Coloncancersdevelopadaptivemechanismstosurviveunderextremeconditionsanddisplayhallmarksofunlimitedproliferationandresistancetocelldeath.Thederegulationofcelldeathisakeyfactorthatcontri-butestochemoresistanceintumors.Inaphysiologicalcontext,balancebetweencellproliferationanddeath,andprotectionagainstcelldamagearefundamentalprocessesformaintaininggutepithelialhomeostasis.Themechanismsunderlyinganti-deathcytoprotectionandtumorresistanceoftenbearcommonpathways,andalthoughdistinguishingthemwouldbeachallenge,itwouldalsoprovideanopportunitytodevelopadvancedanti-cancertherapeutics.Thisreviewwilloutlinecelldeathpathways(i.e.,apoptosis,necrosis,andnecroptosis),anddiscusscytoprotectivestrategiesinnormalintestinalepitheliumanddeathresistancemechanismsofcolontumor.Incolorectalcancers,theintracellularmechanismsofdeathresistanceincludethedirectalterationofapoptoticandnecroptoticmachineryandtheupstreameventsmodulatingdeatheffectorssuchastumorsuppressorgeneinactivationandpro-survivalsignalingpathways.Theautocrine,paracrineandexogenousfactorswithinatumormicroenvironmentcanalsoinstigateresistanceagainstapoptoticandnecroptoticcelldeathincoloncancersthroughchangesinreceptorsignalingortransporteruptake.Therolesofcyclooxygenase-2/prostaglandinE2,growthfactors,glucose,andbacteriallipopolysaccharidesincolorectalcancerwillbehighlighted.Targetinganti-deathpathwaysinthecoloncancertissuemightbeapromisingapproachoutsideofanti-proliferationandanti-angiogenesisstrategiesfordevelopingnoveldrugstotreatrefractorytumors.
