Nuclear factor-κB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101

Duan, Jianming; Friedman, Jay; Nottingham, Liesl; Chen, Zhong; Ara, Gulshan; Waes, Carter Van

doi:10.1158/1535-7163.mct-05-0285

Cited by 70 publications

(77 citation statements)

References 58 publications

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“…Bortezomib enhances cell death caused by the death ligand tumor necrosis factor -related apoptosis-inducing ligand (21 -23), the BH3 mimetic GX15-070 (20), and the histone deacetylase inhibitors trichostatin A, sodium butyrate, and PXD101 (41). In addition, bortezomib has been shown to enhance the activities of the epidermal growth factor receptor inhibitors PKI166 and PD153035 (33,42).…”

Section: Discussionmentioning

confidence: 99%

Bortezomib induces apoptosis via Bim and Bik up-regulation and synergizes with cisplatin in the killing of head and neck squamous cell carcinoma cells

Grandis

et al. 2008

Molecular Cancer Therapeutics

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Section: Discussionmentioning

confidence: 99%

Bortezomib induces apoptosis via Bim and Bik up-regulation and synergizes with cisplatin in the killing of head and neck squamous cell carcinoma cells

Grandis

et al. 2008

Molecular Cancer Therapeutics

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“…However, Duan et al 18 reported that TSA promoted the acetylation of p65 and increased the NF-kB activity in head and neck cancer cells, which was responsible for the modest antitumor effect of TSA on these cancer cells. In this study, TSA enhanced the acetylation of p65 and accumulation of p65 in the nucleus of oral SCC cells.…”

Section: Discussionmentioning

confidence: 99%

“…HDACi has been shown to inhibit deacetylation and increases the level of nuclear p65. 18 SAS cells were cultured in the presence or absence of 0.3 mM TSA, and the acetylated p65 was detected in combination with anti-p65 and anti-acetylated polypeptide antibodies. Acetylated p65 increased in a time-dependent manner from 6 h after the treatment (Figure 2a).…”

Section: Nuclear Accumulation Of Nf-kb By Infection With Hsv-1 Mutantmentioning

confidence: 99%

“…16 Indeed, HDAC inhibitors (HDACi's) have been shown to exhibit antitumor activity in a number of cancers. 15,17,18 HDACs function not only to deacetylate core histones leading to repressive changes in chromatin structure, but also to deacetylate various host transcription factors, altering their transcriptional activity. NF-kB is subjected to reversible acetylation, and HDACs play important roles in its deacetylation.…”

Section: Introductionmentioning

confidence: 99%

“…The limited effect of TSA was associated with NF-kB's activation by this HDACi. 18 With regard to HSV infections, NF-kB is activated early during an HSV-1 infection, translocates to the nucleus 24,25 and prevents virus-induced early apoptosis of infected cells to complete its replication cycle. [25][26][27] Whether an HDACi that activates NF-kB could affect the replication of oncolytic HSV-1 mutants has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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The effects of trichostatin A on the oncolytic ability of herpes simplex virus for oral squamous cell carcinoma cells

et al. 2008

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Combining the use of a chemotherapeutic agent with oncolytic virotherapy is a useful way to increase the efficiency of the treatment of cancer. The effect of the histone diacetylase (HDAC) inhibitor trichostatin A (TSA) on the antitumor activity of a herpes simplex virus type-1 (HSV-1) mutant was examined in oral squamous cell carcinoma (SCC) cells. Immunoblotting analysis and immunoflourescence staining revealed that a cytoplasmic nuclear factor-kB (NF-kB) component, p65, translocated into the nucleus after infection with g 1 34.5 gene-deficient HSV-1 R849, indicating that R849 activated NF-kB. TSA induced acetylation of p65 and increased the amount of p65 in the nucleus of oral SCC cells. Treatment of R849-infected cells with TSA also increased the amount of nuclear p65 and binding of NF-kB to its DNA-binding site and an NF-kB inhibitor SN50 diminished the increase in nuclear p65. In the presence of TSA, the production of virus and the expression of LacZ integrated into R849 and glycoprotein D, but not ICP0, ICP6 and thymidine kinase, were increased. The viability of cells treated with a combination of R849 and TSA was lower than that of those treated with R849 only. After treatment with TSA, expression of the cell cycle kinase inhibitor p21 was upregulated and the cell cycle was arrested at G1. These results indicate that TSA enhanced the replication of the HSV-1 mutant through the activation of NF-kB and induced cell cycle arrest at G1 to inhibit cell growth. TSA can be used as an enhancing agent for oncolytic virotherapy for oral SCC with g 1 34.5 gene-deficient HSV-1.

