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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Cellular Thiols and Reactive Oxygen Species in Drug-Induced Apoptosis

Warren Davis Jr., Ze'ev Ronai and Kenneth D. Tew
Journal of Pharmacology and Experimental Therapeutics January 2001, 296 (1) 1-6;
Warren Davis Jr.
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Ze'ev Ronai
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Kenneth D. Tew
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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

  • 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

  • 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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Journal of Pharmacology and Experimental Therapeutics: 296 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 296, Issue 1
1 Jan 2001
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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Cellular Thiols and Reactive Oxygen Species in Drug-Induced Apoptosis

Warren Davis, Ze'ev Ronai and Kenneth D. Tew
Journal of Pharmacology and Experimental Therapeutics January 1, 2001, 296 (1) 1-6;

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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Cellular Thiols and Reactive Oxygen Species in Drug-Induced Apoptosis

Warren Davis, Ze'ev Ronai and Kenneth D. Tew
Journal of Pharmacology and Experimental Therapeutics January 1, 2001, 296 (1) 1-6;
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