Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone deacetylases (HDACs) mediate changes in nucleosome conformation and are important in the regulation of gene expression. HDACs are involved in cell cycle progression and differentiation, and their deregulation is associated with several cancers. HDAC inhibitors have emerged recently as promising chemotherapeutic agents. One such agent, suberoylanilide hydroxamic acid, is a potent inhibitor of HDACs that causes growth arrest, differentiation, and/or apoptosis of many tumor types in vitro and in vivo. Because of its low toxicity, suberoylanilide hydroxamic acid is currently in clinical trials for the treatment of cancer. HDAC inhibitors induce the expression of <2% of genes in cultured cells. In this study, we show that low micromolar concentrations of suberoylanilide hydroxamic acid induce the expression of 15-lipoxygenase-1 in human colorectal cancer cells. The expression of 15-lipoxygenase-1 correlates with suberoylanilide hydroxamic acid-induced increase in 13-S-hydroxyoctadecadienoic acid levels, growth inhibition, differentiation, and apoptosis observed with these cells. Furthermore, specific inhibition of 15-lipoxygenase-1 significantly reduced the suberoylanilide hydroxamic acid-induced effects. These novel findings are the first demonstration of a mechanistic link between the induction of 15-lipoxygenase-1 by a HDAC inhibitor and apoptosis in cancer cells. This result has important implications for the study of suberoylanilide hydroxamic acid and other HDAC inhibitors in the prevention and therapy of colorectal cancer and supports future investigations of the mechanisms by which HDAC inhibitors up-regulate 15-lipoxygenase-1.
 ...
PMID:The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis via induction of 15-lipoxygenase-1 in colorectal cancer cells. 1557 91

Valproic acid (VA) is a well-tolerated drug used to treat seizure disorders and has recently been shown to inhibit histone deacetylase (HDAC). Because HDAC modulates chromatin structure and gene expression, parameters considered to influence radioresponse, we investigated the effects of VA on the radiosensitivity of human brain tumor cells grown in vitro and in vivo. The human brain tumor cell lines SF539 and U251 were used in our study. Histone hyperacetylation served as an indicator of HDAC inhibition. The effects of VA on tumor cell radiosensitivity in vitro were assessed using a clonogenic survival assay and gammaH2AX expression was determined as a measure of radiation-induced DNA double strand breaks. The effect of VA on the in vivo radioresponse of brain tumor cells was evaluated according to tumor growth delay analysis carried out on U251 xenografts. Irradiation at the time of maximum VA-induced histone hyperacetylation resulted in significant increases in the radiosensitivity of both SF539 and U251 cells. The radiosensitization was accompanied by a prolonged expression of gammaH2AX. VA administration to mice resulted in a clearly detectable level of histone hyperacetylation in U251 xenografts. Irradiation of U251 tumors in mice treated with VA resulted in an increase in radiation-induced tumor growth delay. Valproic acid enhanced the radiosensitivity of both SF539 and U251 cell lines in vitro and U251 xenografts in vivo, which correlated with the induction of histone hyperacetylation. Moreover, the VA-mediated increase in radiation-induced cell killing seemed to involve the inhibition of DNA DSB repair.
 ...
PMID:Enhancement of in vitro and in vivo tumor cell radiosensitivity by valproic acid. 1557 1

Histone deacetylases (HDACs) regulate transcription and specific cellular functions, such as tumor suppression by p53, and are frequently altered in cancer. Inhibitors of HDACs (HDACIs) possess antitumor activity and are well tolerated, supporting the idea that their use might develop as a specific strategy for cancer treatment. The molecular basis for their selective antitumor activity is, however, unknown. We investigated the effects of HDACIs on leukemias expressing the PML-RAR or AML1-ETO oncoproteins, known to initiate leukemogenesis through deregulation of HDACs. Here we report that: (i) HDACIs induce apoptosis of leukemic blasts, although oncogene expression is not sufficient to confer HDACI sensitivity to normal cells; (ii) apoptosis is p53 independent and depends, both in vitro and in vivo, upon activation of the death receptor pathway (TRAIL and Fas signaling pathways); (iii) TRAIL, DR5, FasL and Fas are upregulated by HDACIs in the leukemic cells, but not in normal hematopoietic progenitors. These results show that sensitivity to HDACIs in leukemias is a property of the fully transformed phenotype and depends on activation of a specific death pathway.
 ...
PMID:Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. 1561 34

