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

摘要

Substantial evidence indicates that the cyclo-oxygerase-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 ([Ca2+](i)). Digital ratiometric imaging analysis indicates that exposure of PC-3 cells to celecoxib stimulates an immediate [Ca2+](i) rise in a dose- and time-dependent manner. Kinetic data show that this Ca2+ signal arises from internal Ca2+ release in conj. unction with external Ca2+ influx. Examinations of the biochemical mechanism responsible for this Call mobilization indicate that celecoxib blocks endoplasmic reticulum (ER) Ca2+-ATPases. Consequently, inhibition of this Ca2+ reuptake mechanism results in Ca2+ mobilization from ER stores followed by capacitative calcium entry, leading to [Ca 21] elevation. In view of the important role of Ca2+ in apoptosis regulation, this Ca2+ perturbation may represent part of the signalling mechanism that celecoxib uses to trigger rapid apoptotic death in cancer cells. This Ca2+-ATPase inhibitory activity is highly specific for celecoxib, and is not noted with other COX inhibitors tested, including aspirin, ibuprofen, naproxen, rofecoxib (Vioxx(R)), 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 Ca2+-perturbing effect may provide a plausible link with the reported toxicities of celecoxib such as increased cardiovascular risks in long-term anti-inflammatory therapy.