Histone deacetylase inhibitors such as sodium butyrate and trichostatin A induce apoptosis through an increase of the bcl-2-related protein Bad

Sawa, Hiroki; Murakami, Hiromi; Ohshima, Yuko; Sugino, Toshiyuki; Nakajyo, Takahito; Kisanuki, Takao; Tamura, Yasuo; Satone, Akira; Ide, Wataru; Hashimoto, Ikuo; Kamada, Hajime

doi:10.1007/bf02479423

Cited by 79 publications

(48 citation statements)

References 17 publications

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“…For example, in hepatoma and breast cancer cells, HDAC inhibition decreased the expression of Bcl-2, while expression of pro-apoptotic Bax was increased [33,44] , in line with the present study. On the other hand, no changes in the expression pattern of Bax and Bcl-2 were found in HDAC-inhibitor-treated glioma cells [45] , and in gastrointestinal neuroendocrine tumor cells, Bcl-2 expression was down-regulated upon MS-275 treatment, while Bax remained unchanged [24] . Especially for an estimation of suitable combination treatment regimens being based on the enhanced induction of apoptosis, it is necessary to check out cell type-specific changes in the expression pattern of HDAC-induced pro-and antiapoptotic proteins.…”

Section: Discussionmentioning

confidence: 88%

Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells

Baradari

Höpfner²,

Huether³

et al. 2007

WJG

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AIM:To investigate the antiproliferative effect of the histone deacetylase (HDAC) inhibitor MS-275 on cholangiocarcinoma cells alone and in combination with conventional cytostatic drugs (gemcitabine or doxorubicin) or the novel anticancer agents sorafenib or bortezomib. METHODS:Two human bile duct adenocarcinoma cell lines (EGI-1 and TFK-1) were studied. Crystal violet staining was used for detection of cell number changes. Cytotoxicity was determined by measuring the release of the cytoplasmic enzyme lactate dehydrogenase (LDH). Apoptosis was determined by measuring the enzyme activity of caspase-3. Cell cycle status reflected by the DNA content was detected by flow cytometry. RESULTS:MS-275 treatment potently inhibited the proliferation of EGI-1 and TFK-1 cholangiocarcinoma cells by inducing apoptosis and cell cycle arrest. MS-275-induced apoptosis was characterized by activation of caspase-3, up-regulation of Bax and down-regulation of Bcl-2. Cell cycle was predominantly arrested at the G1/S checkpoint, which was associated with induction of the cyclin-dependent kinase inhibitor p21 Waf/CIP1 . Furthermore, additive anti-neoplastic effects were observed when MS-275 treatment was combined with gemcitabine or doxorubicin, while combination with the multikinase inhibitor sorafenib or the proteasome inhibitor bortezomib resulted in overadditive anti-neoplastic effects. CONCLUSION:The growth of human cholangiocarcinoma cells can be potently inhibited by MS-275 alone or in combination with conventional cytostatic drugs or new, targeted anticancer agents.

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Section: Discussionmentioning

confidence: 88%

Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells

Baradari

Höpfner²,

Huether³

et al. 2007

WJG

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“…Differences in the expression pattern of apoptosisrelated proteins seems to be cell-type dependent. For example, in hepatoma cells, TSA decreased the expression of Bcl-2, while expression of proapoptotic Bax was increased (Herold et al 2002), no change of Bax and Bcl-2 expression was found in glioma cells with either TSA or NaB treatment (Sawa et al 2001). MS-275 has been described to downregulate Bcl-2 and upregulate Bax expression in breast cancer cells (Singh et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Antiproliferative and proapoptotic effects of histone deacetylase inhibitors on gastrointestinal neuroendocrine tumor cells

