Sulindac enhances arsenic trioxide-mediated apoptosis by inhibition of NF-kappaB in HCT116 colon cancer cells.
To study whether the apoptotic effect of arsenic trioxide (As2O3) on colon cancer cells could be enhanced by the addition of sulindac, HCT116 cells were treated with As2O3 (1, 5, 10 microM) and sulindac (0.5 mM), either alone or in combination. As2O3 alone slightly inhibited the growth of HCT116 cells, whereas the combination of As2O3 and sulindac reduced cell growth by 30-40%. Annexin V staining indicated that the synergistic effect of the combination was mediated through increased apoptosis. We examined whether the combination of As2O3 and sulindac on apoptosis is mediated by inhibition of the NF-kappaB pathway in HCT116 colon cancer cells. Western blot analysis showed that the level of nuclear NF-kappaB (p65) was not changed significantly by As2O3 or sulindac treatment alone, while the level of nuclear NF-kappaB (p65) was drastically decreased in the combination treatment by inhibiting the phosphorylation and the degradation of IkappaB-alpha. These results suggest that sulindac enhances apoptosis when combined with As2O3 by inhibiting NF-kappaB activation mediated through the blocking of phosphorylation and degradation of IkappaB-alpha.
Department of Internal Medicine, Inje University, Ilsan Paik Hospital, Seoul 140-743, Korea.
Hye Ran
HR
Lee
Hee-Jeong
HJ
Cheong
Sook-Ja
SJ
Kim
Nam-Su
NS
Lee
Hee-Sook
HS
Park
Jong-Ho
JH
Won
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D053148:Caspase 3 / Q000502:physiology; D053181:Caspase 8 / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D045325:HCT116 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010087:Oxides / Q000494:pharmacology*; D010766:Phosphorylation; D013467:Sulindac / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001152:Arsenicals; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010087:Oxides; D000072000:NF-KappaB Inhibitor alpha; D013467:Sulindac; D053148:Caspase 3; D053181:Caspase 8; D000077237:Arsenic Trioxide