title: Inhibition of store-operated calcium entry contributes to the anti-proliferative effect of non-steroidal anti-inflammatory drugs in human colon cancer cells.
abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit proliferation and angiogenesis in colorectal cancer. We examined a possible involvement of store-operated calcium (SOC) entry in human colon carcinoma cells (HRT-18), which require calcium for proliferation. Acetyl-salicylic-acid (ASA), mefenamic acid (MEF) and sulindac sulfide (SUS) inhibited cell proliferation with the following order of potency: SUS > MEF >> ASA. SUS but not MEF and ASA induced apoptosis following low-dose treatment. Furthermore, SUS and MEF significantly altered the cell cycle distribution. The ability of NSAIDs to inhibit SOC entry was assessed by measuring the intracellular calcium concentration ([Ca2+]i) in response to calcium store depletion using the endoplasmic calcium ATPase inhibitor thapsigargin. SUS and MEF, but not ASA significantly inhibited SOC entry. A causal link between SOC entry inhibition and anti-proliferative activity was tested using the inorganic SOC entry inhibitor La3+ and the specific organic inhibitor N-1-n-octyl-3,5-bis-(4-pyridyl)triazole (DPT). Both La3+ and DPT inhibited cell proliferation and SOC entry. Analogous to MEF, the anti-proliferative effect of DPT was mediated by cell cycle arrest and not by induction of apoptosis. These data indicate a role of SOC entry for cell proliferation in cancer cells and suggest a novel anti-proliferative NSAID mechanism in addition to its known influence on lipid metabolism.
authors.affiliation: Department of General Surgery, University Hospital Innsbruck and The Tyrolean Cancer Research Institute, Innsbruck, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Weiss
authors.forename: A
authors.initials: A
authors.lastname: Amberger
authors.forename: M
authors.initials: M
authors.lastname: Widschwendter
authors.forename: R
authors.initials: R
authors.lastname: Margreiter
authors.forename: D
authors.initials: D
authors.lastname: Ofner
authors.forename: P
authors.initials: P
authors.lastname: Dietl
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis; D001241:Aspirin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects*; D002469:Cell Separation; D003110:Colonic Neoplasms / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D007811:Lanthanum / Q000494:pharmacology; D050356:Lipid Metabolism; D008528:Mefenamic Acid / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; C429109:N-1-n-octyl-3,5-bis(4-pyridyl)triazole; D011725:Pyridines; D014230:Triazoles; D013467:Sulindac; D008528:Mefenamic Acid; D019284:Thapsigargin; D007811:Lanthanum; C025462:sulindac sulfide; D001241:Aspirin; D002118:Calcium