Nonradioactive iodide effectively induces apoptosis in genetically modified lung cancer cells.
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 NIS and TPO facilitated 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/TPO genes.
Zhang
Ling
L
Division of Pulmonary and Critical Care Medicine, University of California Los Angeles and Veterans Affairs Greater Los Angeles Healthcare System, California 90073, USA.
Sharma
Sherven
S
Zhu
Li X
LX
Kogai
Takahiko
T
Hershman
Jerome M
JM
Brent
Gregory A
GA
Dubinett
Steven M
SM
Huang
Min
M
D000111:Acetylcysteine / Q000037:antagonists & inhibitors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007453:Iodide Peroxidase / Q000235:genetics*; D007454:Iodides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins; D009368:Neoplasm Transplantation; D000077022:Survivin; D027981:Symporters / Q000235:genetics*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D000099209:Sodium-Iodide Symporters
D000111:Acetylcysteine; D051034:Inhibitor of Apoptosis Proteins; D007453:Iodide Peroxidase; D007454:Iodides; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C107489:BIRC5 protein, human