Induction of apoptosis in human gastric adenocarcinoma cells by two novel organoselenium compounds, TS-2 and TS-6

Two new organoselenium compounds, 4-ethyl-4-hydroxy-2-p-tolyl-4H-5, 6-dihyd ro-1,3-selenazine (TS-2) and 4-hydroxy-4-methyl-6-propyl-2-p-tolyl-4H-5,6-d ihydro-1,3-selenazine (TS-6) were investigated for their inhibitory effect on the growth of 8 human tumor cell lines, including stomach, lung, prostat e and colon cancer cell lines, in vitro. Both TS-2 and TS-6 exhibited the s trongest cytotoxicity against a gastric adenocarcinoma (TMK-1) among 8 huma n tumor cell lines, and their IC50 were 2.38 mu M and 2.78 mu M, respective ly. Twenty-four-h exposure of TMK-1 cells to TS-2 or TS-6 (0.1-100 mu M) in the absence of serum led to a concentration-dependent increase of cytotoxi city. Exposure of TMK-1 cells to TS-2 or TS-6 (5, 10 or 20 mu M) in the pre sence of 5% serum resulted in significant inhibition of TMK-1 cell prolifer ation in a concentration- and time-dependent manner. Morphological changes including shrinkage of the nucleus, and DNA lander fragmentation, which are considered to be the typical features of apoptosis, were observed in TMK-1 cells in response to TS-2 or TS-6. Furthermore, the caspase-3 activity in TMK- 1 cells treated with TS-2 or TS-6 was also found to be increased in a time- dependent manner, in parallel with the induction of DNA fragmentation . Taken together, the results of the present study suggest that the inhibit ion of growth of TMK-1 cells by TS-2 and TS-6 is mediated by the induction of apoptosis.