Aberrant gene regulation plays an important role in tumor initiation and progression, and the acetylation of histones is a well understood key component of gene regulation. Histone acetylation involves the opposing activities of the histone acetyltransferases (HATs) and histone deacetylases (HDACs)--histone acetylation is associated with increased transcriptional activity while histone deacetylation is associated with repression of gene expression. In addition, the modification of non-histone proteins by HATs and HDACs is also an important process in regulating gene expression. Several lines of evidence suggest that inappropriate transcriptional activation and repression mediated by HATs and HDACs is a common occurrence in the formation of many different types of cancer. These enzymes thus represent novel molecular targets for which inhibitors are sought that could reprogram transcription and inhibit tumor cell growth and progression. Much of the research has focused on HDAC inhibitors, where several agents have demonstrated in vitro and in vivo activity against different tumor cell models and have entered Phase I clinical trials. HDAC inhibitors are believed to exert their antiproliferative effects by inducing a small set of genes involved in regulating cellular activities such as proliferation and differentiation. Future research is expected to lead to a better understanding of the molecular targets of HDACs and facilitate the development of more potent inhibitors of these enzymes. First results from clinical trials will help to determine the optimal strategy for utilizing these agents for the treatment of cancer patients.
 ...
PMID:Histone deacetylase inhibitors and cancer: from cell biology to the clinic. 1581 94

The activity of genes encoded by the highly-condensed DNA in cellular nuclei must be precisely regulated. Regulation of the accessibility of gene promoters to transcription complexes is one level of gene regulation and is influenced by histone tail modifications such as acetylation, methylation, and phosphorylation. Acetylation is a reversible modification catalyzed by histone acetyl transferase (HAT) and histone deacetyltransferase (HDAC) enzymes. Histone deacetylation is associated with transcriptional repression of genes, as the removal of acetyl groups from lysine residues allows for tighter electrostatic interactions between DNA and histones, limiting accessibility of the DNA for transcription. Inhibition of HDAC activity permits histones to remain in an acetylated state, and through the resulting alterations in gene regulation, inhibits cell cycle progression, inhibits differentiation, and in some cases induces apoptosis. Inhibition of proliferation by HDAC inhibitors is characterized by arrest at the G1 or G2/M phases of the cell cycle. Many types of tumor cells then undergo programmed cell death. Exposure to HDAC inhibitors may also allow reactivation of tumor suppressor genes which had been silenced by hypoacetylation during tumorigenesis. HDAC inhibitors from a number of chemical classes have shown promise as anti-cancer agents in animal studies and early clinical trials. The development of HDAC inhibitors which specifically target HDAC isozymes, and more detailed understanding of their anti-neoplastic actions, heralds a new epigenetic antitumor therapeutic strategy.
 ...
PMID:A mechanistic approach to anticancer therapy: targeting the cell cycle with histone deacetylase inhibitors. 1585 58

Histone deacetylases (HDAC) and histone acetyltransferases exert opposing enzymatic activities that modulate the degree of acetylation of histones and other intracellular molecular targets, thereby regulating gene expression, cellular differentiation, and survival. HDAC inhibition results in accumulation of acetylated histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of two HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and m-carboxycinnamic acid bis-hydroxamide, on thyroid carcinoma cell lines, including lines originating from anaplastic and medullary carcinomas. In these models, both SAHA and m-carboxycinnamic acid bis-hydroxamide induced growth arrest and caspase-mediated apoptosis and increased p21 protein levels, retinoblastoma hypophosphorylation, BH3-interacting domain death agonist cleavage, Bax up-regulation, down-regulation of Bcl-2, A1, and Bcl-x(L) expression, and cleavage of poly(ADP-ribose) polymerase and caspase-8, -9, -3, -7, and -2. Transfection of Bcl-2 cDNA partially suppressed SAHA-induced cell death. SAHA down-regulated the expression of the apoptosis inhibitors FLIP and cIAP-2 and sensitized tumor cells to cytotoxic chemotherapy and death receptor activation. Our studies provide insight into the tumor type-specific mechanisms of antitumor effects of HDAC inhibitors and a framework for future clinical applications of HDAC inhibitors in patients with thyroid cancer, including histologic subtypes (e.g., anaplastic and medullary thyroid carcinomas) for which limited, if any, therapeutic options are available.
 ...
PMID:Novel histone deacetylase inhibitors in the treatment of thyroid cancer. 1589 98

