Antitumor effects of amlodipine, a Ca2+ channel blocker, on human epidermoid carcinoma A431 cells in vitro and in vivo.
Amlodipine, a dihydropyridine Ca(2+) channel blocker, is reported to inhibit proliferation of human epidermoid carcinoma A431 cells, and specifically attenuates Ca(2+) responses evoked by thapsigargin, an inhibitor of endoplasmic reticulum Ca(2+)-ATPases. In this study, we further examined the possible mechanism of the antiproliferative action of amlodipine and its antitumor effect on A431 xenografts in nude mice. Amlodipine reduced BrdU incorporation into nucleic acids in serum-starved A431 cells, and the reduction was diminished by uridine 5'-triphosphate (UTP), a phospholipase C (PLC)-linked agonist. Fluorometric measurement of intracellular free Ca(2+) concentration revealed that amlodipine blunted the UTP-induced Ca(2+) release from the internal Ca(2+) stores and consequently Ca(2+) influx through Ca(2+)-permeable channels on the plasma membrane. Although amlodipine alone caused Ca(2+) release from thapsigargin-sensitive Ca(2+) stores, such an effect was not reproduced by other dihydropyridine Ca(2+) channel blockers, including nicardipine and nimodipine, despite their antiproliferative effects in the cells. Daily intraperitoneal administration of amlodipine (10 mg/kg) for 20 days into mice bearing A431 xenografts retarded tumor growth and prolonged the survival of mice. Our results suggest a potential antitumor action for amlodipine in vitro and in vivo, which may be in part mediated by inhibiting Ca(2+) influx evoked by the passive depletion of internal Ca(2+) stores and by PLC-linked agonist stimulation.
Yoshida
Junko
J
Department of Pharmacology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan. yayuyo@kanazawa-med.ac.jp
Ishibashi
Takaharu
T
Nishio
Matomo
M
D017311:Amlodipine / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000401:mortality; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005470:Fluorometry; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism; D014544:Uridine Triphosphate / Q000494:pharmacology
D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D017311:Amlodipine; D019284:Thapsigargin; D010738:Type C Phospholipases; D002118:Calcium; D014544:Uridine Triphosphate