A pharmacological model reveals biased dependency on PI3K isoforms for tumor cell growth
文献类型：期刊论文
| 作者 | Wang, Xiang; Li, Jia-peng; Yang, Yan; Ding, Jian ; Meng, Ling-hua
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| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2013-09 |
| 卷号 | 34期号:9页码:1201-1207 |
| 关键词 | anticancer drug PI3K inhibitor drug selectivity WJD008 prostate cancer B cell type leukemia screening model |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2013.81 |
| 文献子类 | Article |
| 英文摘要 | Aim: To identify the contribution of individual isoform (alpha, beta, gamma, delta ) of class I PI3Ks to tumor cell growth for proper use of PI3K inhibitors in cancer therapy. Methods: A panel of human rhabdomyosarcoma Rh30 cells stably expressing myristoylation (Myr)-tagged one of class I PI3K p110 subunits was established. PI3K activity was analyzed by measuring phosphorylated Akt with Western blotting, and isoform-specific PI3K activities were validated with PI3K isoform-selective inhibitors. The growth of prostate cancer PC-3 cells and B cell type leukemia Raji cells was determined using SRB assay and CCK-8 assay, respectively. Results: The phosphorylation of Akt in Rh30-Myr-p110 alpha, beta, gamma, delta cells was preferentially inhibited by PI3K isoform-selective inhibitors A66 (PI3K alpha), TGX221 (PI3K beta), AS604850 (PI3K gamma) and CAL-101 (PI3K delta), respectively. A newly obtained PI3K inhibitor WJD008 (10 mu mol/L) completely abrogated Akt phosphorylation by all the isoforms of class I PI3Ks, thus acted as a pan-PI3K inhibitor. In prostate cancer PC-3 cells, the PI3K isoform-selective inhibitors were much less potent than WJD008 in suppression of the proliferation. In B cell type leukemia Raji cells, inhibition of PI3Kd alone or all the isoforms of class I PI3Ks displayed similar potency against the cell proliferation, whereas selective inhibition of individual PI3K alpha/beta/gamma isoforms resulted in negligible activity. Conclusion: Rh30-Myr-p110 alpha, beta, gamma, delta cells are a useful cell model to identify the selectivity of PI3K inhibitors. Pan-PI3K inhibitors are suitable for treating PC-3 cells, whereas selective PI3Kd inhibitor is sufficient to block Raji cell growth. The biased dependency on PI3K isoforms for tumor cell growth rationalizes the use of PI3K inhibitors with different selectivity for cancer therapy. |
| WOS关键词 | CHRONIC LYMPHOCYTIC-LEUKEMIA ; CANCER-THERAPY ; INHIBITOR ; P110-ALPHA ; DISCOVERY ; TARGET ; AGENT ; DRUGS |
| 资助项目 | National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program"[2012ZX09301-001] ; National Natural Science Foundation of China[81021062] ; National Natural Science Foundation of China[81173079] ; Knowledge Innovation Program of Chinese Academy of Sciences[KSCX2-EW-Q-3] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:4921447 |
| WOS记录号 | WOS:000324170400010 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277476]  |
| 专题 | 药理学第一研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Ding, Jian |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Xiang,Li, Jia-peng,Yang, Yan,et al. A pharmacological model reveals biased dependency on PI3K isoforms for tumor cell growth[J]. ACTA PHARMACOLOGICA SINICA,2013,34(9):1201-1207. |
| APA | Wang, Xiang,Li, Jia-peng,Yang, Yan,Ding, Jian,&Meng, Ling-hua.(2013).A pharmacological model reveals biased dependency on PI3K isoforms for tumor cell growth.ACTA PHARMACOLOGICA SINICA,34(9),1201-1207. |
| MLA | Wang, Xiang,et al."A pharmacological model reveals biased dependency on PI3K isoforms for tumor cell growth".ACTA PHARMACOLOGICA SINICA 34.9(2013):1201-1207. |
入库方式： OAI收割
来源：上海药物研究所
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