Involvement of proapoptotic Bcl-2 family members in terbinafine-induced mitochondrial dysfunction and apoptosis in HL60 cells.
Terbinafine (TB, lamisil), a promising world widely used oral-anti-fungal agent, has been used in the treatment of superficial mycosis. In this study, we found that apoptosis but not cell growth arrest was induced by TB (1 microM, for 24 h) in human promyelocytic leukemia (HL60) cells. The apoptotic effect induced by TB in the HL60 cell was not through the general differentiation mechanisms evidenced by evaluation of three recognized markers, including CD11b, CD33, and morphological features. In addition, our results also revealed that TB-induced apoptosis was not through the cellular surface CD 95 receptor-mediated signaling pathway. We found that the mitochondria membrane in the TB-treated HL60 cells was dissipated by decreasing of the electrochemical gradient (DeltaPsi(m)) led to leakage of cytochrome c from mitochondria into cytosol. Such effects were completely blocked by in vitro transfection of the HL60 cells with Bcl-2 overexpression plasmid (HL60/Bcl-2). However, our data found that TB-mediated apoptosis could not be completely prevented in the Bcl-2 over expressed (HL60/Bcl-2) cells. Such results implied that additional mediators (such as caspase-9) other than mitochondria membrane permeability might contribute to the TB-induced cellular apoptosis signaling. This hypothesis was supported by the evidence that administration of caspases-9 specific inhibitor (z-LEHD-fmk) blocked the TB-induced apoptosis. Our studies highlight the molecular mechanisms of TB-induced apoptosis in human promyelocytic leukemia (HL60) cells.
Yang
Kuo-Ching
KC
Department of Internal Medicine, Division of Gastroenterology, Shin Kong Wu Ho-Su Memory Hospital, Taipei 112, Taiwan.
Wu
Chi-Chen
CC
Wu
Chih-Hsiung
CH
Chen
Jur-Hao
JH
Chu
Chien-Hwa
CH
Chen
Chien-Ho
CH
Chou
Yean-Hwei
YH
Wang
Ying-Jan
YJ
Lee
Wen-Sen
WS
Tseng
How
H
Lin
Shyr-Yi
SY
Lee
Chia-Hwa
CH
Ho
Yuan-Soon
YS
D000954:Antigens, Surface / Q000502:physiology; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D015153:Blotting, Western; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D019254:Genes, bcl-2 / Q000502:physiology*; D016158:Genes, p53 / Q000502:physiology; D018922:HL-60 Cells; D006801:Humans; D047468:Immunoprecipitation; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000077291:Terbinafine; D014162:Transfection; D019014:fas Receptor / Q000502:physiology
D000954:Antigens, Surface; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D019014:fas Receptor; D045304:Cytochromes c; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D000077291:Terbinafine