[The Bcl-2 family of proteins as drug targets].
Programmed cell death or apoptosis is a crucial process for normal embryonic development and homeostasis. Apoptosis is known to be coupled to multiple signalling pathways. Identification of critical points in the regulation of apoptosis is of major interest both for the understanding of control of cell fate and for the discovery of new pharmacological targets, particularly in oncology. Indeed, defects in the execution of apoptosis are known to participate in tumour initiation and progression as well as in chemoresistance. The Bcl-2 family members constitute essential intracellular players in the apoptotic machinery. Those proteins are either pro or anti-apoptotic, they interact with each other to regulate apoptosis. Inhibiting the heterodimerisation between pro- and anti-apoptotic members is sufficient to promote apoptosis in mammalian cells. Small molecules, antagonists or peptidomimetics inhibiting this heterodimerisation, represent a therapeutic prototype targeting the apoptotic cascade. They induce cell death by activating directly the mitochondrial apoptotic pathway. Considerable evidence indicate that such Bcl-2 antagonists could be useful drugs to induce apoptosis preferentially in neoplastic cells.
Institut de Recherches Servier, Division Recherche Cancérologie, 125, Chemin de Ronde, 78290 Croissy/Seine, France. anne.mazars@fr.netgrs.com
Anne
A
Mazars
Olivier
O
Geneste
John
J
Hickman
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016375:Antisense Elements (Genetics) / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000502:physiology; D015195:Drug Design; D005419:Flavonoids / Q000627:therapeutic use; D019254:Genes, bcl-2; D015316:Genetic Therapy; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D005810:Multigene Family; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D010636:Phenols / Q000627:therapeutic use; D059808:Polyphenols; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D016375:Antisense Elements (Genetics); D051017:Apoptosis Regulatory Proteins; D005419:Flavonoids; D009842:Oligopeptides; D010636:Phenols; D059808:Polyphenols; D019253:Proto-Oncogene Proteins c-bcl-2