Sulindac sulfide, an aspirin-like compound, inhibits proliferation, causes cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells.
Nonsteroidal antiinflammatory drugs (NSAIDs), have cancer preventive and tumor regressive effects in the human colon. They lower the incidence of and mortality from colorectal cancer and sulindac reduces the number and size of polyps in patients with familial adenomatous polyposis. We studied the effect of sulindac, and its metabolite sulindac sulfide, on the proliferation of HT-29 colon adenocarcinoma cells. Both compounds reduced the proliferation rate of these cells, changed their morphology, and caused them to accumulate in the G0/G1 phase of the cell cycle. These responses were time- and concentration-dependent and reversible. In addition, these compounds reduced the level and activity of several cyclin-dependent kinases (cdks), which regulate cell cycle progression. Sulindac and sulindac sulfide also induced apoptosis in these cells at concentrations that affected their proliferation, morphology, and cell cycle phase distribution. Sulindac sulfide was approximately sixfold more potent than sulindac in inducing these cellular responses. Our results indicate that inhibition of cell cycle progression and induction of apoptotic cell death contribute to the anti-proliferative effects of sulindac and sulindac sulfide in HT-29 cells. These findings may be relevant to the cancer preventive and tumor regressive effects of these compounds in humans.
Shiff
S J
SJ
Rockefeller University Hospital, Laboratory of Human Behavior and Metabolism, New York, New York 10021, USA.
Qiao
L
L
Tsai
L L
LL
Rigas
B
B
D000230:Adenocarcinoma / Q000473:pathology*; D000595:Amino Acid Sequence; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016203:CDC2 Protein Kinase / Q000032:analysis; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000032:analysis; D004273:DNA, Neoplasm / Q000032:analysis; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D011518:Proto-Oncogene Proteins; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004273:DNA, Neoplasm; D011518:Proto-Oncogene Proteins; D013467:Sulindac; C025462:sulindac sulfide; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases