Histone Deacetylase Inhibitors and 15-Deoxy-Δ12,14-Prostaglandin J2 Synergistically Induce Apoptosis

Koyama, Makoto; Izutani, Yasuyuki; Goda, Ahmed E.; Matsui, Takaaki; Horinaka, Mano; Tomosugi, Mitsuhiro; Fujiwara, Junichi; Nakamura, Yoshitaka; Wakada, Miki; Yogosawa, Shingo; Sowa, Yoshihiro; Sakai, Toshiyuki

doi:10.1158/1078-0432.ccr-09-2301

Cited by 25 publications

(21 citation statements)

References 41 publications

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“…Our findings point to distinct growth blocking properties of Vpa on colon tumor cells in vitro and in vivo, which are in accordance with previous reports that hdac inhibition triggers growth inhibition of colon cancer cell lines alone or in combination with other drugs (10,11). Of note, the antiproliferative effect of Vpa in vivo peaked between treatment days 17 and 21. thereafter, the treatment effect subsided slightly as tumor growth increased again at day 24 of the administration period.…”

Section: Discussionsupporting

confidence: 92%

Valproate inhibits colon cancer growth through cell cycle modification in vivo and in vitro

Strey

Schamell

Oppermann

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Valproate (Vpa) is a well-characterized histone deacetylase inhibitor with anti-neoplastic properties. We analyzed the growth blocking effects and the molecular mode of action of this compound in colorectal cancer cells in vitro and in vivo. caco-2, SW-480, cx-1 or Widr cell lines were exposed to Vpa (0.25-2 mm) for various time periods. cell growth, cell cycle progression and apoptosis were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide dye reduction assay and flow cytometry. Cell cycle-and apoptosisregulating proteins and histone acetylation were assessed by Western blotting. In vivo tumor growth and regulating protein expression under Vpa were investigated in a subcutaneous xenograft tumor model. Vpa inhibited the growth of all cell lines with cell cycle arrest paralleled by the up-regulation of h3 and h4 acetylation. In vivo tumor growth was substantially depressed by Vpa (200 mg/kg bw). cell cycle proteins (cdk1, cdk2, cdk4, cyclin d, cyclin E, p19, p21 and p27) were differentially altered by Vpa. predominantly cdk1 was decreased and p27 was up-regulated in all models. apoptosis-related proteins were altered in vivo with up-regulation of bax and down-regulation of bcl-2. Vpa exerts anti-neoplastic activity in colorectal tumor cell lines in vitro and in vivo by altering cell cycle regulation.

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Section: Discussionsupporting

confidence: 92%

Valproate inhibits colon cancer growth through cell cycle modification in vivo and in vitro

Strey

Schamell

Oppermann

et al. 2011

Experimental and Therapeutic Medicine

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“…Apoptosis was induced in colorectal cancer cells following treatment with the dehydration product of PGD 2 , 15d-PGJ 2 [116]. This observation was supported by a number of further studies, both in CRC and other cancer types [117][118][119][120][121][122]. These subsequent studies also identified that 15d-PGJ 2 treatment induced cell-cycle arrest [118].…”

Section: Regulation Of Apoptosis By Eicosanoidsmentioning

confidence: 65%

Eicosanoid signalling pathways in the development and progression of colorectal cancer: novel approaches for prevention/intervention

Cathcart

Lysaght

Pidgeon

2011

Cancer Metastasis Rev

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Arachidonic acid metabolism through cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P-450 epoxygenase (EPOX) pathways leads to the generation of biologically active eicosanoids, including prostanoids, leukotrienes, hydroxyeicosatetraenoic acid, epoxyeicosatrienoic acid and hydroperoxyeicosatetraenoic acids. Eicosanoid expression levels vary during tumor development and progression of a range of malignancies, including colorectal cancer. The actions of these autocoids are also directly influenced by diet, as demonstrated by recent evidence for omega-3 fatty acids in colorectal cancer (CRC) prevention and/or treatment. Eicosanoids regulate CRC development and progression, while inhibition of these pathways has generally been shown to inhibit tumor growth/progression. A progressive sequence of colorectal cancer development has been identified, ranging from normal colon, to colitis, dysplasia, and carcinoma. While both COX and LOX inhibition are both promising candidates for colorectal cancer prevention and/or treatment, there is an urgent need to understand the mechanisms through which these signalling pathways mediate their effects on tumorigenesis. This will allow identification of safer, more effective strategies for colorectal cancer prevention and/or treatment. In particular, binding to/signalling through prostanoid receptors have recently been the subject of considerable interest in this area. In this review, we discuss the role of the eicosanoid signalling pathways in the development and progression of colorectal cancer. We discuss the effects of the eicosanoids on tumor cell proliferation, their roles in cell death induction, effects on angiogenesis, migration, invasion and their regulation of the immune response. Signal transduction pathways involved in these processes are also discussed. Finally, novel approaches targeting these arachidonic acid-derived eicosanoids (using pharmacological or natural agents) for chemoprevention and/or treatment of colorectal cancer are outlined.

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“…Histone deacetylase (HDAC) inhibitors are promising anticancer agents that induce growth arrest, differentiation and apoptosis in various types of tumor cell lines (7,8). We identified OBP-801, also known as YM753, as a novel HDAC inhibitor with attractive pharmacodynamic and pharmacokinetic properties by screening for a p21 WAF1/Cip1 -inducing agent (9).…”

Section: Introductionmentioning

confidence: 99%

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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Histone Deacetylase Inhibitors and 15-Deoxy-Δ12,14-Prostaglandin J2 Synergistically Induce Apoptosis

Cited by 25 publications

References 41 publications

Valproate inhibits colon cancer growth through cell cycle modification in vivo and in vitro

Valproate inhibits colon cancer growth through cell cycle modification in vivo and in vitro

Eicosanoid signalling pathways in the development and progression of colorectal cancer: novel approaches for prevention/intervention

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

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