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Activity of the histone deacetylase inhibitor belinostat (PXD101) in preclinical models of prostate cancer

Qian

Ara

Mills

et al. 2007

Intl Journal of Cancer

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Histone deacetylase inhibitors (HDACi) represent a promising new class of anticancer agents. In the current investigation, we examined the activity of the HDACi belinostat in preclinical models of prostate cancer. In vitro proliferation assays demonstrated that belinostat potently inhibited the growth of prostate cancer cell lines (IC 50 < 1.0 lM) and was cytotoxic to these cells. Washout experiments indicated that exposure to belinostat for relatively short periods of time (<12 hr) induced suboptimal growth-inhibition and that cells exposed to 1.0 lM belinostat for 48 hr retained the capacity for regrowth following drug withdrawal, while cells exposed to 4.0 lM belinostat were irreversibly growth-inhibited. Cell cycle analyses demonstrated that belinostat induced G2/M arrest and increased the percentage of cells with subG1 DNA content, thus confirming the growth-inhibitory and cytotoxic effects of this compound. Normal prostate epithelial cells were generally less susceptible to the effects of belinostat than were prostate cancer cells. In an orthotopic prostate cancer tumor model, belinostat inhibited tumor growth by up to 43%. Moreover, metastatic lung lesions were present in 47% of vehicle-treated animals but in none of the animals administered belinostat. Consistent with its observed antimetastatic activity, belinostat inhibited the migration of prostate tumor cells and increased the production of tissue inhibitor of metalloproteinase-1 (TIMP-1) by these cells, the latter effect being replicated by siRNA knockdown of HDAC3. Belinostat also increased the expression of p21 and decreased the expression of potentially oncogenic proteins (mutant p53 and ERG). These results support the clinical evaluation of belinostat for the treatment of prostate cancer. ' 2007 Wiley-Liss, Inc.Key words: PXD101; belinostat; HDAC inhibitor; histone deacetylase inhibitor; prostate cancer Histone deacetylase inhibitors (HDACi) represent a relatively new and interesting class of anticancer agent which, as their nomenclature would suggest, inhibit the enzymes that deacetylate histone proteins.1,2 Histones play an important role in maintaining chromatin structure, and posttranslational modifications to these molecules serve to regulate chromatin density. As a result of histone deacetylase (HDAC) inhibition, histones become hyperacetylated and DNA is maintained in a relatively open conformation that is conducive to interaction with transcription factors. Consistent with this scenario, HDACi have been shown to alter the transcription of a number of genes. In addition, these compounds have been shown to mediate tumor cell differentiation, growth-inhibition and death, and a number of such HDACi are in clinical trials with one (Zolinza TM ) recently receiving FDA approval for the treatment of cutaneous T-cell lymphoma.In contrast to the relatively detailed understanding that has been attained regarding the role that histones and their modifications play in maintaining chromatin structure, the mechanism(s) by which HDACi mediate anticancer...

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Nuclear factor-κB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101

Cited by 70 publications

References 58 publications

Bortezomib induces apoptosis via Bim and Bik up-regulation and synergizes with cisplatin in the killing of head and neck squamous cell carcinoma cells

Bortezomib induces apoptosis via Bim and Bik up-regulation and synergizes with cisplatin in the killing of head and neck squamous cell carcinoma cells

The effects of trichostatin A on the oncolytic ability of herpes simplex virus for oral squamous cell carcinoma cells

Activity of the histone deacetylase inhibitor belinostat (PXD101) in preclinical models of prostate cancer

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