The mechanism of bifonazole-induced [Ca(2+)]i rises and non-Ca(2+)-triggered cell death in PC3 human prostate cancer cells.
Bifonazole is an antifungal drug widely used for treating skin diseases. The effect of bifonazole on physiology of cancer cells is unclear. The effect of bifonazole on cytosolic free Ca(2+) concentrations ([Ca(2+)]i) and viability in PC3 human prostate cancer cells was explored. The Ca(2+)-sensitive fluorescent dye, fura-2, was applied to measure [Ca(2+)]i. Bifonazole at concentrations of 5-30 µM induced a [Ca(2+)]i rise in a concentration-dependent manner. The response was reduced by 50% by removing extracellular Ca(2+). Bifonazole-evoked [Ca(2+)]i rise was not altered by nifedipine, econazole, SK&F96365 and protein kinase C activator, but was inhibited by 75% by GF109203X, a protein kinase C inhibitor. In Ca(2+)-free medium, treatment with the endoplasmic reticulum Ca(2+) pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) nearly abolished bifonazole-evoked [Ca(2+)]i rise. Conversely, treatment with bifonazole abolished BHQ-evoked [Ca(2+)]i rise. Inhibition of phospholipase C with U73122 abolished bifonazole-induced [Ca(2+)]i rise. At 30-100 µM, bifonazole decreased cell viability concentration-dependently, which was not reversed by chelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N″,N'-tetraacetic acid/acetoxy methyl. Annexin V/propidium iodide staining data suggest that bifonazole (30-100 µM) induced apoptosis concentration-dependently. Together, in PC3 human prostate cancer cells, bifonazole induced [Ca(2+)]i rises by inducing phospholipase C- and protein kinase C-dependent Ca(2+) release from the endoplasmic reticulum and Ca(2+) influx via non-store-operated pathways. Bifonazole induced cell death that might involve apoptosis.
Department of Medicine, Kaohsiung Veterans General Hospital Tainan Branch , Tainan , Taiwan .
Jin Shiung
JS
Cheng
Chiang-Ting
CT
Chou
Wei-Zhe
WZ
Liang
Chun-Chi
CC
Kuo
Pochuen
P
Shieh
Daih-Huang
DH
Kuo
Chung-Ren
CR
Jan
D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*
D007093:Imidazoles; C036596:bifonazole; D002118:Calcium
Apoptosis; Ca2+; bifonazole; human prostate cancer cells