Histone Deacetylase Inhibitors and 15-Deoxy-Δ12,14-Prostaglandin J2 Synergistically Induce Apoptosis
Histone Deacetylase Inhibitors and 15-Deoxy-Δ12,14-Prostaglandin J2 Synergistically Induce Apoptosis
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DOI：
10.1158/1078-0432.ccr-09-2301
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发表时间：
2010-04-15
影响因子：
11.5
通讯作者：
Sakai, Toshiyuki
中科院分区：
文献类型：
--
作者：
Koyama, Makoto;Izutani, Yasuyuki;Sakai, Toshiyuki
用途：临床相关的组蛋白去乙酰化酶抑制剂（HDI）、丙戊酸（VPA）和辛二酰苯胺异羟肟酸发挥不同的抗肿瘤活性，但与其他药物联合使用时可提高疗效。过氧化物酶体增殖物激活受体的天然内源性配体。15-脱氧-δ（12，14）-前列腺素J（2）（15 d-PGJ（2））是一种有效的抗肿瘤药物。因此，我们研究了这些HDI与15 d-PGJ（2）组合是否可以在结肠癌DLD-1细胞中显示协同抗肿瘤活性。细胞凋亡和活性氧（ROS）的产生采用流式细胞术分析。Western blotting和real-time RT-PCR检测细胞凋亡相关分子的表达。将携带DLD-1异种移植物的小鼠分成四组（n = 5），每天（i. p.）结果：HDI/15 d-PGJ（2）联合用药可协同诱导DLD-1细胞凋亡，凋亡途径为caspase依赖性凋亡。此外，HDIs/15 d-PGJ（2）引起组蛋白去乙酰化酶抑制，导致随后的ROS产生和内质网应激，从而降低抗凋亡分子Bcl-X-L和XIAP的表达，并增加促凋亡分子CAAT/增强子结合蛋白同源蛋白和死亡受体5的表达。此外，VPA/15 d-PGJ（2）联合治疗在其他恶性肿瘤细胞中诱导ROS依赖性凋亡，并且在体内比VPA或15 dPGJ（2）单药治疗更有效。配体15 d-PGJ（2）有望用于治疗广谱恶性肿瘤。临床癌症研究; 16（8）; 2320-32。(C)2010年AACR。
Purpose: The clinically relevant histone deacetylase inhibitors (HDI) valproic acid (VPA) and suberoylanilide hydroxamic acid exert variable antitumor activities but increase therapeutic efficacy when combined with other agents. The natural endogenous ligand of peroxisome proliferator-activated receptor. 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is a potent antineoplastic agent. Therefore, we investigated whether these HDIs in combination with 15d-PGJ(2) could show synergistic antitumor activity in colon cancer DLD-1 cells.Experimental Design: Cell viability was determined using a Cell Counting Kit-8 assay. Apoptosis and reactive oxygen species (ROS) generation were determined using flow cytometry analysis. Western blotting and real-time reverse transcription-PCR analysis were carried out to investigate the expression of apoptosis-related molecules. Mice bearing DLD-1 xenograft were divided into four groups (n = 5) and injected everyday (i.p.) with diluent, VPA (100 mg/kg), 15d-PGJ(2) (5 mg/kg), or a combination for 25 days.Results: HDI/15d-PGJ(2) cotreatments synergistically induced cell death through caspase-dependent apoptosis in DLD-1 cells. Moreover, HDIs/15d-PGJ(2) caused histone deacetylase inhibition, leading to subsequent ROS generation and endoplasmic reticulum stress to decrease the expression of antiapoptotic molecules Bcl-X-L and XIAP and to increase that of proapoptotic molecules CAAT/enhancer binding protein homologous protein and death receptor 5. Additionally, VPA/15d-PGJ(2) cotreatment induced ROS-dependent apoptosis in other malignant tumor cells and was more effective than a VPA or 15dPGJ(2) monotherapy in vivo.Conclusions: Cotreatments with the clinically relevant HDIs and the endogenous peroxisome proliferator-activated receptor. ligand 15d-PGJ(2) are promising for the treatment of a broad spectrum of malignant tumors. Clin Cancer Res; 16(8); 2320-32. (C) 2010 AACR.