Combining histone deacetylase inhibitors with MDA-7/IL-24 enhances killing of renal carcinoma cells.
Combining histone deacetylase inhibitors with MDA-7/IL-24 enhances killing of renal carcinoma cells.
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DOI：
10.4161/cbt.26110
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发表时间：
2013-11
影响因子：
3.6
通讯作者：
Dent P
中科院分区：
文献类型：
--
作者：
Hamed HA;Das SK;Sokhi UK;Park MA;Cruickshanks N;Archer K;Ogretmen B;Grant S;Sarkar D;Fisher PB;Dent P
在本研究中，我们表明，组蛋白去乙酰化酶抑制剂（HDACIs）增强黑色素瘤分化相关基因-7/白细胞介素24（mda-7/IL-24）在人肾癌细胞中的抗肿瘤作用。在其他GU肿瘤细胞中获得了类似的数据。这两种药物的组合导致依赖于神经酰胺合成酶6表达的自噬增加，HDACI通过增加ROS和Ca 2+的产生来增强MDA-7/IL-24毒性。CD 95的敲低保护细胞免于HDACI和MDA-7/IL-24致死。索拉非尼处理进一步增强（HDACI + MDA-7/IL-24）致死率。失巢凋亡抵抗的肾癌细胞对MDA-7/IL-24更敏感，这与SRC活性和CD 95酪氨酸磷酸化的升高相关。我们使用了最近构建的血清型5/3腺病毒，其在将mda-7/IL-24递送至肾癌细胞方面比血清型5病毒更有效，并且通过将腺病毒E1 A基因置于癌症特异性启动子进展升高基因3的控制下，其在表达MDA-7/IL-24的肿瘤细胞中条件性复制（CR 5/3-PEG-E1 A-mda-7; CRAd. 5/3-mda-7，Ad. 5/3-CTV），以确定在肾癌细胞中的功效。Ad.5/3-CTV降低肾癌肿瘤生长的程度明显大于非复制型病毒Ad.5/3-mda-7。在对侧未感染的肾癌肿瘤中，Ad.5/3-CTV也比Ad.5/3-mda-7在更大程度上降低了肿瘤的生长。总之，我们的数据表明HDACI增强MDA-7/IL-24介导的毒性和肿瘤特异性腺病毒递送，并且mda-7/IL-24的病毒复制是有效的临床前肾癌治疗剂。
In the present study we show that histone deacetylase inhibitors (HDACIs) enhance the anti-tumor effects of melanoma differentiation associated gene-7/interleukin 24 (mda-7/IL-24) in human renal carcinoma cells. Similar data were obtained in other GU tumor cells. Combination of these two agents resulted in increased autophagy that was dependent on expression of ceramide synthase 6, with HDACIs enhancing MDA-7/IL-24 toxicity by increasing generation of ROS and Ca2+. Knock down of CD95 protected cells from HDACI and MDA-7/IL-24 lethality. Sorafenib treatment further enhanced (HDACI + MDA-7/IL-24) lethality. Anoikis resistant renal carcinoma cells were more sensitive to MDA-7/IL-24 that correlated with elevated SRC activity and tyrosine phosphorylation of CD95. We employed a recently constructed serotype 5/3 adenovirus, which is more effective than a serotype 5 virus in delivering mda-7/IL-24 to renal carcinoma cells and which conditionally replicates (CR) in tumor cells expressing MDA-7/IL-24 by virtue of placing the adenoviral E1A gene under the control of the cancer-specific promoter progression elevated gene-3 (Ad.5/3-PEG-E1A-mda-7; CRAd.5/3-mda-7, Ad.5/3-CTV), to define efficacy in renal carcinoma cells. Ad.5/3-CTV decreased the growth of renal carcinoma tumors to a significantly greater extent than did a non-replicative virus Ad.5/3-mda-7. In contralateral uninfected renal carcinoma tumors Ad.5/3-CTV also decreased the growth of tumors to a greater extent than did Ad.5/3-mda-7. In summation, our data demonstrates that HDACIs enhance MDA-7/IL-24-mediated toxicity and tumor specific adenoviral delivery and viral replication of mda-7/IL-24 is an effective pre-clinical renal carcinoma therapeutic.
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影响因子：
5.6
作者：
Azab, Belal;Dash, Rupesh;Das, Swadesh K.;Bhutia, Sujit K.;Shen, Xue-Ning;Quinn, Bridget A.;Sarkar, Siddik;Wang, Xiang-Yang;Hedvat, Michael;Dmitriev, Igor P.;Curiel, David T.;Grant, Steven;Dent, Paul;Reed, John C.;Pellecchia, Maurizio;Sarkar, Devanand;Fisher, Paul B.
通讯作者：
Fisher, Paul B.
影响因子：
5.7
作者：
Park, Margaret A.;Walker, Teneille;Dent, Paul
通讯作者：
Dent, Paul
DOI：
10.3390/ph3082441
发表时间：
2010-08-01
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Ellis L;Pili R
通讯作者：
Pili R
影响因子：
11.2
作者：
Gupta, Pankaj;Walter, Mark R.;Fisher, Paul B.
通讯作者：
Fisher, Paul B.
影响因子：
6.4
作者：
Ekmekcioglu, S;Ellerhorst, J;Grimm, EA
通讯作者：
Grimm, EA