A novel class I HDAC inhibitor, MPT0G030, induces cell apoptosis and differentiation in human colorectal cancer cells via HDAC1/PKCδ and E-cadherin

Wang, Li Ting; Liou, Jing Ping; Li, Yu Hsuan; Liu, Yi Min; Pan, Shiow Lin; Teng, Che Ming

doi:10.18632/oncotarget.2155

Cited by 30 publications

(30 citation statements)

References 27 publications

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“…We also found that SAHA decreased tumor size in lung cancer xenograft model (Supplementary Figure 5). Our results support that HDAC inhibitor show anti-cancer effect on various cancer cells including colorectal and lung [28, 29]. The susceptibility of lung cancer cells to SAHA was higher than that of normal lung cells.…”

Section: Discussionsupporting

confidence: 86%

Suberoylanilide hydroxamic acid increases anti-cancer effect of tumor necrosis factor-α through up-regulation of TNF receptor 1 in lung cancer cells

2017

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Suberoylanilide hydroxamic acid (SAHA) as a histone deacetylase (HDAC) inhibitor has anti-cancer effect. Here, we evaluated the effect of SAHA on HDAC activity and cell growth in many normal lung and cancer cells. We observed that the HDAC activities of lung cancer cells were higher than that of normal lung cells. SAHA inhibited the growth of lung cancer cells regardless of the inhibitory effect on HDAC. This agent induced a G2/M phase arrest and apoptosis, which was accompanied by mitochondrial membrane potential (MMP: ΔΨm) loss in lung cancer cells. However, SAHA did not induce cell death in normal lung cells. All tested caspase inhibitors prevented apoptotic cell death in SAHA-treated A549 and Calu-6 lung cancer cells. Treatment with tumor necrosis factor-alpha (TNF-α) enhanced apoptosis in SAHA-treated lung cancer cells through caspase-8 and caspase-9 activations. Especially, SAHA increased the expression level of TNF-α receptor 1 (TNFR1), especially acetylation of the region of TNFR1 promoter −223/-29 in lung cancer cells. The down-regulation of TNFR1 suppressed apoptosis in TNF-α and SAHA-treated lung cancer cells. In conclusion, SAHA inhibited the growth of lung cancer cells via a G2/M phase arrest and caspase-dependent apoptosis. SAHA also enhanced apoptotic effect of TNF-α in human lung cancer cells through up-regulation of TNFR1. TNF-α may be a key to improve anti-cancer effect of HDAC inhibitors.

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Section: Discussionsupporting

confidence: 86%

Suberoylanilide hydroxamic acid increases anti-cancer effect of tumor necrosis factor-α through up-regulation of TNF receptor 1 in lung cancer cells

2017

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“…HDACs can be divided into 4 classes: Class-I (HDAC1, 2, 3 and 8), Class-II (HDAC4, 5, 6, 7, 9 and 10), Class-III (SIRT1-7) and Class-IV (HDAC11) (16). Recent studies suggest that Class-I HDACs are upregulated in many malignancies, and that they inhibit the expression of specific tumor-suppressor genes through epigenetic modulation (17)(18)(19). Our previous studies demonstrated that high levels of HDAC3 expression and activity play a critical role in CCA, and that the inhibition of HDAC3 could induce apoptosis in CCA cells (20).…”

Section: Metformin Facilitates Bg45-induced Apoptosis Via An Anti-warmentioning

confidence: 99%

Metformin facilitates BG45‑induced apoptosis via an anti‑Warburg effect in cholangiocarcinoma cells

Tang

Zhang

et al. 2018

Oncol Rep

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Cholangiocarcinoma (CCA) is a highly lethal malignancy with an often late diagnosis and consequent poor prognosis. Chemotherapy is the only therapeutic strategy for most patients. Compared to normal cells, tumor cells preferentially metabolize glucose to lactate, even in aerobic conditions. Such metabolic alterations not only support the growth and invasion of tumor cells, but also promote their chemoresistance. The purpose of our study was to explore the role of metformin in regulating the metabolism of CCA, as well as to investigate whether metformin could act as a chemosensitizer of the HDAC3 inhibitor BG45, and therefore have potential for the treatment of CCA. Through bioinformatic analysis, we found that aberrant metabolism contributed to the proliferation of CCA cells. Seahorse XF96 Extracellular Flux Analyzer analysis and lactate production analysis showed that metformin could act as a suppressor of the Warburg effect in CCA cells. Western blotting showed that metformin decreased the expression of LDHA, which plays a key role in the Warburg effect. However, suppression of the Warburg effect was not sufficient to induce CCA cellular apoptosis. According to our previous research, which showed that an HDAC3 inhibitor (MI192) was involved in CCA apoptosis, we observed that metformin combined with BG45 (a novel specific HDAC3 inhibitor) effectively induced the apoptosis of CCA cells in vitro. Furthermore, in vivo experiments revealed that the combined treatment with metformin and BG45 markedly reduced CCA growth in a CCA xenograft model. Our data revealed that reversing the Warburg effect with metformin sensitizes cells to the antitumor effects of HDAC3 inhibitors. This provides a rationale for using the combination of metformin and BG45 as a new therapeutic strategy in the treatment of CCA.

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“…The body weights of treated mice were used as indicators of health [33]. AR-42 treatment did not affect mouse body weight, indicating that the mice did not experience evident toxicity in vivo (Figure 5B).…”

Section: Resultsmentioning

confidence: 99%

AR-42 induces apoptosis in human hepatocellular carcinoma cells via HDAC5 inhibition

et al. 2016

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Histone deacetylases (HDACs) play critical roles in apoptosis and contribute to the proliferation of cancer cells. AR-42 is a novel Class I and II HDAC inhibitor that shows cytotoxicity against various human cancer cell lines. The present study aims to identify the target of AR-42 in hepatocellular carcinoma (HCC) as well as evaluate its therapeutic efficacy. We found that HDAC5 was upregulated in HCC tissues compared to adjacent normal tissues, and this was correlated with reduced patient survival. CCK8 and colony-formation assays showed that HDAC5 overexpression promotes proliferation in HCC cell lines. Treatment with AR-42 decreased HCC cell growth and increased caspase-dependent apoptosis, and this was rescued by HDAC5 overexpression. We demonstrated that AR-42 can inhibit the deacetylation activity of HDAC5 and its downstream targets in vitro and in vivo. Taken together, these results demonstrate for the first time that AR-42 targets HDAC5 and induces apoptosis in human hepatocellular carcinoma cells. AR-42 therefore shows potential as a new drug candidate for HCC therapy.

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A novel class I HDAC inhibitor, MPT0G030, induces cell apoptosis and differentiation in human colorectal cancer cells via HDAC1/PKCδ and E-cadherin

Cited by 30 publications

References 27 publications

Suberoylanilide hydroxamic acid increases anti-cancer effect of tumor necrosis factor-α through up-regulation of TNF receptor 1 in lung cancer cells

Suberoylanilide hydroxamic acid increases anti-cancer effect of tumor necrosis factor-α through up-regulation of TNF receptor 1 in lung cancer cells

Metformin facilitates BG45‑induced apoptosis via an anti‑Warburg effect in cholangiocarcinoma cells

AR-42 induces apoptosis in human hepatocellular carcinoma cells via HDAC5 inhibition

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