Baradari¹,

Huether²,

Höpfner³

et al. 2006

Endocr Relat Cancer

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Treatment options of advanced neuroendocrine tumors (NETs) are unsatisfactory. Hence, innovative therapeutic approaches are urgently needed. Inhibition of histone deacetylases (HDACs) is a promising new approach in cancer therapy. While several HDAC inhibitors have already entered clinical trials, the effect of HDAC inhibition on NET has not been investigated. Therefore, we evaluated the antineoplastic effects of three different HDAC inhibitors, trichostatin A (TSA), sodium butyrate (NaB), and MS-275, on growth and apoptosis of the gastrointestinal NET cell lines CM and BON. We could demonstrate that HDAC inhibition dose-dependently inhibited proliferation of both cell lines with IC 50 values varying from the millimolar (NaB) to the micromolar (MS-275) and the nanomolar range (TSA). Moreover, HDAC inhibition potently induced apoptosis, which was accompanied by DNA-fragmentation, an up to 12-fold caspase-3 activation and downregulated Bcl-2 expression. Furthermore, HDAC inhibition resulted in cell cycle arrest at the G 1 -S-transition, which was associated with the suppression of cyclin D1 expression and induction of p21 and p27 expression. For BON cells, we observed an additional block in the G 2 /M phase, which was aligned with a downregulation of cyclin B1. In addition, combined treatment with MS-275 and somatostatin or the synthetic somatostatin analog octreotide was evaluated. Neither somatostatin nor its stable analog octreotide augmented the antiproliferative effect of MS-275 in NET cells. To conclude, our data show that HDAC inhibition is a promising new approach in the treatment of NET disease, which should be evaluated in clinical studies.

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“…The clinical potential of these agents has been documented by several Phase I trials of different HDIs in patients with solid tumors or leukemias (12)(13)(14)(15)(16)(17). Various HDIs have been evaluated in brain tumors in a few studies (18)(19)(20)(21)(22) but, with the exception of MS-275 (23) and phenylbutyrate and phenylacetate (24), not in pediatric medulloblastoma.…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibitors induce cell death and enhance the susceptibility to ionizing radiation, etoposide, and TRAIL in medulloblastoma cells

Sonnemann

Kumar²,

Heesch³

et al. 2006

Int J Oncol

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Abstract. Histone deacetylase inhibitors (HDIs) are a promising new class of antineoplastic agents with the ability to induce apoptosis and growth arrest of cancer cells. In addition, HDIs have been suggested to enhance the anticancer efficacy of other therapeutic regimens, such as ionizing radiation (IR) or chemotherapy. The objective of this study was to evaluate the activity of HDIs against medulloblastoma cells when applied either as single agents or in combination with IR, cytostatics, or TRAIL. The HDIs, suberoyl anilide hydroxamic acid (SAHA), sodium butyrate, and trichostatin A, were examined for their effects on the medulloblastoma cell lines, DAOY and UW228-2. We found that treatment with HDIs induced the dissipation of mitochondrial membrane potential, activation of caspase-9 and -3 and, consequently, apoptotic cell death. Moreover, all three HDIs significantly enhanced the cytotoxic effects of IR in DAOY cells. Likewise, treatment with SAHA markedly augmented the cytotoxicity of etoposide, while it had no effect on vincristine-mediated cell death. HDIs also potently increased the killing efficiency of TRAIL. TRAIL-induced, but not SAHA-induced, cell killing could be prevented by the caspase-8 inhibitor, z-IEDT-fmk. We conclude that HDIs may be useful for the treatment of medulloblastoma as monotherapy and particularly when given in combination with IR, appropriate cytostatics, or TRAIL.

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Histone deacetylase inhibitors such as sodium butyrate and trichostatin A induce apoptosis through an increase of the bcl-2-related protein Bad

Cited by 79 publications

References 17 publications

Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells

Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells

Antiproliferative and proapoptotic effects of histone deacetylase inhibitors on gastrointestinal neuroendocrine tumor cells

Histone deacetylase inhibitors induce cell death and enhance the susceptibility to ionizing radiation, etoposide, and TRAIL in medulloblastoma cells

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