TheBcl2genehasbeenimplicatedinanumberofcancers,includingmelanoma,breast,prostate,and

lungcarcinomas,aswellasschizophreniaandautoimmunity.Itisalsothoughttobeinvolvedin
resistancetoconventionalcancertreatment.Thissupportsarolefordecreasedapoptosisinthe
mechanismofcancer.
Cancerisoneoftheworld'sleadingcausesofdeathandoccurswhenthehomeostaticbalancebetween
cellgrowthanddeathisdisturbed.Researchincancerbiologyhasdiscoveredthatavarietyof
aberrationsingeneexpressionofantiapoptotic,proapoptoticandBH3onlyproteins[clarificationneeded]can
contributetothemanyformsofthedisease.Aninterestingexamplecanbeseeninlymphomas.The
overexpressionoftheantiapoptoticBcl2proteininlymphocytesalonedidnotactinanoncogenic
manner.ButsimultaneousoverexpressionofBcl2andtheprotooncogenemycmayproduce
aggressiveBcellmalignanciesincludinglymphoma.[5]Infollicularlymphoma,achromosomal
translocationcommonlyoccursbetweenthefourteenthandtheeighteenthchromosomest(14;18)
whichplacestheBcl2genenexttotheimmunoglobulinheavychainlocus.Thisfusiongeneis
deregulated,leadingtothetranscriptionofexcessivelyhighlevelsofbcl2.[6]Thisdecreasesthe
propensityofthesecellsforundergoingapoptosis.
Apoptosisalsoplaysaveryactiveroleinregulatingtheimmunesystem.Whenitisfunctional,itcan
causeimmuneunresponsivenesstoselfantigensviabothcentralandperipheraltolerance.Inthecase
ofdefectiveapoptosis,itmaycontributetoetiologicalaspectsofautoimmunediseases. [7]The
autoimmunedisease,type1diabetescanbecausedbydefectiveapoptosis,whichleadstoaberrantT
cellAICDanddefectiveperipheraltolerance.Duetothefactthatdendriticcells(DCs)arethemost
importantantigenpresentingcellsoftheimmunesystem,theiractivitymustbetightlyregulatedby
suchmechanismsasapoptosis.ResearchershavefoundthatmicecontainingDCsthatareBim/,thus
unabletoinduceeffectiveapoptosis,obtainautoimmunediseasesmoresothanthosethathavenormal
DCs.[7]OtherstudieshaveshownthatthelifespanofDCsmaybecontrolledbyfactorssuchasatimer
dependentonantiapoptoticBcl2.[7]Theseinvestigationsilluminatetheimportanceofregulating
antigenpresentationasdisregulationcanleadtoautoimmunity.
Apoptosisplaysaveryimportantroleinregulatingavarietyofdiseasesthathaveenormoussocial
impacts.Forexample,schizophreniaisaneurodegenerativediseasethatmayresultfromanabnormal
ratioofproandantiapoptoticfactors.[8]Thereissomeevidencethatthisdefectiveapoptosismay
resultfromabnormalexpressionofBcl2andincreasedexpressionofcaspase3.[8]
FurtherresearchintothefamilyofBcl2proteinswillprovideamorecompletepictureonhowthese
proteinsinteractwitheachothertopromoteandinhibitapoptosis.Anunderstandingofthemechanisms
involvedwillhelpdiscoverpotentialtreatmentssuchasinhibitorstotargetoverexpressedproteinsthat
mayleadtonewtherapiesincancer,autoimmuneconditions,andneurologicaldiseases.

Targetedtherapies
Bcl2inhibitorsinclude:

[edit]Genasense
AnantisenseoligonucleotidedrugGenasense(G3139)hasbeendevelopedbyGentaIncorporatedto
targetBcl2.AnantisenseDNAorRNAstrandisnoncodingandcomplementarytothecodingstrand
(whichisthetemplateforproducingrespectivelyRNAorprotein).Anantisensedrugisashort
sequenceofRNAwhichhybridiseswithandinactivatesmRNA,preventingtheproteinfrombeing
formed.

Itwasshownthattheproliferationofhumanlymphomacells(witht(14;18)translocation)couldbe
inhibitedbyantisenseRNAtargetedatthestartcodonregionofBcl2mRNA.Invitrostudiesledto
theidentificationofGenasense,whichiscomplementarytothefirst6codonsofBcl2mRNA. [9]
ThesehaveshownsuccessfulresultsinPhaseI/IItrialsforlymphoma,andalargePhaseIIItrialwas
launchedin2004[10]
Bythefirstquarter2010,GenasensehadnotreceivedFDAapprovalduetodisappointingresultsina
melanomatrial.AlthoughsafetyandefficacyofGenasensehavenotbeenestablishedforanyuse,
GentaIncorporatedstillclaimsonitswebsitethatstudiesarecurrentlyunderwaytoexaminethe
potentialroleofGenasenseinavarietyofclinicalindications.

ABT737
AbbottLaboratoriesdescribedinthemid2000sanovelinhibitorofBcl2,BclxLandBclw,known
asABT737.[11]ABT737isoneamongmanysocalledBH3mimeticsmallmoleculeinhibitors(SMI)
targetingBcl2andBcl2relatedproteinssuchasBclxLandBclwbutnotA1andMcl1,whichmay
provevaluableinthetherapyoflymphomaandotherbloodcancers

Others

obatoclax(GX15070)hasphaseIIresultsforsmallcelllungcancer