Effects of econazole on Ca2+ levels in and the growth of human prostate cancer PC3 cells.
1. Econazole is used clinically as an antifungal drug with many different in vitro effects. However, the effects of econazole on prostate cancer cells are unknown. The effects of econazole on intracellular Ca2+ concentrations ([Ca2+]i) in and the proliferation of human PC3 prostate cancer cells was explored in the present study using fura-2 and tetrazolium as fluorescent dyes. 2. At a concentration of 0.1 micromol/L, econazole started to increase [Ca2+]i in a concentration-dependent manner. The econazole-induced increase in [Ca2+]i was reduced by 48% by removal of extracellular Ca2+, suggesting that the econazole-induced increase in [Ca2+]i was composed of extracellular Ca2+ influx and intracellular Ca2+. 3. This econazole-induced Ca2+ influx was via an L-type Ca2+ channel-like pathway. In Ca2+-free medium, 1 micromol/L thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-ATPase, caused a monophasic increase in [Ca2+]i, after which the effect of econazole to increase [Ca2+]i was substantially inhibited. Conversely, pretreatment with 5 micromol/L econazole to deplete intracellular Ca2+ stores totally prevented thapsigargin from releasing more Ca2+. 4. The phospholipase C (PLC) inhibitor U73122 (2 micromol/L) abolished the increase in [Ca2+]i induced by 10 micromol/L ATP (a Ca2+ mobilizer that needs inositol 1,4,5-trisphosphate). 5. Overnight incubation with 1-30 micromol/L econazole inhibited proliferation of PC3 cells in a concentration-dependent manner. 6. These findings suggest that, in PC3 cells, econazole increases [Ca2+]i by stimulating Ca2+ influx into cells and Ca2+ release from the endoplasmic reticulum via a PLC-independent mechanism. Econazole is cytotoxic at submicromolar concentrations.
Huang
Jong-Khing
JK
Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of China.
Liu
Chung-Shin
CS
Chou
Chiang-Ting
CT
Liu
Shiuh-Inn
SI
Hsu
Shu-Shong
SS
Chang
Hong-Tai
HT
Hsieh
Ching-Hong
CH
Chang
Chih-Hung
CH
Chen
Wei-Chuan
WC
Jan
Chung-Ren
CR
D000970:Antineoplastic Agents / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004464:Econazole / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism
D000970:Antineoplastic Agents; D020746:Calcium Channels, L-Type; D004464:Econazole; D010738:Type C Phospholipases