Histone Deacetylase Inhibitor–Mediated Radiosensitization of Human Cancer Cells: Class Differences and the Potential Influence of p53

Kim, In Ah; Shin, Jin Hee; Kim, Il Han; Kim, Jin Ho; Kim, Jae Sung; Wu, Hong Gyun; Chie, Eui Kyu; Ha, Sung Whan; Park, Charn Il; Kao, Gary D.

doi:10.1158/1078-0432.ccr-05-1230

Cited by 65 publications

(45 citation statements)

References 48 publications

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“…6,7,11,[30][31][32][33][34] In addition, studies that included these essential control experiments often used cells expressing either a non-functional p53 mutant or a p53 protein that is inactivated by the papilloma virus E6 protein. 12,34,35 The inability, shown herein, of PFT-a to protect these cells from apoptosis might, however, be because of a competitive Figure 6 PFT-a prevents hyperphosphorylation of pRb, but does not mediate its protective effect through this tumor suppressor. (a) Western blot analysis for the status of pRb in wild-type and p53-deficient HCT116 cells that were either left untreated or transfected for 24 h with a control or the pRb siRNA.…”

Section: Discussionmentioning

confidence: 99%

Pifithrin-α protects against DNA damage-induced apoptosis downstream of mitochondria independent of p53

et al. 2009

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Pifithrin-a (PFT-a) was shown to specifically block transcriptional activity of the tumor suppressor p53 and was therefore proposed to be useful in preventing the severe side effects often associated with chemo-and radiotherapy. We report here that although PFT-a efficiently protected different cell types from DNA damage-induced apoptosis, it mediated this effect regardless of the presence or absence of p53. Interestingly, PFT-a blocked the apoptosome-mediated processing and activation of caspase-9 and -3 without interfering with the activation of mitochondria. Neither the DNA damage-induced activation of Bax or Bak nor the loss of the mitochondrial membrane potential or the final release of cytochrome c were inhibited by this compound. Instead, the ability of PFT-a to protect p53-deficient cells from DNA damage-induced caspase activation and apoptosis was greatly diminished after siRNA-mediated downregulation of cyclin-D1 expression. In contrast, downregulation of other proteins involved in cell-cycle progression, such as the retinoblastoma protein, cyclin D3, as well as the cyclin-dependent kinases, 2, 4 and 6, could not abolish this protection. Thus, our data show that PFT-a protects cells from DNA damage-induced apoptosis also by a p53-independent mechanism that takes place downstream of mitochondria and that might involve cyclin D1.

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Section: Discussionmentioning

confidence: 99%

Pifithrin-α protects against DNA damage-induced apoptosis downstream of mitochondria independent of p53

et al. 2009

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“…SK7041, structurally composed of hydroxamic acid and benzamide (21), was a gift from Professor Y.J. Bang (Seoul National University Hospital).…”

Section: Methodsmentioning

confidence: 99%

Combination therapy of conditionally replicating adenovirus and histone deacetylase inhibitors

Lee¹

2011

Int J Mol Med

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Abstract. Combination therapy of adenoviral gene therapy and a histone deacetylase (HDAC) inhibitor is important due to the enhancing effect of HDAC inhibitors on adenoviral transduction and transcription. However, contradictory results have been reported on the effect of combination of CRAd (conditionally replicating adenovirus) and HDAC inhibitors. This study was designed to investigate the interaction of CRAd and HDAC inhibitors and determine the ideal way to combine the two agents. Combination of HDAC inhibitors (SK7041, SBHA and vorinostat) at pre-and post-transductional periods with CRAd enhanced the transduction of CRAd and expression of luciferase expression from Δ24-luc in vitro. However, suppression of luciferase expression from Δ24-luc injected tumor mass was observed by in vivo tumor bioluminescence imaging and drug interaction analysis also showed an antagonistic interaction that was probably related with the inhibitory effect of the HDAC inhibitor on adenoviral replication. Suppression of p21 induction by p21 siRNA reversed the suppressive effect of vorinostat on the replication of CRAd, but still failed to reverse the antagonistic interaction. Addition of vorinostat at the pre-transductional period revealed an improvement in the transduction efficiency of CRAd and also induced a synergistic interaction between CRAd and vorinostat, which was possibly related with prevention of the suppressive effect of vorinostat on adenoviral replication. In conclusion, the addition of HDAC inhibitor before CRAd injection showed synergistic antitumor effects, which warrants further investigation on the sequence of HDAC inhibitor and CRAd treatment in an animal tumor model.

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“…Clonogenic assay was done according to a previously described protocol (11). Radiation-survival data were fitted to a linear-quadratic model using Kaleidagraph version 3.51 (Synergy Software).…”

Section: Clonogenic Assaysmentioning

confidence: 99%

Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response

Choi

Ryu

Kim

et al. 2010

Molecular Cancer Research

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Several studies have shown solid evidence for the potential value of targeting epidermal growth factor receptor (EGFR) signaling to enhance the antitumor activity of radiation. However, therapeutic resistance has emerged as an important clinical issue. Here, we investigated whether strategies for targeting EGFR-associated downstream signaling would radiosensitize a panel of non-small cell lung cancer cell lines. Inhibition of K-RAS using RNA interference attenuated downstream signaling and increased radiosensitivity of A549 and H460 cells, whereas inhibition of EGFR did not. A549 cells harboring a K-RAS mutation at codon V12 were radiosensitized by small interfering RNA (siRNA) targeting this codon. H460 cells having mutation at codon V61 was radiosensitized by siRNA targeting of this mutation. K-RAS siRNA did not radiosensitize H1299 cells possessing wild-type K-RAS. Inhibition of the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin pathway led to significant radiosensitization of the two cell lines, whereas selective inhibition of extracellular signal-regulated kinase signaling did not. Inhibitors targeting the PI3K-AKT-mTOR pathway also abrogated G 2 arrest following irradiation and induced γH2AX foci formation. A dual inhibitor of class I PI3K and mammalian target of rapamycin effectively increased the radiosensitivity of A549 and H460 cells. Inhibition of PI3K-AKT signaling was associated with the downregulation of DNA-PKs. Although apoptosis was the primary mode of cell death when cells were pretreated with LY294002 or AKT inhibitor VIII, cells pretreated with rapamycin or PI-103 showed mixed modes of cell death, including apoptosis and autophagy. Our results suggest possible mechanisms for counteracting EGFR prosurvival signaling implicated in radioresistance and offer an alternative strategy for overcoming resistance to EGFR inhibitors used in combination with irradiation.

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Histone Deacetylase Inhibitor–Mediated Radiosensitization of Human Cancer Cells: Class Differences and the Potential Influence of p53

Cited by 65 publications

References 48 publications

Pifithrin-α protects against DNA damage-induced apoptosis downstream of mitochondria independent of p53

Pifithrin-α protects against DNA damage-induced apoptosis downstream of mitochondria independent of p53

Combination therapy of conditionally replicating adenovirus and histone deacetylase inhibitors

Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response

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