p38MAPK inhibitor SB203580 sensitizes human SNU-C4 colon cancer cells to exisulind-induced apoptosis.
Sulindac sulfone (exisulind), is a promising anticancer agent because of its ability to induce apoptosis in a variety of malignant cell types and its minimal toxicity to normal cells. The induction of apoptosis is thought to account for the growth inhibitory effect of exisulind. The mitogen-activated protein kinase (MAPK) cascade has been implicated in the regulation of apoptosis in response to exisulind. With human SNU-C4 colon cancer cells that were much more resistant to exisulind than other colon cancer cells, in this study, we investigated whether the modulation of MAPK activity by using selective MAPK inhibitors can contribute to sensitizing SNU-C4 cells to exisulind. Exisulind (400 and 600 microM) slightly increased the phosphorylation of pERK1/2 but pretreatment with the pERK1/2 inhibitor PD98059 did not significantly change the apoptotic response of SNU-C4 cells. The same doses of exisulind increased the phosphorylation of p38MAPK, and pretreatment with the p38MAPK inhibitor SB203580 significantly potentiated growth inhibition and apoptosis induced by exisulind in SNU-C4 cells. We further found that apoptosis induced by a combination of exisulind and SB203580 was mediated through caspase activation. Collectively, our findings indicate that selective p38MAPK inhibitors potentiate apoptosis induction by exisulind in SNU-C4 cells. Such combinations may provide a more effective and less toxic strategy for the prevention or treatment of colon cancer.
Lim
Soo-Jeong
SJ
Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747, Korea. sjlim@sejong.ac.kr
Lee
Young-Ju
YJ
Lee
Eunmyong
E
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D005419:Flavonoids / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D013467:Sulindac / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D005419:Flavonoids; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013467:Sulindac; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C025463:sulindac sulfone; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one