title: Effect of Miconazole on [Ca²⁺]i and Cytotoxicity in ZR-75-1 Human Breast Cancer Cells.
abstract: The effect of the antifungal drug miconazole on Ca²⁺ signaling in human breast cancer cells is unknown. This study examined the effect of miconazole on cytosolic free Ca²⁺ concentrations ([Ca²⁺]i) in ZR-75-1 human breast cancer cells. The Ca²⁺-sensitive fluorescent dye fura-2 was used to measure [Ca²⁺]i. Miconazole induced [Ca²⁺]i rises concentration-dependently. The response was reduced by 60% by removing extracellular Ca²⁺. Miconazole-induced Ca²⁺ entry was abolished by the protein kinase C (PKC) inhibitor GF109203X, and nifedipine, but was insensitive to econazole, SKF96365 and the protein kinase C activator phorbol 12-myristate 13 acetate (PMA). In Ca²⁺-free medium, treatment with the endoplasmic reticulum Ca²⁺ pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) or thapsigargin (TG) greatly inhibited miconazole-evoked [Ca²⁺]i rises. Conversely, treatment with miconazole abolished TG and BHQ-evoked [Ca²⁺]i rises. Inhibition of phospholipase C (PLC) with U73122 abolished miconazole-induced [Ca²⁺]i rises. At concentrations of 30-50 μM, micronazole killed cells in a concentration-dependent manner. This cytotoxic effect was not reversed by chelating cytosolic Ca²⁺ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/acetoxy methyl (BAPTA/AM). Together, in ZR-75-1 cells, miconazole induced [Ca²⁺]i rises by evoking PLC-dependent Ca²⁺ release from the endoplasmic reticulum, and PKC-regulated nifedipine-sensitive Ca²⁺ entry. Miconazole-caused cell death was not triggered by a preceding [Ca²⁺]i rise.
authors.affiliation: Department of Obstetrics and Gynecology, E-DA Hospital, Kaohsiung 82445, Taiwan, Republic of China.
authors.forename: Cherng-Jau
authors.initials: CJ
authors.lastname: Roan
authors.affiliation: Department of Nursing, Division of Basic Medical Sciences, Chang Gung Institute of Technology, Chia-Yi 61363, Taiwan, Republic of China.|Chronic Diseases and Health Promotion Research Center, Chang Gung Institute of Technology, Chia-Yi 61363, Taiwan, Republic of China.
authors.forename: Chiang-Ting
authors.initials: CT
authors.lastname: Chou
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan, Republic of China.
authors.forename: Wei-Zhe
authors.initials: WZ
authors.lastname: Liang
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan, Republic of China.
authors.forename: Hong-Tai
authors.initials: HT
authors.lastname: Chang
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 90741, Taiwan, Republic of China.
authors.forename: Daih-Huang
authors.initials: DH
authors.lastname: Kuo
authors.affiliation: Department of Nursing, Tzu Hui Institute of Technology, Pingtung 92641, Taiwan, Republic of China.
authors.forename: Chun-Chi
authors.initials: CC
authors.lastname: Kuo
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 90741, Taiwan, Republic of China.
authors.forename: Fu-An
authors.initials: FA
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 90741, Taiwan, Republic of China.
authors.forename: Pochuen
authors.initials: P
authors.lastname: Shieh
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 90741, Taiwan, Republic of China.
authors.forename: Chung-Ren
authors.initials: CR
authors.lastname: Jan
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008825:Miconazole / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000502:physiology
chemical_list: D008825:Miconazole; D010738:Type C Phospholipases; D002118:Calcium