Exisulind and CP248 induce growth inhibition and apoptosis in human esophageal adenocarcinoma and squamous carcinoma cells.
We examined the effects of exisulind (sulindac sulfone) and a potent derivative CP248 on the Barrett's esophagus (BE)-related adenocarcinoma cell lines Seg-1 and Bic-1, and on HCE7 esophageal squamous carcinoma cells. Marked growth inhibition and apoptosis occurred in all cell lines with IC50 values of 100-300 microM for exisulind and 100 nM for CP248. Bic-1 and HCE7 cells were more sensitive to the growth inhibitory properties of exisulind. Treatment of all cell lines with CP248 for 24 h increased the proportion of cells in mitosis. Exisulind had no effect on cell-cycle progression. Treatment with either compound induced rapid activation of the c-Jun NH2-terminal kinase 1 (JNK1), suggesting that JNK1 activation plays a role in the induction of apoptosis by these compounds. Only Seg-1 cells expressed a detectable basal level of cyclooxygenase-2 (cox-2), providing further evidence that cox-2 is not the critical target for the growth inhibitory and apoptotic effects of these compounds. Cellular levels of reduced glutathione (GSH) increased approximately five-fold in all cell lines after 24 h of treatment with either compound. These studies provide support for the use of exisulind in BE chemoprevention trials, and of exisulind or CP248 in the therapy of patients with esophageal carcinoma.
Joe
Andrew K
AK
Herbert Irving Comprehensive Cancer Center, 701 West 168th Street, HHSC-1509, New York, NY 10032, USA. akj3@columbia.edu
Liu
Hui
H
Xiao
Danhua
D
Soh
Jae-Won
JW
Pinto
John T
JT
Beer
David G
DG
Piazza
Gary A
GA
Thompson
W Joseph
WJ
Weinstein
I Bernard
IB
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D015415:Biomarkers; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism; D008565:Membrane Proteins; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008938:Mitosis; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000378:metabolism; D013467:Sulindac / Q000031:analogs & derivatives / Q000627:therapeutic use*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D015415:Biomarkers; D007527:Isoenzymes; D008565:Membrane Proteins; D013467:Sulindac; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione; C025463:sulindac sulfone