Small-molecule BH3 mimetics to antagonize Bcl-2-homolog survival functions in cancer.
Cancer arises through genetic alterations that improve cellular fitness and increase autonomy. These alterations, in addition to those invoked by genomic, metabolic and mechanical stressors, activate checkpoints that cancer cells must circumvent, including mitochondrial apoptosis. Thus, there is selective pressure to bypass apoptotic signaling in cancer cells, and this process is largely governed by Bcl-2 homology (BH) proteins. Given the primacy of the mitochondrial apoptosis checkpoint, it is surprising that the integrity of the apoptotic machinery is preserved in most cancers. Instead, it is the threshold for activating cell death that is elevated in cancer cells to provide a survival bias. Therapeutic opportunities are emerging as the roles for BH proteins are elucidated in normal and cancer cells. This review discusses small-molecule BH3 mimetics for the restoration of cancer-cell sensitivity to apoptotic stressors. Neuroblastoma, a lethal childhood tumor in which emergent therapy resistance is common, is presented to provide a model for the rational integration of BH3 mimetics into the clinic.
Goldsmith
Kelly C
KC
The Children's Hospital of Philadelphia, Division of Oncology, 3615 Civic Center Boulevard, Philadelphia, PA 19104-4318, USA.
Hogarty
Michael D
MD
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002986:Clinical Trials as Topic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2