Effects of celecoxib on voltage-gated calcium channel currents in rat pheochromocytoma (PC12) cells.
Cyclooxygenase-2 (COX-2) plays crucial roles in the development and invasion of tumors. Celecoxib, a selective COX-2 inhibitor, has been shown to be chemopreventive against cancer. However, to date, the mechanisms of these effects remain unclear. In this study, we investigate the effects of celecoxib on voltage-gated calcium channel (VGCC) currents in undifferentiated pheochromocytoma (PC12) cells using whole-cell patch clamp. Our results showed that celecoxib, instead of rofecoxib or NS-398, another selective COX-2 inhibitor, reversibly inhibited the current density of VGCC in a concentration-dependent manner, but had no apparent effects on the cells treated with nifedipine (1 microM), an L-type calcium channel blocker. Upon pre-incubation of PC12 cells with omega-conotoxia GVIA (1 microM), an N-type calcium channel blocker, omega-agatoxin IVA (1microM), a P/Q-type calcium channel blocker, or SNX-482 (1microM), a R-type calcium channel blocker, celecoxib (1microM) inhibited the currents by 36%, 28%, and 25%, respectively. Celecoxib up-shifted the current-voltage (I-V), and hyperpolarizedly shifted the inactivation curve, but did not markedly affect the activation curve. Intracellular application of H89, a protein kinase A inhibitor, failed to affect the celecoxib's VGCC currents inhibition. Taken together, our present results suggested that celecoxib inhibited L-type calcium channels in PC12 cells via a COX-2 independent pathway, which might be responsible for its clinical effects including anti-tumor.
Zhang
Yuan
Y
Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China.
Tao
Jin
J
Huang
Hua
H
Ding
Guoxian
G
Cheng
Yunlin
Y
Sun
Weihao
W
D000310:Adrenal Gland Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001464:Barium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007546:Isoquinolines / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology; D009578:Nitrobenzenes / Q000494:pharmacology; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D013111:Spider Venoms / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D020867:omega-Agatoxin IVA / Q000494:pharmacology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D052246:Cyclooxygenase 2 Inhibitors; D007546:Isoquinolines; D007783:Lactones; D009578:Nitrobenzenes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C115521:SNX 482; D013111:Spider Venoms; D013449:Sulfonamides; D013450:Sulfones; D020867:omega-Agatoxin IVA; C116926:rofecoxib; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D001464:Barium; D020866:omega-Conotoxin GVIA; D009543:Nifedipine; D000068579:Celecoxib; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide