EFFECTS OF ECONAZOLE ON Ca²⁺ LEVELS IN AND THE GROWTH OF HUMAN PROSTATE CANCER PC3 CELLS

Abstract

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.

Effect of econazole on Ca2+ signaling in human colorectal adenocarcinoma cells

“…Fig. 8 , but it remains to be uncertain the type of channels implicated, as nifedipine, an L-type channels antagonist, failed to inhibit the entry, in clear connection with previous reports [28,29]. Moreover, a phospholipase D (PLD) pathway did not seem to be implicated in econazole response, as cells treated with propanolol failed to abolish the econazole response.…”

“…Moreover, a phospholipase D (PLD) pathway did not seem to be implicated in econazole response, as cells treated with propanolol failed to abolish the econazole response. Concerning the stores implicated in the econazoleinduced Ca 2+ release, thapsigargin-sensitive stores proved to be econazole's target, as demonstrated for different cell lines [28,29]. U73122, a pharmacological inhibitor of PLC, significantly abolished the econazoleinduced rise in [Ca 2+ ] i .…”

“…Being calcium signaling an essential tool for the development of different cellular responses as cell proliferation or apoptosis [23][24][25][26] and being colorectal cancer one of the commonest tumors in the Westernized world [27], the present study aims to investigate the role of econazole on Ca 2+ signaling in a human adenocarcinoma cell line. Previous reports showed the effect of econazole on Ca 2+ movements in different cell lines [28][29][30], but our paper is the first to investigate the role of econazole on Ca 2+ signaling in HT29 cells.…”

Mitochondrial regulation by c-Myc and hypoxia-inducible factor-1α controls sensitivity to econazole

“…Furthermore, the sensitivity of breast cancer cells to econazole could be enhanced 10-fold by concurrently stimulating them with epidermal growth factor or bombesin. Other groups have shown that prostate cancer cells (14) and colon cancer cells (13) are also sensitive to econazole. However, genetic or other factors associated with tumor cells that might regulate sensitivity to econazole have not yet been identified.…”

A Parenteral Econazole Formulation Using a Novel Micelle-to-Liposome Transfer Method: In Vitro Characterization and Tumor Growth Delay in a Breast Cancer Xenograft Model

“…1) presently under investigation for its anticancer effects. Econazole has shown cytotoxicity in several human cancer cell lines including breast cancer (3,4), osteosarcoma (5), PC3 prostate cancer cells (6), colon cancer (7) and myeloid leukemia cells (8,9). In this manner, econazole depletes cellular calcium stores and leads to inhibition of protein synthesis and cell death (1,2).…”