Apoptosis: biochemical aspects and clinical implications.
Apoptosis and necrosis represent two distinct types of cell death. Apoptosis possesses unique morphologic and biochemical features which distinguish this mechanism of programmed cell death from necrosis. Extrinsic apoptotic cell death is receptor-linked and initiates apoptosis by activating caspase 8. Intrinsic apoptotic cell death is mediated by the release of cytochrome c from mitochondrial and initiates apoptosis by activating caspase 3. Cancer chemotherapy utilizes apoptosis to eliminate tumor cells. Agents which bind to the minor groove of DNA, like camptothecin and Hoechst 33342, inhibit topoisomerase I, RNA polymerase II, DNA polymerase and initiate intrinsic apoptotic cell death. Hoechst 33342-induced apoptosis is associated with disruption of TATA box binding protein/TATA box complexes, replication protein A/single-stranded DNA complexes, topoisomerase I/DNA cleavable complexes and with an increased intracellular concentration of E2F-1 transcription factor and nitric oxide concentration. Nitric oxide and transcription factor activation or respression also regulate the two apoptotic pathways. Some human diseases are associated with excess or deficient rates of apoptosis, and therapeutic strategies to regulate the rate of apoptosis include inhibition or activation of caspases, mRNA antisense to reduce anti-apoptotic factors like Bcl-2 and survivin and recombinant TRAIL to activate pro-apoptotic receptors, DR4 and DR5.
Kiechle
Frederick L
FL
Department of Clinical Pathology, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, MI 48073-6769, USA. fkeichle@beaumont.edu
Zhang
Xinbo
X
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001562:Benzimidazoles / Q000494:pharmacology; D006690:Bisbenzimidazole / Q000737:chemistry / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D035181:TATA-Box Binding Protein / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D001562:Benzimidazoles; D016376:Oligonucleotides, Antisense; D035181:TATA-Box Binding Protein; D014157:Transcription Factors; D009569:Nitric Oxide; D004247:DNA; D020169:Caspases; D006690:Bisbenzimidazole; C017807:bisbenzimide ethoxide trihydrochloride