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-dihydro-1,3-selenazine (TS-2) and 4-hydroxy-4-methyl-6-propyl-2-p-tolyl-4H-5,6-dihydro-1,3-selenazine++ + (TS-6) were investigated for their inhibitory effect on the growth of 8 human tumor cell lines, including stomach, lung, prostate and colon cancer cell lines, in vitro. Both TS-2 and TS-6 exhibited the strongest cytotoxicity against a gastric adenocarcinoma (TMK-1) among 8 human tumor cell lines, and their IC50 were 2.38 microM and 2.78 microM, respectively. Twenty-four-h exposure of TMK-1 cells to TS-2 or TS-6 (0.1-100 microM) in the absence of serum led to a concentration-dependent increase of cytotoxicity. Exposure of TMK-1 cells to TS-2 or TS-6 (5, 10 or 20 microM) in the presence of 5% serum resulted in significant inhibition of TMK-1 cell proliferation in a concentration- and time-dependent manner. Morphological changes including shrinkage of the nucleus, and DNA ladder 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 inhibition of growth of TMK-1 cells by TS-2 and TS-6 is mediated by the induction of apoptosis.
Wu
W
W
Department of Pathogenic Biochemistry, Toyama Medical and Pharmaceutical University, Japan.
Murakami
K
K
Koketsu
M
M
Yamada
Y
Y
Saiki
I
I
D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D016566:Organoselenium Compounds / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000201:enzymology / Q000473:pathology*
C405507:4-ethyl-4-hydroxy-2-(4-tolyl)-4H-5,6-dihydro-1,3-selenazine; C405506:4-hydroxy-4-methyl-6-propyl-2-(4-tolyl)-4H-5,6-dihydro-1,3-selenazine; D000970:Antineoplastic Agents; D016566:Organoselenium Compounds; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases