S9, a Novel Anticancer Agent, Exerts Its Anti-Proliferative Activity by Interfering with Both PI3K-Akt-mTOR Signaling and Microtubule Cytoskeleton 英文参考文献.docVIP

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S9, a Novel Anticancer Agent, Exerts Its Anti-Proliferative Activity by Interfering with Both PI3K-Akt-mTOR Signaling and Microtubule Cytoskeleton 英文参考文献.doc

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S9, a Novel Anticancer Agent, Exerts Its Anti-Proliferative Activity by Interfering with Both PI3K-Akt-mTOR Signaling and Microtubule Cytoskeleton 英文参考文献

S9,aNovelAnticancerAgent,ExertsItsAnti-Proliferative ActivitybyInterferingwithBothPI3K-Akt-mTOR SignalingandMicrotubuleCytoskeleton ChaoZhang1.,NaYang1.,Chun-haoYang2,Hua-shengDing2,ChengLuo3,YuZhang3,Mao-jiangWu2, Xiong-wenZhang1,XuShen3,4,Hua-liangJiang3,4,Ling-huaMeng1*,JianDing1* 1DivisionofAnti-TumorPharmacology,StateKeyLaboratoryofDrugResearch,ShanghaiInstituteofMateriaMedica,ChineseAcademyofSciences,Shanghai,China, 2Division of Organic Synthesis, Shanghai Institute of Materia Medica, ChineseAcademy ofSciences, Shanghai, China, 3Drug Discovery and Design Center, Shanghai InstituteofMateriaMedica,ChineseAcademyofSciences,Shanghai,China,4SchoolofPharmacy,EastChinaUniversityofScienceandTechnology,Shanghai,China Abstract Background: Deregulation of the phosphatidylinositol 3-kinases (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathwayplaysacentralroleintumorformationandprogression,providingvalidatedtargetsforcancertherapy.S9,ahybrid ofa-methylene-c-lactoneand2-phenylindolecompound,possessedpotentactivityagainstthispathway. Methodology/Principal Findings: Effects of S9 on PI3K-Akt-mTOR pathway were determined by Western blot, immunofluorescence staining and in vitro kinas assay. The interactions between tubulin and S9 were investigated by polymerization assay, CD, and SPR assay. The potential binding modes between S9 and PI3K, mTOR or tubulin were analyzedbymolecularmodeling.Anti-tumoractivityofS9wasevaluatedintumorcellsandinnudemicebearinghuman cancer xenografts. S9 abrogated EGF-activated PI3K-Akt-mTOR signaling cascade and Akt translocation to cellular membraneinhumantumorcells.S9possessedinhibitoryactivityagainstbothPI3KandmTORwithlittleeffectonother tested 30 kinases. S9 also completely impeded hyper-phosphorylation of Akt as a feedback of inhibition of mTOR by rapamycin.S9unexpectedlyarrestedcellsinMphaseotherthanG1phase,whichwasdistinctfromcompoundstargeting PI3K-Akt-mTORpathway.FurtherstudyrevealedthatS9inhibitedtubulinpolymerizationviabindingtocolch