5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole acts in a reactive oxygen species-dependent manner to suppress human lung cancer growth.
OBJECTIVE
5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560) is a structural analog of celecoxib. Recent studies suggested that SC-560 inhibits the in vivo proliferation of colon and breast cancer cells to an extent similar to that observed in celecoxib, and that SC-560 exerts their growth inhibitory effects in a cyclooxygenase-independent manner.


METHODS
In the current study, we sought to investigate the mechanism by which SC-560 inhibits the growth of human lung cancer cells.


RESULTS
SC-560 more potently inhibited the growth of human A549, H460, and H358 lung cancer cell lines compared with that of human BEAS-2B normal bronchial epithelial cells. SC-560-induced growth inhibition was mainly due to the induction of cell-cycle arrest at the G1 phase without apoptosis induction. SC-560 rapidly and dose-dependently induced the generation of reactive oxygen species (ROS), followed by accumulation of cells at the G1 phase. Antioxidant pretreatment blocked the cell-cycle arrest and growth inhibition induced by SC-560. Combination treatment with other ROS-inducing agents such as alpha-tocopheryl succinate (TOS) augmented cellular response against SC-560, leading to synergistic apoptosis induction and growth suppression. Our data also showed that the apoptosis induced by combination treatment with SC-560 and TOS was mediated through ROS-dependent caspase activation.


CONCLUSIONS
Collectively, our results demonstrate that SC-560 acts in a ROS-dependent manner to induce growth suppression in human lung cancer cells.
Lee
Eunmyong
E
Research Institute, National Cancer Center, 809 Madu-Dong, Ilsan-gu, Goyang, Gyeonggi, Korea.
Choi
Moon-Kyung
MK
Youk
Hee-Jeong
HJ
Kim
Cheol Hyeon
CH
Han
Inn-Oc
IO
Yoo
Byung-Chul
BC
Lee
Mi-Kyung
MK
Lim
Soo-Jeong
SJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D008954:Models, Biological; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D024505:Tocopherols; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives
D000970:Antineoplastic Agents; D004338:Drug Combinations; D011720:Pyrazoles; D017382:Reactive Oxygen Species; C115461:SC 560; D014810:Vitamin E; D020169:Caspases; D024505:Tocopherols