title: Targeting cell death signalling in cancer: minimising 'Collateral damage'.
abstract: Targeting apoptosis for the treatment of cancer has become an increasingly attractive strategy, with agents in development to trigger extrinsic apoptosis via TRAIL signalling, or to prevent the anti-apoptotic activity of BCL-2 proteins or inhibitor of apoptosis (IAP) proteins. Although the evasion of apoptosis is one of the hallmarks of cancer, many cancers have intact apoptotic signalling pathways, which if unblocked could efficiently kill cancerous cells. However, it is becoming increasing clear that without a detailed understanding of both apoptotic and non-apoptotic signalling, and the key proteins that regulate these pathways, there can be dose-limiting toxicity and adverse effects associated with their modulation. Here we review the main apoptotic pathways directly targeted for anti-cancer therapy and the unforeseen consequences of their modulation. Furthermore, we highlight the importance of an in-depth mechanistic understanding of both the apoptotic and non-apoptotic functions of those proteins under investigation as anti-cancer drug targets and outline some novel approaches to sensitise cancer cells to apoptosis, thereby improving the efficacy of existing therapies when used in combination with novel targeted agents.
authors.affiliation: MRC Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Fox
authors.affiliation: MRC Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Marion
authors.initials: M
authors.lastname: MacFarlane
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand