Mechanism of induction of apoptosis by radicals and enhancement of antitumor activity of anticancer drugs and irradiation in head and neck cancer

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Alterations in the SOD content of thyroid tissues occurring in association with thyroid dysfunction were reported. In this study, the Mn-SODcontent was found to increase in thyroid tissues of rats administered TSHand in thyrocytes cultured in medium supplemented with TSH.Furthermore, in the thyroid glands of rats whose serum TSH level was elevated by inhibiting the synthesis of T3 and T4 levels by MTU, the Mn-SOD increased as the TSH concentration increased.In the cultured thyrocytes, the increase in Mn-SOD induced by TSH was inhibited by the C-kinase inhibitor, H17. These findings suggested the induction of Mn-SOD by TSH in the thyroid cells and pointed to a role of C-kinase in this process, thereby indicating that a close relationship exits between the serum TSH level and the change in Mn-SOD content in thyrocytes with thyroid dysfunction. Some malignant tumors are resistantto TNF-alpha or several antineoplastic agents which exert antiturnoral effects mediated by radicals. One predic … More ted reason for this restance is induction of an in vivo enzyme, Mn-SOD, which scavenges O^2. radicals generated by TNF-alpha. In the present study, we investigated whether or not inhibition of this induction recovers the antitumoral effects of TNF-alpha. B 16-melanoma BL6 cell strain was used in this experiments. Mn-SOD content was measured by ELISA using anti-Mn-SOD antibodies (Prof. Taniguchi, Osaka Univ Sch of Med, provided us the Mn-SOD antibodies). Mn-SOD activity was measured according to NBT method. In the B16-melanoma BL6 cell strain cultivated in a medium containing TNF-alpha, there were no deadcells, thereby showing the absence of any influence of the cell growth. Addition of TNF-alpha or TPA significantly increased both the concentration and activity of Mn-SOD, which indicated the induction of Mn-SOD by TNF-alpha and TPA in the BL6 cells. This induction was inhibitedby the addition of H7. Further addition of TNF-alpha after the addition of H7 caused cell death in 50.3% of the BL6 cells. This suggested that C-k inaseybe closely related to the induction of Mn-SOD in part and that the inhibition of C-kinase would recover the tumor necrotizing effect of TNF-alpha .It has been reported that radicals play some role in the induction of apoptosis by irradiation orTNF-alpha. However, the body has scavengers of these radicals. In the present study. we attempted to investigate whether or not inhibition of these scavengers, particularly of cytoplasmic copper, zinc-superoxide dsmutase (Cu, Zn-SOD) that scavenge oxygen radicals induces apoptosis. HL60 cell strain was used in this experiments. DDCwas used to inhibit Cu, Zn-SOD.SODactivities were measured according to NBT method. Cellular ATP levels were determined by luciferin-luciferase method. Intracellular reactive oxygen species were detected by DCFH method Apoptosis was confirmed by the formation of an apoptotic body observed by light microscopy and fragmentation of DNA detected by agarose gel electrophoresis. Admi Less