Antitumor Activity of a Novel Oncrasin Analogue Is Mediated by JNK Activation and STAT3 Inhibition 英文参考文献.docVIP

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Antitumor Activity of a Novel Oncrasin Analogue Is Mediated by JNK Activation and STAT3 Inhibition 英文参考文献.doc

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Antitumor Activity of a Novel Oncrasin Analogue Is Mediated by JNK Activation and STAT3 Inhibition 英文参考文献

AntitumorActivityofaNovelOncrasinAnalogueIs MediatedbyJNKActivationandSTAT3Inhibition WeiGuo1,ShuhongWu1,LiWang1,XiaoliWei1,XiaoyingLiu1,JiWang1,ZhiminLu2 ,Melinda Hollingshead3,BingliangFang1* 1DepartmentofThoracicandCardiovascularSurgery,TheUniversityofTexasMDAndersonCancerCenter,Houston,Texas,UnitedStatesofAmerica,2Departmentof Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America, 3Biological Testing Branch, The National Cancer Institute,Frederick,Maryland,UnitedStatesofAmerica Abstract Background: To optimize the antitumor activity of oncrasin-1, a small molecule identified through synthetic lethality screeningonisogenicK-Rasmutanttumorcells,wedevelopedseveralanaloguesanddeterminedtheirantitumoractivities. Here we investigated in vitro and in vivo antitumor activity of NSC-743380 (1-[(3-chlorophenyl) methyl]-1H-indole-3- methanol,oncrasin-72),oneofmostpotentanaloguesofoncrasin-1. MethodologyandPrincipalFindings:InvitroantitumoractivitywasdeterminedinNCI-60cancercelllinepanelusingcell viability assay. In vivo antitumor activity was determined in parallel with NSC-741909 (oncrasin-60) in xenograft tumors established in nude mice from A498, a human renal cancer cell line. Changes in gene expression levels and signaling pathwayactivitiesupontreatmentwithNSC-743380wereanalyzedinbreastandrenalcancercellsbyWesternblotanalysis. ApoptosiswasdemonstratedbyWesternblotanalysisandflowcytometricanalysis.NSC-743380ishighlyactiveagainsta subsetofcancercelllinesderivedfromhumanlung,colon,ovary,kidney,andbreastcancers.The50%growth-inhibitory concentration (GI50) for eight of the most sensitive cell lines was #10nM. In vivo study showed that NSC-743380 has a better safety profile and greater antitumor activity than NSC-741909. Treatment with NSC-743380 caused complete regressionofA498xenografttumorsinnudemiceatthetesteddosesrangingfrom67mg/kgto150mg/kg.Mechanistic characterization revealed that NSC-743380 suppressed the phos