Histone deacetylases (HDACs) regulate transcription and specific functions, such as tumor suppression by p53, and are frequently altered in cancer. Inhibitors of HDACs (HDACI) possess anti-tumor activity and are well tolerated, suggesting that they might develop into a specific strategy for cancer treatment. Indeed, HDACIs have successfully entered clinical trials, but the molecular basis for their selective anti-tumor activities is not clear. Recent work on leukemias expressing the PML-RAR or AML1-ETO oncogenes, known to initiate leukemogenesis through deregulation of HDACs, shows that HDACIs induce massive blast-cell apoptosis. Interestingly, the pro-apoptotic activity of the drug is not due to the relief of oncogene-mediated inhibition of the p53 tumor-suppressor pathway but, instead, relies on the selective upregulation of the death receptors DR5 and Fas and their cognate ligands TRAIL and FasL. Significantly, normal myeloid progenitors are not sensitive to HDACI-induced apoptosis and oncogene expression is not sufficient to confer HDACI-sensitivity to normal cells, demonstrating that sensitivity to HDACI is a property of the fully transformed phenotype. In principle, our findings could thus apply to other cancers, where the contribution of HDACs to tumorigenesis is not yet defined.
 ...
PMID:Mechanisms of selective anticancer action of histone deacetylase inhibitors. 1590 87

Inhibitors of histone deacetylases (HDACs) activate the sodium iodide symporter (NIS) expression in thyroid tumor cells. In this study, mechanisms accounting for these effects were investigated. Various human thyroid tumor cell lines (ARO, BCPAP, FRO, TPC-1) were treated with the HDAC inhibitors Na butyrate (NaB) and tricostatin A (TSA), and the effects on the expression of NIS and several thyroid-specific transcription factors together with the activity of NIS promoter were evaluated. TSA and NaB increased NIS mRNA levels in all cell lines. Among thyroid-specific transcription factors, only expression of PAX8 in ARO cells was increased. Down-regulation of thyroid-specific transcription factor-1 expression was observed in BCPAP and TPC-1 cell lines. Thyroid-specific transcription factor-2 mRNA was reduced in FRO, BCPAP, and TPC-1 cells. Histone acetylation had no significant effects on HEX expression. Altogether, these data indicate that the increase of NIS expression is not mediated by modification of expression of thyroid-specific transcription factors. Accordingly, in transfection experiments performed in the HeLa cell line (which does not express thyroid-specific transcription factors), treatment with TSA and NaB increased NIS promoter activity. Stimulation of NIS promoter activity was also obtained by overexpressing histone acetylating proteins pCAF and p300 in HeLa cells. Conversely, overexpression of the HDAC 1 enzyme inhibited basal activity of the NIS promoter. Effects of TSA and NaB on NIS expression were also evaluated in nonthyroid cell lines MCF-7, Hep-G2, and SAOS-2. In all cell lines TSA and NaB greatly increased NIS mRNA levels. We concluded that control of NIS expression by inhibition of HDAC appears not to be mediated by cell-specific mechanisms, suggesting it as a potential strategy to induce radioiodine sensitivity in different human tumors.
 ...
PMID:Effects of histone acetylation on sodium iodide symporter promoter and expression of thyroid-specific transcription factors. 1591 54

The acetylation and deacetylation of histones mediated by histone acetylases and deacetylases influence DNA accessibility to factors regulating replication, repair, and transcription. Histone deacetylases inhibitors (HDI) are inducers of growth arrest, differentiation, and/or apoptosis of many tumors cells by altering the transcription of a small number of genes. The selective tumor specificity of these compounds underscores their potential as new agents for the treatment of cancer. Several HDI have shown anti-tumor activity in vitro and in vivo with remarkably low toxicity in preclinical studies and are currently in phase I and II clinical trials. This review summarizes the molecular mechanism of action of HDI and its clinical application in the treatment of cancer.
 ...
PMID:[Histone deacetylase inhibitors as a new generation of anti-cancer agents]. 1592 89

Histone deacetylases (HDACs) have recently emerged as an important target for therapeutic intervention in cancer and potentially other human diseases. By modulating the acetylation status of histones, histone deacetylase inhibitors (HDACIs) alter the transcription of genes involved in cell growth, maturation, survival and apoptosis, among other processes. Early clinical results suggest a potentially useful role for HDACIs in the treatment of certain forms of lymphoma (e.g., cutaneous T cell lymphoma) and acute leukaemia. An unresolved question is how HDACIs induce cell death in tumour cells. Recent studies suggest that acetylation of nonhistone proteins may play an important role in the biological effects of this class of compounds, and may explain lack of correlation between histone acetylation and induction of cell death by HDACIs in some circumstances. Recently, attention has focussed on the effects of HDACIs on disruption of co-repressor complexes, induction of oxidative injury, upregulation of the expression of death receptors, generation of lipid second messengers such as ceramide, interference with the function of chaperone proteins and modulation of the activity of NF-kappaB as critical determinants of lethality. Aside from providing critical insights into the mechanism of action of HDACIs in neoplastic disease, these findings may provide a foundation for the rational development of combination studies, involving HDACIs in combination with either conventional cytotoxic drugs as well as more novel targeted agents.
 ...
PMID:Histone deacetylase inhibitors: insights into mechanisms of lethality. 1608 44


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>