Synergistic effect of trichostatin A and 5‐aza‐2′‐deoxycytidine on growth inhibition of pancreatic endocrine tumour cell lines: A proteomic study

Cecconi, Daniela; Donadelli, Massimo; Pozza, Elisa Dalla; Rinalducci, Sara; Zolla, Lello; Scupoli, Maria Teresa; Righetti, Pier Giorgio; Scarpa, Aldo; Palmieri, Marta

doi:10.1002/pmic.200701089

Cited by 37 publications

(30 citation statements)

References 61 publications

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“…Treatment of cell lines with TSA after 5-Aza-dC increased BMP3 expression to a greater extent than treatment with5-Aza-dC alone, suggesting that expression of BMP3 is dependent on histone acetylation as well as promoter methylation. The extent to which this could be tested was limited by the profound apoptotic effects of TSA on cell lines, preventing treatment with TSA prior to 5-Aza-dC [40]. …”

Section: Discussionmentioning

confidence: 99%

Methylated Bone Morphogenetic Protein 3 (BMP3) Gene: Evaluation of Tumor Suppressor Function and Biomarker Potential in Biliary Cancer

Kisie¹,

Li²

2013

J Mol Biomark Diagn

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Background Although cholangiocarcinoma (CC) is an uncommon and highly lethal malignancy, early detection enables the application of potentially curative therapies and improves survival. Consequently, tools to improve the early diagnosis of CC are urgently needed. During a screen for genes epigenetically suppressed by methylation in CC that might serve as methylation markers for CC, we found that the BMP3 gene is methylated in CC cell lines, but the potential diagnostic value and the function of BMP3 in CC are unknown. Methods We aimed to quantitatively assess BMP3 methylation in resected CC tumor specimens using methylation specific PCR and evaluate the tumor suppressor role of BMP3 in biliary cancer cell lines in comparison to an immortalized normal cholangiocyte cell line. Expression of BMP3 was quantified by mRNA levels before and after treatment with 5-Aza-2’-deoxycytidine and trichostatin A. After transfection with a BMP3-containing plasmid, cell viability was measured using the bromodeoxyuridine incorporation assay and apoptosis quantified by caspase assay. Results In primary CC tumor tissue specimens significantly more methylated BMP3 copies were found when compared to matched benign bile duct epithelium from the same patient, with high specificity. BMP3 expression was absent in cell lines with BMP3 methylation; this suppression of BMP3 expression was reversed by treatment with a DNA demethylating agent and histone de-acetylase inhibitor. Transfection of a BMP3-expressing construct into a BMP3-negative biliary cancer cell line restored BMP3 mRNA expression and reduced cell proliferation and cell viability while increasing the rate of apoptosis. Conclusion These findings strongly support a tumor suppressor role for BMP3 in CC and suggest that BMP3 methylation may be a new biomarker for early detection of CCs. of the peptidome are also involved.

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Section: Discussionmentioning

confidence: 99%

Methylated Bone Morphogenetic Protein 3 (BMP3) Gene: Evaluation of Tumor Suppressor Function and Biomarker Potential in Biliary Cancer

Kisie¹,

Li²

2013

J Mol Biomark Diagn

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“…1) HDAC inhibitors were combined with other epigenetic modifiers. Inhibitors of DNA methyl transferases 5-azacytidine (azacitidine) and 5-aza-2'-deoxycytidine (decitabine) had increased antitumor effects when used with HDAC inhibitors [60][61][62][63][64] . Decitabine and VPA both induced apoptosis and the combination increased their effects both in vitro and in vivo 65,66 .…”

Section: Combination Of Histone Deacetylase Inhibitors With Other Thementioning

confidence: 99%

“…Decitabine and VPA both induced apoptosis and the combination increased their effects both in vitro and in vivo 65,66 . Co-treatment of prostate, pancreatic tumor, acute myelogenous leukemia (AML) AML1/ETO-positive and non small cell lung cancer (NSCLC) cells with trichostatin A and decitabine synergistically induced apoptosis 63,64,67,68 . In addition, an inhibitor of histone demethylases (tranylcypromine) and vorinostat showed synergistic enhancement of apoptosis in glioblastoma cells 45 .…”

