ABSTRACT
PURPOSE: Lipid A has shown promising immunostimulatory effects in both experimental tumor models and advanced stage cancer patients. This study examines whether lipid A may directly modulate the radioresponse of tumor cells by activating inducible nitric oxide synthase (iNOS) or cyclooxygenase-2 (COX-2) through nuclear factor-kappaB (NF-kappaB) signaling. METHODS AND MATERIALS: Hypoxic EMT-6 tumor cells were exposed to lipid A and analyzed for the level of COX-2 and iNOS by Western blotting and enzymatic assays. The hypoxic radioresponse of EMT-6 cells was estimated by clonogenic survival. The activation of NF-kappaB was examined by immunostaining of its p65 subunit and by luciferase reporter gene assay. RESULTS: Lipid A dose-dependently increased the expression and activity of iNOS with a maximal effect at plasma achievable concentrations of 3-30 micro g/mL. The COX-2 mediated production of prostaglandin E2 was constitutively high and further upregulated by lipid A. The radiosensitivity of hypoxic EMT-6 cells was increased up to 2.5 times and counteracted by the iNOS inhibitor aminoguanidine but not by the COX-2 inhibitor NS-398. The mechanism of radiosensitization was linked to NF-kappaB signaling, because its inhibition by phenylarsine oxide impaired both iNOS activation and radioresponse. CONCLUSION: Lipid A is an efficient hypoxic cell radiosensitizer at plasma relevant concentrations, which provides a rationale to combine lipid A with radiotherapy in further studies.
Subject(s)
Isoenzymes/metabolism , Lipid A/pharmacology , NF-kappa B/physiology , Nitric Oxide Synthase/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Radiation-Sensitizing Agents/pharmacology , Signal Transduction/physiology , Cell Hypoxia/drug effects , Cell Line, Tumor/drug effects , Cell Line, Tumor/radiation effects , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacology , Dose-Response Relationship, Drug , Enzyme Activation , Enzyme Inhibitors/pharmacology , Guanidines , Humans , Membrane Proteins , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase Type II , Nitrobenzenes/pharmacology , Sulfonamides/pharmacologyABSTRACT
The association of an asymptomatic mass, normal thyroid function, and a cold nodule can occur months to years after a primary cancer. Work-up should include ruling out other metastases and fine-needle aspiration cytology. We report six cases of secondary thyroid cancer. Two of the patients in our series presented with hyperthyroidism, which may be due to invasion and disruption of thyroid follicles.
