Conflicting data regarding the ability of hydrogen sulfide (H 2 S), which reaches high levels in the large intestine owing to biosynthesis in the intestinal cells and intestinal bacteria, to promote or inhibit colorectal cancer cell proliferation have been reported recently. In the present study, the effect of H 2 S on the proliferation of the human colorectal cancer cell line Caco-2 was examined by using the H 2 S donor GYY4137. At concentrations of 0.5 mM and 1.0 mM, GYY4137 significantly inhibited Caco-2 cell viability. Cell cycle analysis, and apoptosis and necrosis detection revealed that the anti-proliferative effect of GYY4137 was partially attributable to the induction of S-G 2 /M cell cycle arrest, apoptosis and necrosis. These results suggest that H 2 S has the potential to suppress human colorectal cancer cell proliferation by influencing both cell cycle and cell death.

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The twin character of reactive oxygen species is substantiated by a growing body of evidence that reactive oxygen species within cells act as inducers and accelerators of the oncogenic phenotype of cancer cells, while reactive oxygen species can also induce cancer cell death and can therefore function as anti-tumorigenic species. The aim of this study was to assess a possible influence of xanthine/xanthine oxidase on the proliferation of colorectal cancer cell line Caco-2. xanthine/xanthine oxidase (2.5 µM/0.25 mU/ml–25 µM/2.5 mU/ml) dose-dependently inhibited the proliferation of Caco-2 cells. Experiments utilizing reactive oxygen species scavengers (superoxide dismutase, catalase and mannitol) and exogenous hydrogen peroxide revealed a major role of hydrogen peroxide in the xanthine/xanthine oxidase effect. Investigations utilizing annexin V-fluorescein/PI assay using flow cytometry, and the lactate dehydrogenase extracellular release assay indicated that hydrogen peroxide induced necrosis, but not apoptosis, in Caco-2 cells. These results suggest that hydrogen peroxide generated by xanthine/xanthine oxidase has the potential to suppress colorectal cancer cell proliferation.

SummaryThe present study was undertaken to investigate the mechanism by which 1 ␣ , 25-dihydroxy-cholecalciferol [1 ␣ ,25-(OH) 2 -VD 3 ] modulates the differentiation of mouse 3T3-L1 preadipocytes into mature adipocytes. Treatment with 1 ␣ ,25-(OH) 2 -VD 3 in the presence of insulin, dexamethasone and 3-isobutyl-1-methyl-xanthine significantly inhibited the triacylglycerol accumulation, and mRNA expressions of adipocytokines (adiponectin and tumor necrosis factor-␣ ) and plasminogen activator inhibitor-1 in the piconanomolar concentration range, indicating that 1 ␣ ,25-(OH) 2 -VD 3 under physiological conditions inhibits the differentiation of 3T3-L1 cells. 1 ␣ ,25-(OH) 2 -VD 3 potently reduced the mRNA and/or protein expressions of CCAAT-enhancer binding protein ␣ (C/EBP ␣ ) and peroxisome proliferator-activated receptor ␥ (PPAR ␥ ), and the nuclear translocation of PPAR ␥ . Furthermore, it inhibited the mRNA expression and phosphorylation of extracellular signalregulated kinase (ERK), one of mitogen-activated protein kinases. These results indicate that 1 ␣ ,25-(OH) 2 -VD 3 can be an inhibitor of adipocyte differentiation, and suggest, in addition to C/EBP ␣ and PPAR ␥ , an important role of ERK in mediating 1 ␣ ,25-(OH) 2 -VD 3 -induced alteration in adipocyte differentiation.

Epidemiologic investigations indicate a close relationship between colorectal cancer and fat intake. However, to date the effects of lipid peroxidation-derived products that are formed from fat (especially free or esterified unsaturated fatty acids) on the initiation or progression of colorectal cancer have not been investigated extensively. Therefore, in the present study, we examined the effects of fatty acids, fatty acid hydroperoxides and aldehydes on the growth of human colorectal cancer cell line HT-29. At concentrations of 1 and 10 µM, linoleic, arachidonic and eicosapentaenoic acids, and 13-hydroperoxyoctadecadienoic and 15-hydroperoxyeicosapentaenoic acids had no significant effects on the growth of HT-29 cells. 4-Hydroxynonenal and 4-hydroxyhexenal had no significant effects on the growth of HT-29 cells up to 10 µM, whereas 4-oxononenal potently inhibited HT-29 cell growth (1–10 µM, 16–85% inhibition). Further experiments concerning DNA fragmentation, expression levels of Bax and Bcl-2 mRNA, expression levels of pro-caspase-3 and caspase-3 proteins, and activity of caspase-3 suggested that 4-oxononenal may increase the sensitivity of HT-29 cells to apoptosis through a decreased expression level of Bcl-2 and then increased formation of caspase-3 from pro-caspase-3.