Valproic acid and butyrate induce apoptosis in human cancer cells through inhibition of gene expression of Akt/protein kinase B

Chen, Jihong; Ghazawi, Feras M.; Bakkar, Wafae; Li, Qiao

doi:10.1186/1476-4598-5-71

Cited by 91 publications

(36 citation statements)

References 53 publications

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“…It has been reported that HDAC inhibitors may cause Akt depletion through modulation of gene expression [16] and inhibit Akt phosphorylation through disruption of HDAC-PP1 (protein-phosphatase 1) complex [17]. In this study, we aimed to determine the relationship between HDAC and Akt under the inhibitory effect of MPT0E028.…”

Section: Resultsmentioning

confidence: 99%

“…Evidence show that HDAC inhibitors, such as valproic acid and butyrate, impede Akt1 and Akt2 expression, which leads to Akt deactivation and apoptotic cell death [16]. In another study, Chen et al .…”

Section: Discussionmentioning

confidence: 99%

“…3B, left panel). One possible mechanism may involve transcription inhibition [16], another possible explanation may relate to Hsp90 and proteasome degradation. Evidence has shown that HDAC6 directly regulates Hsp90 acetylation, and Akt is a client protein of Hsp90; therefore, inhibition of HDAC6 may disrupt the chaperone function of Hsp90, leading to Akt depletion [34, 35].…”

Section: Discussionmentioning

confidence: 99%

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Novel oral histone deacetylase inhibitor, MPT0E028, displays potent growth-inhibitory activity against human B-cell lymphomain vitroandin vivo

et al. 2014

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Histone deacetylase (HDAC) inhibitor has been a promising therapeutic option in cancer therapy due to its ability to induce growth arrest, differentiation, and apoptosis. In this study, we demonstrated that MPT0E028, a novel HDAC inhibitor, reduces the viability of B-cell lymphomas by inducing apoptosis and shows a more potent HDAC inhibitory effect compared to SAHA, the first HDAC inhibitor approved by the FDA. In addition to HDACs inhibition, MPT0E028 also possesses potent direct Akt targeting ability as measured by the kinome diversity screening assay. Also, MPT0E028 reduces Akt phosphorylation in B-cell lymphoma with an IC50 value lower than SAHA. Transient transfection assay revealed that both targeting HDACs and Akt contribute to the apoptosis induced by MPT0E028, with both mechanisms functioning independently. Microarray analysis also shows that MPT0E028 may regulate many oncogenes expression (e.g., TP53, MYC, STAT family). Furthermore, in vivo animal model experiments demonstrated that MPT0E028 (50–200 mg/kg, po, qd) prolongs the survival rate of mice bearing human B-cell lymphoma Ramos cells and inhibits tumor growth in BJAB xenograft model. In summary, MPT0E028 possesses strong in vitro and in vivo activity against malignant cells, representing a potential therapeutic approach for cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Novel oral histone deacetylase inhibitor, MPT0E028, displays potent growth-inhibitory activity against human B-cell lymphomain vitroandin vivo

et al. 2014

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“…VPA was found to be an effective inhibitor of histone deacetylases and has been shown to induce anti-tumor effects by modulating cellular pathways, including cell cycle arrest, apoptosis, angiogenesis, metastasis, differentiation, and senescence [27]. The antitumor effect of VPA in cervical cancer can be explained by either the hyper-acetylation of p53 protein, protecting it from degradation by E6 and increasing p53 activity; or via the inhibition of Akt1 and Akt2 expression, which results in apoptotic cell death [28,29]. Acetylation of p53 is a process that occurs in response to DNA damage and stress and is necessary for p53 transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%

Histone H3 Acetyl K9 and Histone H3 Tri Methyl K4 as Prognostic Markers for Patients with Cervical Cancer

Beyer

Zhu

Mayr

et al. 2017

IJMS

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Chromatin remodeling alters gene expression in carcinoma tissue. Although cervical cancer is the fourth most common cancer in women worldwide, a systematic study about the prognostic value of specific changes in the chromatin structure, such as histone acetylation or histone methylation, is missing. In this study, the expression of histone H3 acetyl K9, which is known to denote active regions at enhancers and promoters, and histone H3 tri methyl K4, which preferentially identifies active gene promoters, were examined as both show high metastatic potential. A panel of patients with cervical cancer was selected and the importance of the histone modifications concerning survival-time (overall survival and relapse-free survival) was analyzed in 250 cases. Histone H3 acetyl K9 staining was correlated with low grading, low FIGO (TNM classification and the International Federation of Gynecology and Obstetrics) status, negative N-status and low T-status in cervical cancer, showing a higher expression in adenocarcinoma than in squamous cell carcinoma. Cytoplasmic expression of histone H3 tri methyl K4 in a cervical cancer specimen was correlated with advanced T-status and poor prognosis. While cytoplasmic H3K4me3 expression seemed to be a marker of relapse-free survival, nuclear expression showed a correlation to poor prognosis in overall survival. Within this study, we analyzed the chemical modification of two histone proteins that are connected to active gene expression. Histone H3 acetyl K9 was found to be an independent marker of overall survival. Histone H3 tri methyl K4 was correlated with poor prognosis and it was found to be an independent marker of relapse-free survival. Therefore, we could show that chromatin remodeling plays an important role in cervical cancer biology.

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“…Their main virtue lies in their ability to regulate the expression of specific genes involved in proliferation, differentiation, and apoptosis (Chen et al 2006). Because of their biological similarities to cancer cells, stem cells have also been tested for responses to HDACi, especially in terms of stem cell specialization.…”

Section: Introductionmentioning

confidence: 99%

5-Azacytidine facilitates osteogenic gene expression and differentiation of mesenchymal stem cells by alteration in DNA methylation

Zhou

Zhang

et al. 2009

Cytotechnology

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Mesenchymal stem cells (MSCs) are considered to be one of the most promising therapeutic cell sources as they encompass a plasticity of multiple cell lineages. The challenge in using these cells lies in developing well-defined protocols for directing cellular differentiation to generate a desired lineage. In this study, we investigated the effect of 5-azacytidine, a DNA demethylating agent, on osteogenic differentiation of MSCs. The cells were exposed to 5-azacytidine in culture medium for 24 h prior to osteogenic induction. Osteogenic differentiation was determined by several the appearance of a number of osteogenesis characteristics, including gene expression, ALP activity, and calcium mineralization. Pretreatment of MSCs with 5-azacytidine significantly facilitated osteogenic differentiation and was accompanied by hypomethylation of genomic DNA and increased osteogenic gene expression. Taking dlx5 as a representative, methylation alterations of the "CpG island shore" in the promoter caused by 5-azacytidine appeared to contribute to osteogenic differentiation.

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Valproic acid and butyrate induce apoptosis in human cancer cells through inhibition of gene expression of Akt/protein kinase B

Cited by 91 publications

References 53 publications

Novel oral histone deacetylase inhibitor, MPT0E028, displays potent growth-inhibitory activity against human B-cell lymphomain vitroandin vivo

Novel oral histone deacetylase inhibitor, MPT0E028, displays potent growth-inhibitory activity against human B-cell lymphomain vitroandin vivo

Histone H3 Acetyl K9 and Histone H3 Tri Methyl K4 as Prognostic Markers for Patients with Cervical Cancer

5-Azacytidine facilitates osteogenic gene expression and differentiation of mesenchymal stem cells by alteration in DNA methylation

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