Cell apoptosis induced by a synthetic carbazole compound LCY-2-CHO is mediated through activation of caspase and mitochondrial pathways.

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 microM LCY-2-CHO, acute myeloid leukemia HL-60 cells underwent apoptosis at 10 microM, while adherent cancer cells, such as PC3, HT29 and MCF-7, were resistant to 30 microM 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.

• Authors: Ming-Jen Hsu, Yee Chao, Ying-Hsin Chang, Feng-Ming Ho, Li-Jiau Huang, Ya-Ling Huang, Tien-Yau Luh, Chih-Ping Chen, Wan-Wan Lin
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 70 Issue 1 Pg. 102-12 (Jul 01 2005) ISSN: 0006-2952 [Print] England
• PMID: 15894295 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 9-(2-chlorobenzyl)-9H-carbazole-3-carbaldehyde
• Anti-Inflammatory Agents
• Carbazoles
• Reactive Oxygen Species
• Cytochromes c
• Cathepsins
• Caspases

Topics

• Anti-Inflammatory Agents (pharmacology)
• Apoptosis (drug effects)
• Carbazoles (pharmacology)
• Caspases (physiology)
• Cathepsins (physiology)
• Cell Line, Tumor
• Cytochromes c (metabolism)
• DNA Fragmentation (drug effects)
• Enzyme Activation
• Humans
• Membrane Potentials (drug effects)
• Mitochondria (drug effects, physiology)
• Reactive Oxygen Species