一种双重PI3激酶/雷帕霉素靶蛋白抑制剂在神经胶质瘤中显示出显著疗效。
A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma.
作者信息
Fan Qi-Wen, Knight Zachary A, Goldenberg David D, Yu Wei, Mostov Keith E, Stokoe David, Shokat Kevan M, Weiss William A
机构信息
Department of Neurology, University of California, San Francisco, San Francisco, California 94143, USA.
出版信息
Cancer Cell. 2006 May;9(5):341-9. doi: 10.1016/j.ccr.2006.03.029.
Abstract
The PI3 kinase family of lipid kinases promotes cell growth and survival by generating the second messenger phosphatidylinositol-3,4,5-trisphosphate. To define targets critical for cancers driven by activation of PI3 kinase, we screened a panel of potent and structurally diverse drug-like molecules that target this enzyme family. Surprisingly, a single agent (PI-103) effected proliferative arrest in glioma cells, despite the ability of many compounds to block PI3 kinase signaling through its downstream effector, Akt. The unique cellular activity of PI-103 was traced directly to its ability to inhibit both PI3 kinase alpha and mTOR. PI-103 showed significant activity in xenografted tumors with no observable toxicity. These data demonstrate an emergent efficacy due to combinatorial inhibition of mTOR and PI3 kinase alpha in malignant glioma.
摘要
脂质激酶的PI3激酶家族通过生成第二信使磷脂酰肌醇-3,4,5-三磷酸来促进细胞生长和存活。为了确定由PI3激酶激活驱动的癌症的关键靶点，我们筛选了一组针对该酶家族的强效且结构多样的类药物分子。令人惊讶的是，尽管许多化合物能够通过其下游效应器Akt阻断PI3激酶信号传导，但单一药物（PI-103）却能使胶质瘤细胞发生增殖停滞。PI-103独特的细胞活性直接归因于其抑制PI3激酶α和mTOR的能力。PI-103在异种移植肿瘤中显示出显著活性，且无明显毒性。这些数据表明，在恶性胶质瘤中，mTOR和PI3激酶α的联合抑制具有新出现的疗效。
相似文献
1
A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma.一种双重PI3激酶/雷帕霉素靶蛋白抑制剂在神经胶质瘤中显示出显著疗效。
Cancer Cell. 2006 May;9(5):341-9. doi: 10.1016/j.ccr.2006.03.029.
2
Isoform specific inhibitors of PI3 kinase in glioma.胶质瘤中PI3激酶的亚型特异性抑制剂
Cell Cycle. 2006 Oct;5(20):2301-5. doi: 10.4161/cc.5.20.3362. Epub 2006 Oct 16.
3
New inhibitors of the PI3K-Akt-mTOR pathway: insights into mTOR signaling from a new generation of Tor Kinase Domain Inhibitors (TORKinibs).新一代的 mTOR 激酶结构域抑制剂（TORKinibs）：来自 mTOR 信号通路的新见解。
Curr Top Microbiol Immunol. 2010;347:241-62. doi: 10.1007/82_2010_64.
4
PTEN down regulates AP-1 and targets c-fos in human glioma cells via PI3-kinase/Akt pathway.在人类胶质瘤细胞中，PTEN通过PI3激酶/蛋白激酶B信号通路下调激活蛋白-1并靶向作用于原癌基因c-fos。
Mol Cell Biochem. 2007 Jun;300(1-2):77-87. doi: 10.1007/s11010-006-9371-8. Epub 2007 Jan 18.
5
Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia.IA类磷脂酰肌醇3激酶和雷帕霉素哺乳动物靶标的双重抑制作为T细胞急性淋巴细胞白血病的一种新治疗选择。
Cancer Res. 2009 Apr 15;69(8):3520-8. doi: 10.1158/0008-5472.CAN-08-4884. Epub 2009 Apr 7.
6
PKB/Akt mediates radiosensitization by the signaling inhibitor LY294002 in human malignant gliomas.蛋白激酶B/蛋白激酶B（PKB/Akt）通过信号抑制剂LY294002介导人恶性胶质瘤的放射增敏作用。
J Neurooncol. 2005 Feb;71(3):215-22. doi: 10.1007/s11060-004-1718-y.
7
NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas.NVP-BEZ235，一种新型的双重磷脂酰肌醇 3-激酶/雷帕霉素哺乳动物靶点抑制剂，在人类神经胶质瘤中引发多方面的抗肿瘤活性。
Mol Cancer Ther. 2009 Aug;8(8):2204-10. doi: 10.1158/1535-7163.MCT-09-0160. Epub 2009 Aug 11.
8
The PTEN/Akt pathway dictates the direct alphaVbeta3-dependent growth-inhibitory action of an active fragment of tumstatin in glioma cells in vitro and in vivo.PTEN/Akt信号通路决定了tumstatin活性片段在体外和体内对胶质瘤细胞直接的αVβ3依赖性生长抑制作用。
Cancer Res. 2006 Dec 1;66(23):11331-40. doi: 10.1158/0008-5472.CAN-06-1540.
9
FK228 augmented temozolomide sensitivity in human glioma cells by blocking PI3K/AKT/mTOR signal pathways.FK228通过阻断PI3K/AKT/mTOR信号通路增强了人胶质瘤细胞对替莫唑胺的敏感性。
Biomed Pharmacother. 2016 Dec;84:462-469. doi: 10.1016/j.biopha.2016.09.051. Epub 2016 Sep 28.
10
Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin.膳食类黄酮漆黄素抑制人非小细胞肺癌细胞中的磷酸肌醇 3-激酶/蛋白激酶 B 和雷帕霉素靶蛋白信号通路。
Int J Cancer. 2012 Apr 1;130(7):1695-705. doi: 10.1002/ijc.26178. Epub 2011 Aug 26.
