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Bcl-2 Antisense Therapy for Cancer: The Art of Persuading Tumour Cells to Commit Suicide

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Abstract

The Bcl-2 oncoprotein is a potent inhibitor of apoptosis induced by numerous physiological and pathological stimuli, and uncontrolled cell survival due to Bcl-2 overexpression has been shown to contribute to tumour formation and the development of autoimmune diseases. The multifunctional action of Bcl-2 is thought to prevent activation of the ced3/caspase-3 subfamily of ICE proteases, resulting in suppression of the death effector machinery. Since most conventional anti-cancer agents act by triggering this suicide pathway, overexpression of Bcl-2 in cancer cells has also been associated with drug resistance. The antisense approach to inhibition of gene expression relies on the binding of small synthetic oligodeoxynucleotides to a complementary base sequence on a target mRNA. As a consequence, expression of the corresponding gene is downregulated due to endonuclease-mediated hydrolysis of the mRNA strand, or to translational arrest arising from sterie hindrance by the RNA:DNA heterodimer. Since these mechanisms of action differ from those exerted by conventional anticancer agents, antisense oligodeoxynucleotides designed to specifically inhibit bcl-2 gene expression hold great promise as agents that could overcome clinical drug resistance, and improve the treatment outcome of many hitherto incurable cancer diseases.

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Authors and Affiliations

  1. Division of Oncology, Department of Internal Medicine, University Hospital Zürich, Häldeliweg 4, CH-8044, Zürich, Switzerland

    U. Zangemeister-Wittke

  2. Department of Hematology/Oncology, Faculty of Medicine, Catholic University of Chile, Alameda 340, PO Box 114-D, Santiago, Chile

    A. Ziegler

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  1. U. Zangemeister-Wittke
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Zangemeister-Wittke, U., Ziegler, A. Bcl-2 Antisense Therapy for Cancer: The Art of Persuading Tumour Cells to Commit Suicide. Apoptosis 3, 67–74 (1998). https://doi.org/10.1023/A:1009636722713

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