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Nonradioactive Iodide Effectively Induces Apoptosis in Genetically Modified Lung Cancer Cells¹

Division of Pulmonary and Critical Care Medicine [L. Z., S. S., L. X. Z., S. M. D., M. H.], Division of Endocrinology and Metabolism, Department of Medicine [T. K., J. M. H., G. A. B.], Lung Cancer Research Program of the Jonsson Comprehensive Cancer Center [S. M. D.], and Department of Pathology, David Geffen School of Medicine [M. H.], University of California Los Angeles and Veterans Affairs Greater Los Angeles Healthcare System, California 90073

We assessed a nonradioactive approach to induce apoptosis in non-small cell lung cancer by a novel iodide uptake and retention mechanism. To enhance tumor apoptosis, we transduced non-small cell lung cancer cells with retroviral vectors containing the sodium iodide symporter (NIS) and thyroperoxidase (TPO) genes. Expression of NISand TPOfacilitated concentration of iodide in tumors. As a consequence of the marked increase in intracellular levels of iodide, apoptosis was seen in >95% of NIS/TPO-modified lung cancer cells. Intraperitoneal injection of potassium iodide resulted in significant tumor volume reduction in NIS/TPO-modified tumor xenografts without apparent adverse effects in SCID mice. Iodide induced an increase in the level of reactive oxygen species. Iodide-induced apoptosis is sensitive to N-acetylcysteine inhibition, suggesting an important role by reactive oxygen species in this apoptotic process. In addition, iodide-induced apoptosis is associated with overexpression of CDKN1A (p21/Waf1)and down-regulation of survivin at both mRNA and protein levels. This is the first report demonstrating that a therapeutic dose of nonradioactive iodide has potent efficacy and high selectivity against lung cancer when used in combination with genetic modification of cancer cells to express the NIS/TPOgenes.

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