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New tricks for old drugs: the anticarcinogenic potential of DNA repair inhibitors

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Abstract

Defective or abortive repair of DNA lesions has been associated with carcinogenesis. Therefore it is imperative for a cell to accurately repair its DNA after damage if it is to return to a normal cellular phenotype. In certain circumstances, if DNA damage cannot be repaired completely and with high fidelity, it is more advantageous for an organism to have some of its more severely damaged cells die rather than survive as neoplastic transformants. A number of DNA repair inhibitors have the potential to act as anticarcinogenic compounds. These drugs are capable of modulating DNA repair, thus promoting cell death rather than repair of potentially carcinogenic DNA damage mediated by error-prone DNA repair processes. In theory, exposure to a DNA repair inhibitor during, or immediately after, carcinogenic exposure should decrease or prevent tumorigenesis. However, the ability of DNA repair inhibitors to prevent cancer development is difficult to interpret depending upon the system used and the type of genotoxic stress. Inhibitors may act on multiple aspects of DNA repair as well as the cellular signaling pathways activated in response to the initial damage. In this review, we summarize basic DNA repair mechanisms and explore the effects of a number of DNA repair inhibitors that not only potentiate DNA-damaging agents but also decrease carcinogenicity. In particular, we focus on a novel anti-tumor agent, β-lapachone, and its potential to block transformation by modulating poly(ADP-ribose) polymerase-1.

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Acknowledgments

This work was supported by NIH grant CA 10Z792 to D.A.B., and DOD Breast Cancer fellowships, X81XWH-05-1-0248 and X81XWH-04-1-0301 to K.E.R. and MSB, respectively.

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  1. Department of Pharmacology, Case Western Reserve University, Cleveland, OH, 44106, USA

    Melissa S. Bentle

  2. Department of Biochemistry, Case Western Reserve University, Cleveland, OH, 44106, USA

    Kathryn E. Reinicke

  3. Department of Pharmacology, Laboratory of Molecular Stress Responses, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Y-4 RM 206C, Dallas, TX, 75390, USA

    Erik A. Bey, Ying Dong & David A. Boothman

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  1. Melissa S. Bentle
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  2. Erik A. Bey
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  5. David A. Boothman
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Correspondence to David A. Boothman.

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Bentle, M.S., Bey, E.A., Dong, Y. et al. New tricks for old drugs: the anticarcinogenic potential of DNA repair inhibitors. J Mol Hist 37, 203–218 (2006). https://doi.org/10.1007/s10735-006-9043-8

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