Combination of a novel HDAC inhibitor OBP-801/YM753 and a PI3K inhibitor LY294002 synergistically induces apoptosis in human endometrial carcinoma cells due to increase of Bim with accumulation of ROS

Yoshioka, Takashi; Yogosawa, Shingo; Yamada, Takeshi; Kitawaki, Jo; Sakai, Toshiyuki

doi:10.1016/j.ygyno.2013.02.008

Cited by 39 publications

(30 citation statements)

References 37 publications

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“…A recent report has shown that the combination of OBP-801 and LY294002 synergistically induces apoptosis through the upregulation of Bim with accumulation of ROS in human endometrial carcinoma HEC-1A cells (37). However, in our experiments, OBP-801/LY294002 co-treatment did not induce Bim expression in RCC 786-O cells (data not shown).…”

Section: Discussioncontrasting

confidence: 78%

A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma

Yamada

Horinaka

Shinnoh

et al. 2013

International Journal of Oncology

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Abstract. Renal cell carcinoma (RCC) is resistant to traditional cancer therapies such as radiation therapy and chemotherapy. The use of targeted therapies has improved the clinical outcomes of patients with metastatic RCC. However, most patients acquire resistance against targeted therapies over time. We report that the combination of the novel histone deacetylase (HDAC) inhibitor OBP-801, also known as YM753 and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 synergistically inhibits cell growth and induces apoptosis in RCC cells. This combination activated caspase-3, -8 and -9 and the pan-caspase inhibitor zVAD-fmk significantly reduced the apoptotic response to the treatment with OBP-801 and LY294002. Moreover, the combined treatment induced intracellular reactive oxygen species (ROS) and the radical scavenger N-acetyl-L-cysteine (NAC) blocked the intracellular ROS and apoptosis induced by OBP-801 and LY294002. The co-treatment with OBP-801 and LY294002 markedly decreased survivin and the X-linked inhibitor of apoptosis protein (XIAP) protein levels, but Bcl-2 family members were not altered by the OBP-801/LY294002 co-treatment. These alterations were restored by NAC treatment. The transient transfection of survivin and XIAP reduced the apoptotic response to the OBP-801/LY294002 co-treatment. Additionally, OBP-801 was significantly more effective than SAHA, another HDAC inhibitor, in the combination with LY294002 against 786-O cells. Taken together, these results strongly suggest the combination of OBP-801 and LY294002 to be a promising treatment for RCC.

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Section: Discussioncontrasting

confidence: 78%

A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma

Yamada

Horinaka

Shinnoh

et al. 2013

International Journal of Oncology

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“…Previously, APO was found to be essential for activation of differentiation in H460 and U251 cells. In the present study, we have demonstrated that N25 was not only involved in apoptosis (Miller et al, 2007;Yoshioka et al, 2013), but also in cell differentiation. These mutations may restrain tumor cell growth advantages and induce apoptosis.…”

Section: Discussionsupporting

confidence: 53%

A Novel Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitor Derivative, N25, Exhibiting Improved Antitumor Activity in both Human U251 and H460 Cells

Song

Huang²,

Li³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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. This invention is a hydroxamic acid compound with a structural formula of RNHCO(CH 2 )6CONHOH (wherein R=2, 5dimethoxyaniline), a pharmaceutically acceptable salt which is soluble. In the present study, we investigated the effects of N25 with regard to drug distribution and molecular docking, and anti-proliferation, apoptosis, cell cycling, and LD 50 . First, we designed a molecular approach for modeling selected SAHA derivatives based on available structural information regarding human HDAC8 in complex with SAHA (PDB code 1T69). N25 was found to be stabilized by direct interaction with the HDAC8. Anti-proliferative activity was observed in human glioma U251, U87, T98G cells and human lung cancer H460, A549, H1299 cells at moderate concentrations (0.5-30μM). Compared with SAHA, N25 displayed an increased antitumor activity in U251 and H460 cells. We further analyzed cell death mechanisms activated by N25 in U251 and H460 cells. N25 significantly increased acetylation of Histone 3 and inhibited HDAC4. On RT-PCR analysis, N25 increased the mRNA levels of p21, however, decreased the levels of p53. These resulted in promotion of apoptosis, inducing G0/G1 arrest in U251 cells and G2/M arrest in H460 cells in a time-dependent and dosedependent manner. In addition, N25 was able to distribute to brain tissue through the blood-brain barrier of mice (LD 50 : 240.840mg/kg). In conclusion, our findings demonstrate that N25 will provide an invaluable tool to investigate the molecular mechanism with potential chemotherapeutic value in several malignancies, especially human glioma.

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“…Exposure of human leukemia cells to a higher concentration of LAQ824 resulted in the early generation of ROS before disruption of mitochondria, which has been implicated in increased oxidative stress following treatment with HDACi [144]. Pre-treatment with the ROS scavenger N-acetyl cysteine (NAC) reduces apoptosis induced by HDACi, suggesting that oxidative stress may play an important role in tumor cell death induced by HDACi [144, 146, 147]. Other studies show that enhanced ROS generation is associated with the synergistic induction of apoptosis by co-treatment with HDAC inhibitor and other drugs [146, 147].…”

Section: Signaling Pathways Involved In Hdaci-induced Apoptosismentioning

confidence: 99%

Histone deacetylase inhibitors and cell death

Zhang

Zhong

2014

Cell. Mol. Life Sci.

181

156

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Histone deacetylases (HDACs) are a vast family of enzymes involved in chromatin remodeling and have crucial roles in numerous biological processes, largely through their repressive influence on transcription. In addition to modifying histones, HDACs also target many other non-histone protein substrates to regulate gene expression. Recently, HDACs have gained growing attention as HDAC-inhibiting compounds are being developed as promising cancer therapeutics. Histone deacetylase inhibitors (HDACi) have been shown to induce differentiation, cell cycle arrest, apoptosis, autophagy and necrosis in a variety of transformed cell lines. In this review, we mainly discuss how HDACi may elicit a therapeutic response to human cancers through different cell death pathways, in particular, apoptosis and autophagy.

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Combination of a novel HDAC inhibitor OBP-801/YM753 and a PI3K inhibitor LY294002 synergistically induces apoptosis in human endometrial carcinoma cells due to increase of Bim with accumulation of ROS

Cited by 39 publications

References 37 publications

A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma

A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma

A Novel Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitor Derivative, N25, Exhibiting Improved Antitumor Activity in both Human U251 and H460 Cells

Histone deacetylase inhibitors and cell death

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