Ansamitocin P3 Depolymerizes Microtubules and Induces Apoptosis by Binding to Tubulin at the Vinblastine Site.docVIP

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Ansamitocin P3 Depolymerizes Microtubules and Induces Apoptosis by Binding to Tubulin at the Vinblastine Site.doc

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Ansamitocin P3 Depolymerizes Microtubules and Induces Apoptosis by Binding to Tubulin at the Vinblastine Site

AnsamitocinP3DepolymerizesMicrotubulesand InducesApoptosisbyBindingtoTubulinatthe VinblastineSite JubinaB.Venghateri1,TilakKumarGupta2,PaulJ.Verma3,AmbarishKunwar2,DulalPanda2* 1IITB-MonashResearchAcademy,IndianInstituteofTechnologyBombay,Mumbai,India,2DepartmentofBiosciencesandBioengineering,IndianInstituteofTechnology Bombay,Powai,Mumbai,India,3CentreforReproductionandDevelopment,MonashInstituteofMedicalResearch,MonashUniversity,Clayton,Victoria,Australia Abstract Maytansinoidconjugatesarecurrentlyunderdifferentphasesofclinicaltrialsandhavebeenshowingpromisingactivityfor varioustypesofcancers.Inthisstudy,wehaveelucidatedthemechanismofactionofansamitocinP3,astructuralanalogue ofmaytansineforitsanticanceractivity.AnsamitocinP3potentlyinhibitedtheproliferationofMCF-7,HeLa,EMT-6/AR1and MDA-MB-231 cells in culture with a half-maximal inhibitory concentration of 2063, 5060.5, 140617, and 15061.1pM, respectively.AnsamitocinP3stronglydepolymerizedbothinterphaseandmitoticmicrotubulesandperturbedchromosome segregationatitsproliferationinhibitoryconcentrationrange.TreatmentofansamitocinP3activatedspindlecheckpoint surveillance proteins, Mad2 and BubR1 and blocked the cells in mitotic phase of the cell cycle. Subsequently, cells underwentapoptosisviap53mediatedapoptoticpathway.Further,ansamitocinP3wasfoundtobindtopurifiedtubulin invitrowithadissociationconstant(Kd)of1.360.7mM.ThebindingofansamitocinP3inducedconformationalchangesin tubulin.AdockinganalysissuggestedthatansamitocinP3maybindpartiallytovinblastinebindingsiteontubulinintwo differentpositions.TheanalysisindicatedthatthebindingofansamitocinP3totubulinisstabilizedbyhydrogenbonds.In addition,weakinteractionssuchashalogen-oxygeninteractionsmayalsocontributetothebindingofansamitocinP3to tubulin.Thestudyprovidedasignificantinsightinunderstandingtheantiproliferativemechanismofactionofansamitocin P3. Citation: Venghateri JB, Gupta TK, Verma PJ, Kunwar A, Panda D (2013) Ansamitocin P3 Depolymerizes Microtubules and Induces