Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Transformed cell-derived reactive oxygen species drive efficiency and selectivity of natural antitumor systems

G Bauer PhD

Abteilung Virologie, Institut fuer Medizinische Mikrobiologie und Hygiene, University Freiburg, Freiburg, Germany,

AIMS. Oncogene-transformed cells generate extracellular superoxide anions through membrane-associated NAD(P)H oxidases. The presence of membrane-associated NAD(P)H oxidases represents a typical biochemical feature of most tumor cells. The aim of our study was to delineate the role of transformed cell-derived superoxide anions for selective apoptosis induction of these cells during the control of oncogenesis. METHODS. The studies were performed through reconstitution experiments, using myeloperoxidase and defined reactive oxygen (ROS) or nitrogen species (RNS). In parallel, the challenge of transformed cells by natural antitumor systems was mimicked by coculture with macrophages, promyelocytes or TGF-beta-pretreated fibroblasts. TGF-beta pretreated fibroblasts have been recently shown to exert a strong and selective apoptosis inducing effect on transformed cells, which has been termed intercellular induction of apoptosis. RESULTS and CONCLUSIONS. Our results demonstrate that different natural antitumor systems use the same ROS and RNS-based signaling pathways for selective apoptosis induction in transformed cells. Nitric oxide released by effector cells is converted to the apoptosis inducer peroxynitrite through interaction with target cell derived superoxide anions. In parallel, superoxide anions spontaneously dismutate and form hydrogen peroxide, which is converted to hypochlorous acid. The interaction of hypochlorous acid with superoxide anions results in the generation of apoptosis inducing hydroxyl radicals in the direct vicinity of transformed cells and thus warrants selectivity of the toxic effect. Interference with ROS and RNS-based apoptosis induction is likely to represent a basic requirement for tumor cell survival and tumor development. The detailed knowledge of the underlying mechanisms may have prognostic and therapeutic potential in the future.

KEY WORDS: nitric oxide, peroxynitrite, nitrylchloride, hydroxyl radical.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on satellite symposium.