Abstract
In higher eukaryotes, reactive oxygen species (ROS) are generated during respiration in mitochondria in the course of reduction of molecular oxygen as well as by distinct enzyme systems. ROS have been implicated in the regulation of diverse cellular functions including defense against pathogens, intracellular signaling, transcriptional activation, proliferation, and apoptosis. The reduction-oxidation (redox) state of the cell is primarily a consequence of the precise balance between the levels of ROS and endogenous thiol buffers present in the cell, such as glutathione and thioredoxin, which protect cells from oxidative damage. Dramatic elevation of ROS, exceeding compensatory changes in the level of the endogenous thiol buffers, may result in the sustained activation of signaling pathways and expression of genes that induce apoptosis in affected cells. Many cytotoxic drugs function selectively to kill cancer cells by the abrogation of proliferative signals, leading to cell death, and numerous reports have demonstrated that ROS are generated following treatment with these drugs. In this review, we will summarize recent contributions to our understanding of the importance of cytotoxic drug-induced modulation of cellular redox status for signaling and transcription leading to activation of apoptotic effector mechanisms.
Footnotes
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Send reprint requests to: Dr. Kenneth D. Tew, Department of Pharmacology, Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111-2412. E-mail: kd_tew{at}fccc.edu
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This work was supported in part by National Institutes of Health Grants CA06927 and RR05539, by National Institutes of Health Grant CA85660 to K.D.T., and by an appropriation from the Commonwealth of Pennsylvania.
- Abbreviations:
- ROS
- reactive oxygen species
- GSH
- glutathione
- TRX
- thioredoxin
- h
- human
- CDDP
- cis-diamminedichloroplatinum (II)
- JNK/SAPK
- c-Jun N-terminal kinase/stress activated protein kinase
- TNF
- tumor necrosis factor
- NAC
- N-acetylcysteine
- PDTC
- pyrrolidine dithiocarbamate
- PKC
- protein kinase C
- PMA
- phorbol 12-myristate 13-acetate
- SM
- sphingomyelin
- ASK1
- apoptosis signal-regulating kinase
- ERK
- extracellular signal-regulated kinase
- MAPK
- mitogen-activated protein kinase
- AP-1
- activator protein-1
- Ref-1
- protein redox factor-1
- MEKK1
- mitogen-activated protein kinase kinase kinase 1
- GST
- glutathione S-transferase
- MKK3/4/6
- mitogen-activated protein kinase kinase
- SEK1
- stress-activated protein kinase kinase
- redox
- reduction-oxidation
- Received April 27, 2000.
- Accepted July 31, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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