引用本文的文献
1
Ribosome Biogenesis and Function in Cancer: From Mechanisms to Therapy.核糖体生物合成与在癌症中的功能：从机制到治疗
Cancers (Basel). 2025 Jul 31;17(15):2534. doi: 10.3390/cancers17152534.
2
PI3K/mTOR Signaling Pathway Dual Inhibition for the Management of Neuroinflammation: Novel Insights from In Vitro Models.PI3K/mTOR信号通路双重抑制用于神经炎症管理：来自体外模型的新见解
Biomolecules. 2025 May 7;15(5):677. doi: 10.3390/biom15050677.
3
pH-responsive bond as a linker for the release of chemical drugs from RNA-drug complexes in endosome or lysosome.pH响应键作为一种连接物，用于在内体或溶酶体中从RNA-药物复合物释放化学药物。
RNA Nanomed. 2024;1(1):91-108. doi: 10.59566/isrnn.2024.0101091.
4
HaloTag as a substrate-based macroautophagy reporter.HaloTag 作为基于底物的巨自噬报告分子。
Proc Natl Acad Sci U S A. 2024 Aug 6;121(32):e2322500121. doi: 10.1073/pnas.2322500121. Epub 2024 Jul 29.
5
Advances in synthetic lethality modalities for glioblastoma multiforme.多形性胶质母细胞瘤合成致死模式的进展。
Open Med (Wars). 2024 Jun 10;19(1):20240981. doi: 10.1515/med-2024-0981. eCollection 2024.
6
PI3K/mTOR inhibition induces tumour microenvironment remodelling and sensitises pS6 uterine leiomyosarcoma to PD-1 blockade.PI3K/mTOR 抑制诱导肿瘤微环境重塑，并使 pS6 子宫平滑肌肉瘤对 PD-1 阻断敏感。
Clin Transl Med. 2024 May;14(5):e1655. doi: 10.1002/ctm2.1655.
7
Shear stress induces autophagy in Schlemm's canal cells via primary cilia-mediated SMAD2/3 signaling pathway.剪切应力通过初级纤毛介导的SMAD2/3信号通路诱导小梁网细胞自噬。
Autophagy Rep. 2023;2(1). doi: 10.1080/27694127.2023.2236519. Epub 2023 Jul 20.
8
Protein Kinase Inhibitors as a New Target for Immune System Modulation and Brain Cancer Management.蛋白激酶抑制剂作为免疫系统调节和脑癌管理的新靶点。
Int J Mol Sci. 2022 Dec 10;23(24):15693. doi: 10.3390/ijms232415693.
9
Initiation of muscle protein synthesis was unrelated to simultaneously upregulated local production of IGF-1 by amino acids in non-proliferating L6 muscle cells.肌肉蛋白合成的启动与非增殖 L6 肌细胞中氨基酸同时上调局部 IGF-1 的产生无关。
PLoS One. 2022 Jul 8;17(7):e0270927. doi: 10.1371/journal.pone.0270927. eCollection 2022.
10
Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment.用于肿瘤治疗的双PI3K/mTOR抑制剂的最新进展
Front Pharmacol. 2022 May 9;13:875372. doi: 10.3389/fphar.2022.875372. eCollection 2022.
本文引用的文献
1
A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling.PI3-K家族的药理学图谱确定了p110α在胰岛素信号传导中的作用。
Cell. 2006 May 19;125(4):733-47. doi: 10.1016/j.cell.2006.03.035. Epub 2006 Apr 27.
2
TORgeting oncogene addiction for cancer therapy.靶向癌基因成瘾用于癌症治疗。
Cancer Cell. 2006 Feb;9(2):77-9. doi: 10.1016/j.ccr.2006.01.021.
3
Exploiting the PI3K/AKT pathway for cancer drug discovery.利用PI3K/AKT信号通路进行癌症药物研发。
Nat Rev Drug Discov. 2005 Dec;4(12):988-1004. doi: 10.1038/nrd1902.
4
Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase.氨基酸通过激活3类磷脂酰肌醇3-羟基激酶介导mTOR/raptor信号传导。
Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14238-43. doi: 10.1073/pnas.0506925102. Epub 2005 Sep 21.
5
The Akt-mTOR tango and its relevance to cancer.Akt-mTOR信号通路及其与癌症的相关性。
Cancer Cell. 2005 Sep;8(3):179-83. doi: 10.1016/j.ccr.2005.08.008.
6
Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition.雷帕霉素介导的雷帕霉素哺乳动物靶标抑制对Akt和eIF4E存活途径的激活作用。
Cancer Res. 2005 Aug 15;65(16):7052-8. doi: 10.1158/0008-5472.CAN-05-0917.
7
hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase.人Vps34是一种营养调节脂质激酶，是p70 S6激酶激活所必需的。
J Biol Chem. 2005 Sep 23;280(38):33076-82. doi: 10.1074/jbc.M507201200. Epub 2005 Jul 27.
8
Tyrosine kinases as targets for cancer therapy.酪氨酸激酶作为癌症治疗的靶点。
N Engl J Med. 2005 Jul 14;353(2):172-87. doi: 10.1056/NEJMra044389.
9
CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium.CCI-779用于转移性黑色素瘤：加利福尼亚癌症联盟的一项II期试验。
Cancer. 2005 Sep 1;104(5):1045-8. doi: 10.1002/cncr.21265.
10
An expanding role for mTOR in cancer.mTOR在癌症中的作用不断扩大。
Trends Mol Med. 2005 Aug;11(8):353-61. doi: 10.1016/j.molmed.2005.06.007.
Zotero 插件