Section: Combination Of Histone Deacetylase Inhibitors With Other Thementioning

confidence: 99%

Histone deacetylase inhibitors in cancer therapy. A review

Hraběta¹,

Stiborová²,

Adam³

et al. 2014

BIOMED PAP

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a Background. Despite recent success toward discovery of more effective anticancer drugs, chemoresistance remains a major cause of treatment failure. There is emerging evidence that epigenetics plays a key role in the development of the resistance. Epigenetic regulators such as histone acetyltransferases (HATs) and histone deacetylases (HDACs) play an important role in gene expression. The latter are found to be commonly linked with many types of cancers and influence cancer development. Overall, histone acetylation is being investigated as a therapeutic target because of its importance in regulating gene expression. This review summarizes mechanisms of the anticancer effects of histone deacetylase (HDAC) inhibitors and the results of clinical studies. Results. Different HDAC inhibitors induce cancer cell death by different mechanisms that include changes in gene expression and alteration of both histone and non-histone proteins. Enhanced histone acetylation in tumors results in modification of expression of genes involved in cell signaling. Inhibition of HDACs causes changed expression in 2-10 % of genes involved in important biological processes. The results of experiments and clinical studies demonstrate that combination of HDAC inhibitors with some anticancer drugs have synergistic or additive effects. Conclusions. Even though many biological effects of HDAC inhibitors have been found, most of the mechanisms of their action remain unclear. In addition, their use in combination with other drugs and the combination regime need to be investigated. The discovery of predictive factors is also necessary. Finally, a key question is whether the pan-HDAC inhibitors or the selective inhibitors will be more efficient for different types of cancers.

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“…As synergistic effects have been described using 5-AzadC in combination with HDAC inhibitors (38), the cell lines were also treated in combination with TSA. In FTC133 cells treated for 7 days with 0.5 or 1 lM 5-AzadC alone, a faint NIS mRNA expression was observed, which was increased when 5-AzadC was combined with 100 nM TSA during the last 24-72 hours (Fig.…”

Section: Effect Of Drug Combinations and Various Culture Conditions Omentioning

confidence: 99%

5-Aza-2′-Deoxycytidine Has Minor Effects on Differentiation in Human Thyroid Cancer Cell Lines, But Modulates Genes That Are Involved in Adaptation In Vitro

Dom

Galdo

Tarabichi

et al. 2013

Thyroid

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Background: In thyroid cancer, the lack of response to specific treatment, for example, radioactive iodine, can be caused by a loss of differentiation characteristics of tumor cells. It is hypothesized that this loss is due to epigenetic modifications. Therefore, drugs releasing epigenetic repression have been proposed to reverse this silencing. Methods: We investigated which genes were reinduced in dedifferentiated human thyroid cancer cell lines when treated with the demethylating agent 5-aza-2¢-deoxycytidine (5-AzadC) and the histone deacetylase inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid, by using reverse transcriptase-polymerase chain reaction and microarrays. These results were compared to the expression patterns in in vitro human differentiated thyrocytes and in in vivo dedifferentiated thyroid cancers. In addition, the effects of 5-AzadC on DNA quantities and cell viability were investigated. Results: Among the canonical thyroid differentiation markers, most were not, or only to a minor extent, reexpressed by 5-AzadC, whether or not combined with TSA or forskolin, an inducer of differentiation in normal thyrocytes. Furthermore, 5-AzadC-modulated overall mRNA expression profiles showed only few commonly regulated genes compared to differentiated cultured primary thyrocytes. In addition, most of the commonly strongly 5-AzadC-induced genes in cell lines were either not regulated or upregulated in anaplastic thyroid carcinomas. Further analysis of which genes were induced by 5-AzadC showed that they were involved in pathways such as apoptosis, antigen presentation, defense response, and cell migration. A number of these genes had similar expression responses in 5-AzadC-treated nonthyroid cell lines. Conclusions: Our results suggest that 5-AzadC is not a strong inducer of differentiation in thyroid cancer cell lines. Under the studied conditions and with the model used, 5-AzadC treatment does not appear to be a potential redifferentiation treatment for dedifferentiated thyroid cancer. However, this may reflect primarily the inadequacy of the model rather than that of the treatment. Moreover, the observation that 5-AzadC negatively affected cell viability in cell lines could still suggest a therapeutic opportunity. Some of the genes that were modulated by 5-AzadC were also induced in nonthyroid cancer cell lines, which might be explained by an epigenetic modification resulting in the adaptation of the cell lines to their culture conditions.

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Synergistic effect of trichostatin A and 5‐aza‐2′‐deoxycytidine on growth inhibition of pancreatic endocrine tumour cell lines: A proteomic study

Cited by 37 publications

References 61 publications

Methylated Bone Morphogenetic Protein 3 (BMP3) Gene: Evaluation of Tumor Suppressor Function and Biomarker Potential in Biliary Cancer

Methylated Bone Morphogenetic Protein 3 (BMP3) Gene: Evaluation of Tumor Suppressor Function and Biomarker Potential in Biliary Cancer

Histone deacetylase inhibitors in cancer therapy. A review

5-Aza-2′-Deoxycytidine Has Minor Effects on Differentiation in Human Thyroid Cancer Cell Lines, But Modulates Genes That Are Involved in Adaptation In Vitro

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