Drug insight: cancer therapy strategies based on restoration of endogenous cell death mechanisms.
Cell death is a normal facet of human physiology, ensuring tissue homeostasis by offsetting cell production with cell demise. Neoplasms arise in part because of defects in physiological cell death mechanisms, contributing to pathological cell expansion. Defects in normal cell death pathways also contribute to cancer progression by permitting progressively aberrant cell behaviors, while also desensitizing tumor cells to immune-mediated attack, radiation, and chemotherapy. Through basic research, much has been learned about the molecular mechanisms responsible for cell turnover and how tumors escape cell death. By exploiting this knowledge base, several innovative strategies for eradicating malignancies have materialized that are based on restoration of natural pathways for cell autodestruction. Some of these strategies have advanced into human clinical trials. Several of the current strategies based on targeting core components of the cell death machinery for cancer therapy are reviewed here, and a summary of progress toward clinical applications is provided.
Reed
John C
JC
Burnham Institute for Medical Research, La Jolla, CA 92037, USA. reedoffice@burnham.org
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002986:Clinical Trials as Topic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000494:pharmacology / Q000627:therapeutic use; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D051034:Inhibitor of Apoptosis Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand