and central nervous system inflammation. 105,106 For inflammatory diseases with no currently effective treatments, such as idiopathic pulmonary fibrosis, HDACis may offer a new therapeutic approach.…”

Section: Antiinflammatory Effects Of Hdacismentioning

confidence: 96%

Protein Acetylation in the Cardiorenal Axis

Bush

McKinsey

2010

Circulation Research

116

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Acetylation of histone and nonhistone proteins provides a key mechanism for controlling signaling and gene expression in heart and kidney. Pharmacological inhibition of protein deacetylation with histone deacetylase (HDAC) inhibitors has shown promise in preclinical models of cardiovascular and renal disease. Efficacy of HDAC inhibitors appears to be governed by pleiotropic salutary actions on a variety of cell types and pathophysiological processes, including myocyte hypertrophy, fibrosis, inflammation and epithelial-tomesenchymal transition, and occurs at compound concentrations below the threshold required to elicit toxic side effects. We review the roles of acetylation/deacetylation in the heart and kidney and provide rationale for extending HDAC inhibitors into clinical testing for indications involving these organs. (Circ Res. 2010; 106:272-284.)Key Words: acetylation Ⅲ histone deacetylase Ⅲ heart failure Ⅲ kidney failure Ⅲ fibrosis I t has been estimated that more than 5 million adults in the United States experience heart failure, and more than 20 million adults show signs of chronic kidney disease (CKD). 1,2 Of the patients with heart failure, Ϸ50% experience heart failure with preserved ejection fraction (HFpEF), also known as diastolic heart failure, which is characterized at the cellular level by myocyte hypertrophy and activation of extracellular matrix (ECM)-producing fibroblasts. Current standard of care for systolic heart failure (eg, ACE inhibitors and ␤-blockers) provide little to no benefit to patients with HFpEF. 3 Likewise, therapy for CKD primarily focuses on lowering blood pressure through modulation of the renin-angiotensin system and maintaining blood glucose control, and this strategy only minimally slows the glomerular injury and insidious fibrotic mechanisms that culminate in end-stage renal disease. 4 The high rate of morbidity and mortality in patients with HFpEF and CKD underscores the urgent need for novel therapeutics. Histone deacetylases (HDACs) are emerging as key players in the pathogenesis of these diseases, suggesting unexpected potential for pharmacological inhibitors of HDACs in the treatment of disorders of the cardiorenal axis.Histone acetyltransferases (HATs) and HDACs act in an opposing manner to control the acetylation state of proteins. The most well characterized role for protein acetylation is in Original received September 15, 2009; revision received October 6, 2009; accepted October 27, 2009 the control of gene transcription. Acetylation of the -amino groups of lysine residues in nucleosomal histone tails by HATs is thought to relax chromatin structure by weakening the interaction of the positively charged histone tails with the negatively charged phosphate backbone of DNA, allowing access of transcriptional activators and gene induction. Deacetylation of histones by HDACs alters the electrostatic properties of chromatin in a manner that favors gene repression. Interestingly, a recent genome-wide chromatin immunoprecipitation analysis revealed preferen...

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HDAC inhibitors in models of inflammation-related tumorigenesis

Cited by 68 publications

References 50 publications

Novel Application of Proton Pump Inhibitor for the Prevention of Colitis-Induced Colorectal Carcinogenesis beyond Acid Suppression

Novel Application of Proton Pump Inhibitor for the Prevention of Colitis-Induced Colorectal Carcinogenesis beyond Acid Suppression

Entinostat Prevents Leukemia Maintenance in a Collaborating Oncogene-Dependent Model of Cytogenetically Normal Acute Myeloid Leukemia

Protein Acetylation in the Cardiorenal Axis

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