The histone deacetylase inhibitor trichostatin A induces cell cycle arrest and apoptosis in colorectal cancer cells via p53-dependent and -independent pathways

Ji, Meng; Zhang, Haihua; Zhou, Chunxiang; Li, Chen; Zhang, Feng; Mei, Qibing

doi:10.3892/or.2012.1793

Cited by 19 publications

(17 citation statements)

References 23 publications

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“…PRI-2205 slightly decreased only PI positive cells, but did not affect caspase-3 or p-53 positive cells as compared to 5-FU alone. HT-29 possessed mutated p53 (67) and, according to recent studies, a functional and physical interaction between mutated p53 and the vitamin D transcriptional regulatory pathway exists. This interaction lies in the cooperation between mutated p53 with 1,25(OH) 2 D 3 to elicit an anti-apoptotic state (68).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment

et al. 2014

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In the present study, we evaluated the antitumor effect of two synthetic analogs of vitamin D, namely PRI-2191 [(24R)-1,24-dihydroxyvitamin D3] and PRI-2205 (5,6-trans calcipotriol), in combined human colon HT-29 cancer treatment with 5-fluorouracil (5-FU). Mice bearing HT-29 tumors transplanted subcutaneously or orthotopically were injected with vitamin D analogs and 5-FU in various schedules. A statistically significant inhibition of subcutaneous or orthotopic tumor growth was observed as a result of combined therapy. In HT-29 tumors and in cells from in vitro culture, we observed increased vitamin D receptor (VDR) expression after treatment with either PRI-2205 or 5-FU alone, or in combination. Moreover, PRI-2205 decreased the percentage of cells from intestinal tumors in G2/M and S stages and increased sub-G1. Increased VDR expression was also observed after combined treatment of mice with 5-FU and PRI-2191. Moreover, our docking studies showed that PRI-2205 has stronger affinity for VDR, DBP and CAR/RXR ligand binding domains than PRI-2191. PRI-2191 analog, used with 5-FU, increased the percentage of subcutaneous tumor cells in G0/G1 and decreased the percentage in G2/M, S and sub-G1 populations as compared to 5-FU alone. In in vitro studies, we observed increased expression of p21 and p-ERK1/2 diminution via use of both analogs as compared to use of 5-FU alone. Simultaneously, PRI-2191 antagonizes some pro-apoptotic activities of 5-FU in vitro. However, in spite of these disadvantageous effects in terms of apoptosis, the therapeutic effect expressed as tumor growth retardation by PRI-2191 is significant. Our results suggest that the mechanism of potentiation of 5-FU antitumor action by both analogs is realized via increased p21 expression and decreased p-ERK1/2 level which may lead to diminution of thymidylate synthase expression. Higher binding affinity for VDR, DBP, but also for CAR\RXR ligand binding domain of PRI-2205 may, in part, explain its very low toxicity with sustained anticancer activity.

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Section: Discussionmentioning

confidence: 99%

Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment

et al. 2014

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“…In this study, we delineated p53-dependent and -independent activities of HDACi and, in part, resolved the controversies (Vrana et al , 1999; Huang et al , 2000; Ruefli et al , 2001; Yu et al , 2002; Henderson et al , 2003; Insinga et al , 2005; Joseph et al , 2005; Kim et al , 2006; Sonnemann et al , 2006; Lindemann et al , 2007; Condorelli et al , 2008; Ellis et al , 2009; Hacker et al , 2011; Bajbouj et al , 2012; Meng et al , 2012) over the impact of p53 on HDACi-driven effects. As general bottom line, we have shown that HDACi accomplish the ultimate goal of cancer therapy, the demise of malignant cells, independent of the tumour's p53 status.…”

Section: Discussionmentioning

confidence: 99%

“…The majority of works addressing this issue point to a largely p53-independent action of HDACi (Vrana et al , 1999; Huang et al , 2000; Ruefli et al , 2001; Yu et al , 2002; Insinga et al , 2005; Sonnemann et al , 2006; Lindemann et al , 2007; Ellis et al , 2009). Other studies, however, suggest an essential role of p53 in the response of tumour cells to HDACi treatment (Henderson et al , 2003; Joseph et al , 2005; Kim et al , 2006; Condorelli et al , 2008; Hacker et al , 2011; Bajbouj et al , 2012; Meng et al , 2012). These inconsistent observations may in part be due to methodological differences, but they may also be due to the use of different HDACi or divergent HDACi-induced effects examined.…”

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confidence: 98%

p53-dependent and p53-independent anticancer effects of different histone deacetylase inhibitors

et al. 2013

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Background:Histone deacetylase inhibitors (HDACi) are promising antineoplastic agents, but their precise mechanisms of actions are not well understood. In particular, the relevance of p53 for HDACi-induced effects has not been fully elucidated. We investigated the anticancer effects of four structurally distinct HDACi, vorinostat, entinostat, apicidin and valproic acid, using isogenic HCT-116 colon cancer cell lines differing in p53 status.Methods:Effects were assessed by MTT assay, flow-cytometric analyses of propidium iodide uptake, mitochondrial depolarisation and cell-cycle distribution, as well as by gene expression profiling.Results:Vorinostat was equally effective in p53 wild-type and null cells, whereas entinostat was less effective in p53 null cells. Histone deacetylase inhibitors treatment suppressed the expression of MDM2 and increased the abundance of p53. Combination treatments showed that vorinostat enhanced the cytotoxic activity of TRAIL and bortezomib, independent of the cellular p53 status. Investigations into the effects of an inhibitor of the sirtuin class of HDAC, tenovin-1, revealed that tenovin-1-mediated cell death hinged on p53.Conclusion:These results demonstrate that vorinostat activates p53, but does not require p53 for inducing its anticancer action. Yet they also demonstrate that entinostat-induced cytotoxic effects partially depend on p53, indicating that different HDACi have a different requirement for p53.

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“…p53 is an important protein involved in apoptosis and has been shown to participate in cell cycle regulation (17,18). In the present study, the mRNA and protein expression levels of p53 were investigated in the chorionic villus (placental) tissues of females with URSA by qPCR and immunohistochemical analysis.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis and p53 expression in the placental villi of females with unexplained recurrent spontaneous abortion

Dehua

Shi

2013

Experimental and Therapeutic Medicine

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The aim of this study was to explore the level of apoptosis and p53 expression in the placental villi of patients with unexplained recurrent spontaneous abortion (URSA). Fifty-three pregnant females with URSA and 32 pregnant females who required an induced abortion were selected as the subjects of this study. Placental villus tissues were collected from June 2010 to June 2012 and quantitative polymerase chain reaction (qPCR) and immunohistochemical analysis were performed to determine the mRNA and protein levels of p53 in the placental villus tissues. The level of apoptosis in the tissues was studied using terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) assay. The mRNA and protein expression levels of p53 in the URSA group were significantly higher than those in the control group (P<0.05). Furthermore, the levels of apoptosis were increased markedly in the URSA group compared with the control group (P<0.05). In conclusion, the placental villi of patients with URSA express a high level of p53, which may result in cell apoptosis and lead to recurrent spontaneous abortion.

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The histone deacetylase inhibitor trichostatin A induces cell cycle arrest and apoptosis in colorectal cancer cells via p53-dependent and -independent pathways

Cited by 19 publications

References 23 publications

Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment

Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment

p53-dependent and p53-independent anticancer effects of different histone deacetylase inhibitors

Apoptosis and p53 expression in the placental villi of females with unexplained recurrent spontaneous abortion

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