HDAC inhibitor treatment of hepatoma cells induces both TRAIL-independent apoptosis and restoration of sensitivity to TRAIL

Pathil, Anita; Armeanu, Sorin; Venturelli, Sascha; Mascagni, Paolo; Weiss, Thomas S.; Gregor, Michael; Lauer, Ulrich M.; Bitzer, Michael

doi:10.1002/hep.21054

Cited by 112 publications

(93 citation statements)

References 41 publications

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“…This suggests that multiple apoptotic pathways are triggered by ITF2357, in keeping with recent findings which showed that the proapoptotic activity of ITF2357 is determined via both TRAIL-dependent and -independent pathways (Pathil et al, 2006). Concurrently with apoptosis, AML1/ETO protein degradation was also induced in Kasumi-1 cells treated with 0.1 mM ITF2357.…”

Section: Selectivity Of Low-dose Itf2357 In Aml Subtypes V Barbetti Esupporting

confidence: 87%

“…Previous reports demonstrated that ITF2357 has HDAC inhibitory and anti-inflammatory properties in vitro and in vivo by blocking cytokines such as TNFa, IL1b, IL12 and so on (Leoni et al, 2005;Carta et al, 2006). Furthermore, ITF2357 inhibits proliferation and markedly induces downregulation of antiapoptotic, and upregulation of proapoptotic, factors, in parallel with restoring histone acetylation in tumour cells (Armeanu et al, 2005;Pathil et al, 2006). Clinical trials are currently being conducted with oral ITF2357 preparations in autoimmune disorders as well as haematological neoplasias.…”

Section: Introductionmentioning

confidence: 99%

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Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells

et al. 2007

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Section: Selectivity Of Low-dose Itf2357 In Aml Subtypes V Barbetti Esupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells

et al. 2007

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“…We and others have reported that chemical and genetic inhibition of HDACs leads to decreased expression of FLIP mRNA (36)(37)(38)(39)(40)(41)(42)(43). However, the mechanism by which inhibiting HDACs decreases FLIP expression is uncertain.…”

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands

Wood

Dalili

Simpson

et al. 2010

Molecular Cancer Therapeutics

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Evasion of death receptor ligand-induced apoptosis represents an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (that we propose be named droxinostat) was identified as a chemical sensitizer to death receptor stimuli, decreasing the expression of the caspase-8 inhibitor FLIP. However, the direct targets of droxinostat were unknown. To better understand the mechanism of action of droxinostat and highlight new strategies to restore sensitivity to death receptor ligands, we analyzed changes in gene expression using the Connectivity Map after treating cells with droxinostat. Changes in gene expression after droxinostat treatment resembled changes observed after treatment with histone deacetylase (HDAC) inhibitors. Therefore, we examined the effects of droxinostat on HDAC activity and showed that it selectively inhibited HDAC3, HDAC6, and HDAC8 and that inhibition of these HDACs was functionally important for its ability to sensitize cells to death ligands. Thus, we have identified a selective HDAC inhibitor and showed that selective HDAC inhibition sensitizes cells to death ligands, thereby highlighting a new mechanism to overcome resistance to death receptor ligands. Mol Cancer Ther; 9(1); 246-56. ©2010 AACR.

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“…Currently, the first-generation HDAC inhibitors are being tested in phase I and phase II clinical trials (Armeanu et al, 2005;Minucci and Pelicci, 2006;Pathil et al, 2006). Because many malignant diseases share an epigenetic etiology, modulation of chromatin remodeling by HDAC inhibitors has been suggested as an important epigenetic mechanism for cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

et al. 2008

Oncogene

142

129

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Expression level of metastasis-associated protein 1 (MTA1) is closely related to tumor growth and metastasis in various cancers. Although increased expression level of MTA1 was observed in hepatocellular carcinoma (HCC), role of MTA1 complex containing histone deacetylase (HDAC) in hepatitis B virus (HBV)-associated hepatocarcinogenesis has not been studied. Here, we demonstrated that HBx strongly induced the expression of MTA1 and HDAC1 genes at transcription level. MTA1 and HDAC1/2 physically associated with hypoxia-inducible factor-1a (HIF-1a) in vivo in the presence of HBx, which was abolished by knockdown of MTA1 by short interfering RNA (siRNA). HBx induced deacetylation of the oxygen-dependent degradation domain of HIF-1a, which was accompanied with dissociation of prolyl hydroxylases and von Hippel-Lindau tumor suppressor from HIF-1a. These results indicate that HBx-induced deacetylation is important for proteasomal degradation of HIF-1a. Further, we observed that protein levels of MTA1 and HDAC1 were increased in the liver of HBxtransgenic mice. Also, there was a higher expression of HDAC1 in HCC than in the adjacent non-tumorous cirrhotic nodules in 10 out of 12 human HBV-associated HCC specimens. Together, our data indicate a positive cross talk between HBx and the MTA1/HDAC complex in stabilizing HIF-1a, which may play a critical role in angiogenesis and metastasis of HBV-associated HCC.

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HDAC inhibitor treatment of hepatoma cells induces both TRAIL-independent apoptosis and restoration of sensitivity to TRAIL

Cited by 112 publications

References 41 publications

Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells

Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells

Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands

Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

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