|Title:||Cell apoptosis induced by a synthetic carbazole compound LCY-2-CHO is mediated through activation of caspase and mitochondrial pathways||Authors:||Hsu M.-J.
|Keywords:||Apoptosis; Carbazole; Caspases; LCY-2-CHO; Mitochondria||Issue Date:||2005||Journal Volume:||70||Journal Issue:||1||Start page/Pages:||102-112||Source:||Biochemical Pharmacology||Abstract:||
The mechanisms involved in the apoptotic effect of LCY-2-CHO [9-(2-chlorobenzyl)-9H-carbazole-3-carbaldehyde], a synthetic carbazole derivative identified as an anti-inflammatory compound, were studied. Cell cycle analysis by propidium iodide staining in human THP-1 monocytic leukemia cells showed the ability of LCY-2-CHO to increase cell population in sub-G1 stage with time- and concentration-dependent manners. LCY-2-CHO-mediated cell death was also demonstrated by DNA laddering and was not related to the release of lactate dehydrogenase. Apoptosis in THP-1 cells induced by LCY-2-CHO was accompanied by the Bid cleavage, collapse of mitochondrial transmembrane potential, the release of cytochrome c and the activation of caspase-3. The apoptotic effect of LCY-2-CHO was diminished by the presence of zVEID-fmk (caspase-6 inhibitor), zIETD-fmk (caspase-8 inhibitor), and zVAD-fmk (non-selective caspase inhibitor), but was not altered by several antioxidants, and cathepsin inhibitor. The Bid cleavage and loss of mitochondrial transmembrane potential, but not the cytochrome c release, were reversed by zIETD-fmk. Comparing the cell selectivity of LCY-2-CHO, we found T-cell acute lymphoblastic CEM leukemia cells were sensitive to 1 μM LCY-2-CHO, acute myeloid leukemia HL-60 cells underwent apoptosis at 10 μM, while adherent cancer cells, such as PC3, HT29 and MCF-7, were resistant to 30 μM LCY-2-CHO within 24-h incubation. Taken together in the present study, we demonstrated LCY-2-CHO might be apoptotic for malignant hematopoietic cells but not anchorage-dependent cells. This action is mediated by an intrinsic caspase-dependent apoptotic event involving mitochondria. ? 2005 Elsevier Inc. All rights reserved.
|ISSN:||62952||DOI:||10.1016/j.bcp.2005.04.014||SDG/Keyword:||9 (2 chlorobenzyl) 9h carbazole 3 carbaldehyde; antiinflammatory agent; antioxidant; benzyloxycarbonylisoleucylglutamylthreonylaspartyl fluoromethyl ketone; benzyloxycarbonylvalylalanylaspartyl fluoromethyl ketone; benzyloxycarbonylvalylglutamylisoleucylaspartyl fluoromethyl ketone; carbazole derivative; caspase 3; caspase 6 inhibitor; caspase 8 inhibitor; caspase inhibitor; cytochrome c; enzyme inhibitor; lactate dehydrogenase; propidium iodide; protein Bid; unclassified drug; apoptosis; article; cancer cell culture; cell assay; cell cycle G1 phase; cell death; controlled study; DNA damage; drug mechanism; enzyme activation; enzyme release; human; human cell; immunohistochemistry; incubation time; leukemia cell; membrane potential; mitochondrial membrane; mitochondrion; pharmacodynamics; priority journal; protein degradation; signal transduction; Anti-Inflammatory Agents; Apoptosis; Carbazoles; Caspases; Cathepsins; Cell Line, Tumor; Cytochromes c; DNA Fragmentation; Enzyme Activation; Humans; Membrane Potentials; Mitochondria; Reactive Oxygen Species
|Appears in Collections:||藥理學科所|
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