title: The cyclo-oxygenase-2 inhibitor celecoxib perturbs intracellular calcium by inhibiting endoplasmic reticulum Ca2+-ATPases: a plausible link with its anti-tumour effect and cardiovascular risks.
abstract: Substantial evidence indicates that the cyclo-oxygenase-2 (COX-2) inhibitor celecoxib, a widely prescribed anti-inflammatory agent, displays anti-tumour effect by sensitizing cancer cells to apoptosis. As part of our effort to understand the mechanism by which celecoxib mediates apoptosis in androgen-independent prostate cancer cells, we investigated its effect on intracellular calcium concentration ([Ca(2+)](i)). Digital ratiometric imaging analysis indicates that exposure of PC-3 cells to celecoxib stimulates an immediate [Ca(2+)](i) rise in a dose- and time-dependent manner. Kinetic data show that this Ca(2+) signal arises from internal Ca(2+) release in conjunction with external Ca(2+) influx. Examinations of the biochemical mechanism responsible for this Ca(2+) mobilization indicate that celecoxib blocks endoplasmic reticulum (ER) Ca(2+)-ATPases. Consequently, inhibition of this Ca(2+) reuptake mechanism results in Ca(2+) mobilization from ER stores followed by capacitative calcium entry, leading to [Ca(2+)](i) elevation. In view of the important role of Ca(2+) in apoptosis regulation, this Ca(2+) perturbation may represent part of the signalling mechanism that celecoxib uses to trigger rapid apoptotic death in cancer cells. This Ca(2+)-ATPase inhibitory activity is highly specific for celecoxib, and is not noted with other COX inhibitors tested, including aspirin, ibuprofen, naproxen, rofecoxib (Vioxx), DuP697 and NS398. Moreover, it is noteworthy that this activity is also observed in many other cell lines examined, including A7r5 smooth muscle cells, NIH 3T3 fibroblast cells and Jurkat T cells. Consequently, this Ca(2+)-perturbing effect may provide a plausible link with the reported toxicities of celecoxib such as increased cardiovascular risks in long-term anti-inflammatory therapy.
authors.affiliation: Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington 40536-0082, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: Ao-Lin
authors.initials: AL
authors.lastname: Hsu
authors.forename: Ho-Pi
authors.initials: HP
authors.lastname: Lin
authors.forename: Xueqin
authors.initials: X
authors.lastname: Song
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D002319:Cardiovascular System / Q000378:metabolism; D000068579:Celecoxib; D002462:Cell Membrane / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D011720:Pyrazoles; D012433:Ryanodine / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D012433:Ryanodine; D006493:Heparin; D000251:Adenosine Triphosphatases; D000252:Calcium-Transporting ATPases; D000068579:Celecoxib; D002118:Calcium