Nicotinamide Increases Thyroid Radiosensitivity by Stimulating Nitric Oxide Synthase Expression and the Generation of Organic Peroxides

Abstract

Differentiated thyroid cancer and hyperthyroidism are treated with radioiodine. However, when the radioisotope dose exceeds certain limits, the patient must be hospitalized to avoid contact with people that would otherwise be exposed to radiation. It would be desirable to obtain a similar therapeutic effect using lower radioiodine doses. Radiosensitizers can be utilized for this purpose. Nicotinamide (NA) increases thyroid radiosensitivity to ¹³¹I in both normal and goitrous glands. NA causes a significant increase in thyroid blood flow, which would increase tissue oxygenation and tissue damage via free radicals. Wistar rats were treated with either nicotinamide (NA), ¹³¹I or both. The expression of the three isoforms of nitric oxide synthase (NOS) in the thyroid (Western blot) and the activities of SOD, GPx, catalase and organic peroxides were determined. Treatment with NA or ¹³¹I increased the expression of eNOS and the generation of organic peroxides. When administered jointly, they showed a synergistic effect. No changes were observed in the other NOS isoforms or in the activities of catalase, glutathione peroxidase and superoxide dismutase. NA potentiates the effect of ¹³¹I by increasing eNOS, which would in turn stimulate NO production, increasing thyroid blood flow and tissue damage via organic peroxides.

Key words

Thyroid - radiation - radiosensitivity - nicotinamide - nitric oxide

References

• 1 Stratford M RL, Dennis M F, Hoskin P J, Saunders M I, Hodkiss R J, Rojas A. Nicotinamide pharmacokinetics in normal volunteers and patients undergoing palliative radiotherapy.  Acta Oncol. 1996;  35 213-219
• 2 Kaanders J HAM, Stratford M RL, Liefers J, Dennis M F, van der Kogel A J, van Daal W AJ, Rojas A. Administration of nicotinamide during 5 to seven weeks course of radiotherapy: pharmacokinetics, tolerance and compliance.  Radiother Oncol. 1997;  43 67-73
• 3 Agote M, Viaggi M, Kreimann E, Dagrosa M A, Juvenal G J, Pisarev M A. Influence of nicotinamide on the radiosensitivity of normal and goitrous thyroid in the rat.  Thyroid. 2001;  11 1003-1007
• 4 Lowry O H, Rosebrough N H, Farr A L, Randall R J. Protein measurement with the folin-phenol reagent.  J biol Chem. 1951;  193 265-275
• 5 Beauchamp C, Fridovich I. Superoxide dismutase impaired assays: an assay applicable to acrylamide gels.  Anal Biochem. 1971;  44 276-287
• 6 Nelson D P, Kiesow L A. Enthalpy of decomposition of hydrogen peroxide by catalase at 25 degrees C (with molar extinction coefficients of H₂O₂ solutions in the UV.  Anal Biochem. 1972;  49 474-478
• 7 Reiners J J, Hale M A, Cantu A R. Distribution of catalase and modulation by 12-O-tetradecanoylphorbol-13-acetate in murine dermis and subpopulations of keratinocytes differing in their stages of differentiation.  Carcinogenesis. 1988;  9 1259-1263
• 8 Nozaki Y, Hasegawa Y, Takeuchi A, Fan Z H, Isobe K I, Nakashima I, Shimokata K. Nitric oxide as an inflammatory mediator of radiation pneumopathy in rats.  Am J Physiol. 1997;  272 L651-L658
• 9 Giaid A, Lehnert S M, Chehayeb B, Chehayeb D, Kaplan I, Shenouda G. Inducible nitric oxide synthase and nitrotyrosine in mice with radiation-induced lung damage.  Amer J Clin Oncol. 2003;  26 67-72
• 10 MacNaughton W K, Aurora A R, Bhamra J, Sharkey K A, Miller M J. Expression, activity and cellular localization of inducible nitric oxide synthase in rat ileum and colon post irradiation.  Int J Rad Biol. 1998;  74 255-264
• 11 Lestaevel P, Clarencon D, Gharib A, Peinnequin A, Cespuglio R, Gourmel I, Alonson A, Laval J D, Multon E. Nitric oxide voltametric measurements in the rat brain after gamma radiation.  Rad Res. 2003;  160 631-636
• 12 Leach J K, Black S M, Schmidt-Ullrich R K, Mikklelsen R B. Activation of constitutive nitric-oxide synthase activity is an early signaling event induced by ionizing radiation.  J Biol Chem. 2002;  277 15 400-15 406
• 13 Somosy Z, Bognar G, Horvath G, Koteles G J. Role of nitric oxide, cAMP and cGMP in the radiation induced changes of tight junctions in Madin-Darby canine kidney cells.  Cell Mol Biol. 2003;  49 59-63
• 14 Jordan B F, Sonveaux P, Feron O, Gregoire V, Beghein N, Gallez B. Nitric oxide-mediated increase in tumor blood flow and oxygenation of tumors implanted in muscles stimulated by electric pulses.  Int J Radiat Oncol Biol Phys. 2003;  55 1066-1073
• 15 Colin I M, Nava E, Toussaint D, Maiter D M, vanDenHove M F, Luscher T F, Ketelsgers J M, Denef J F, Jameson J L. Expression of nitric oxide synthase isoforms in the thyroid gland: evidence for a role of nitric oxide in vascular control during goiter formation.  Endocrinology. 1995;  136 5283-5290
• 16 Poderoso J J, Carreras M C, Lisdero C, Riobó N A, Shöpfer F, Boveris A. Nitric oxide inhibits electron transfer and increases superoxide radical production in rat heart mitochondria and submitochondrial particles.  Arch Biochem Biophys. 1996;  328 85-92
• 17 Poderoso J J, Lisdero C, Schopfer F, Riobo N, Carreras M C, Cadenas E, Boveris A. The regulation of mitochondrial oxygen uptake by redox reactions involving nitric oxide and ubiquinol.  J Biol Chem. 1999;  274 37 709-37 716
• 18 Yuan Z, Schellekens H, Warner L, Janssen-Heininger Y, Burch P, Heintz N H. Reactive nitrogen species block cell cycle re-entry through sustained production of hydrogen peroxide.  Am J Respir Cell Mol Biol. 2003;  28 705-712
• 19 Galli S, Labato M I, Bal de Kier Joffe E, Carreras M C, Poderoso J J. Decreased mitochondrial nitric oxide synthase activity and hydrogen peroxide relate persistent tumoral proliferation to embryonic behavior.  Cancer Res. 2003;  63 6370-6377
• 20 Demple B. Radical ideas: genetic responses to oxidative stress.  Clin Exp Pharmacol Physiol. 1999;  26 64-68
• 21 Dal-Pizzol F, Ritter C, Klanck F, Andrades M, da Frota M L Jr, Diel C, de Lima C, Braga Filho A, Schwartsmann G, Moreira J C. Modulation of oxidative stress response to gamma radiation in human glioma cell lines.  J Neurooncol. 2003;  16 89-94