Regulation of nitric oxide donor JS-K on tumor energy metabolism in H22 tumor-bearing mice / 中国药理学与毒理学杂志

ABSTRACT

OBJECTIVE To investigate the regulation of{O2 (2,4-dinitrophenyl)1-[(4-ethoxycarbonyl) piperazin-1-yl] diazen-1-ium-1, 2-diolate} (JS-K), a nitric oxide donor, on tumor energy metabolism in H22 tumor-bearing mice. METHODS The hepatoma animal model in BALB/c mice was established with H22 cell line. The inoculated mice were randomly divided into four groups. The JS-K group and model group received JS-K (0.75 and 1.50 mg?kg-1) and saline via tail the vein intravenously once every 3 d for 14 d, and 5 injections, respectively. The fluorouracil (5-FU) group received 5-FU 20 mg·kg-1 by intra-peritoneal injection once a day for 14 d. On the 15th day after the first administration, mice were sacri-ficed and the tumor, thymus and spleen were isolated and weighed immediately. The tumor growth inhibitory rate and organ index were calculated. The activities of hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), succinate dehydrogenase (SDH), adenosinetriphosphatase (ATPase), and the levels of lactic acid (LD) and adenosine triphosphate (ATP) in tumor tissues were determined by colorimetric method. The expression of hypoxia-inducible factor 1 alpha (HIF-1α) and hexokinaseⅡ(HKⅡ) in the tumor tissue was analyzed by Western blotting. RESULTS Compared with model group, the tumor mass of JS-K 0.75 and 1.50 mg · kg-1 groups was significantly reduced (P<0.01), and the tumor growth inhibitory rate was 23.9%and 50.3%, respectively. There was no diffrence in thymic and splenic indexes between JS-K group and model group. The activity of HK, PFK, SDH, PK and ATPase of tumor tissue in model group was 22.6±3.7, 14.4±2.6, (10.5±2.6) U·g-1protein, (12.9±3.2) kU·g-1 protein and (0.70 ± 0.10) mmolPi · g-1protein · h-1, respectively, which dropped by 42.0%, 26.6%, 22.7%, 23.3%and 21.7%respectively (P<0.01, P<0.05) in JS-K 1.50 mg?kg-1 group. Compared with the model group, the level of ATP of tumor tissue in JS-K 1.50 mg?kg-1 groups dropped by 16.6%(P<0.01) and the level of LD in JS-K 0.75 and 1.50 mg?kg-1 groups dropped by 38.7%and 59.4%(P<0.01), respectively. In addi-tion, the expression of HIF-1αof tumor tissue in JS-K 1.50 mg?kg-1 group was decreased (P<0.01), and the expression of HKⅡ of tumor tissue in JS-K 0.75 and 1.50 mg?kg-1 groups was decreased signifi-cantly (P<0.05, P<0.01). CONCLUSION JS-K can inhibit the growth of tumor in H22 tumor-bearing mice and its mechanism may be related to regulating the tumor energy metabolism by inhibiting glycolysis and aerobic oxidation.