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Apoptogenic effect of 7,8-diacetoxy-4-methylcoumarin and 7,8-diacetoxy-4-methylthiocoumarin in human lung adenocarcinoma cell line: role of NF-kappaB, Akt, ROS and MAP kinase pathway.

Abstract
Coumarin (1,2-benzopyrone) is a naturally occurring fragrant compound found in a variety of plants and spices. Coumarins have attracted intense interest in recent years because of their diverse pharmacological activities. This study examines the antioxidant coumarin 7,8-diacetoxy-4-methylcoumarin (DAMC) and its thiocoumarin derivative 7,8-diacetoxy-4-methylthiocoumarin (DAMTC) for their effect on human non-small cell lung cancer A549 cells. Here we show that both DAMC and DAMTC not only inhibited cell proliferation, but also induced apoptosis with an IC(50) of 160 microg/ml as confirmed by morphological examination, annexin-V assay and flow cytometric analysis. Interestingly, it was observed that these two coumarin compounds exhibited little cytotoxicity towards peripheral blood mononuclear cells but induced apoptosis in malignant cells. DAMC/DAMTC treatment also resulted in pronounced release of apoptogenic cytochrome c from mitochondria to cytosol, alteration of mitochondrial membrane potential (DeltaPsi(m)), and activation of caspase-9 and caspase-3. Although an increase in the levels of reactive oxygen species (ROS) was observed, pre-treatment with antioxidant showed no protective effect against DAMC/DAMTC-induced apoptosis. Results of present study suggest that downregulation of Bcl-xl, Cox-2 and mitogen activated protein kinase pathway and upregulation of p53, Akt and NF-kappaB pathway are involved in the underlying molecular mechanism of apoptosis induction by DAMC and DAMTC in A549 cells.
AuthorsAnita Goel, Ashok K Prasad, Virinder S Parmar, Balaram Ghosh, Neeru Saini
JournalChemico-biological interactions (Chem Biol Interact) Vol. 179 Issue 2-3 Pg. 363-74 (May 15 2009) ISSN: 1872-7786 [Electronic] Ireland
PMID19061872 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 7,8-diacetoxy-4-methylcoumarin
  • 7,8-diacetoxy-4-methylthiocoumarin
  • Coumarins
  • NF-kappa B
  • Reactive Oxygen Species
  • Cytochromes c
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Caspases
Topics
  • Adenocarcinoma (enzymology, metabolism, pathology)
  • Apoptosis (drug effects)
  • Caspases (metabolism)
  • Cell Proliferation (drug effects)
  • Coumarins (pharmacology)
  • Cytochromes c (metabolism)
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Lung Neoplasms (enzymology, metabolism, pathology)
  • Mitochondria (metabolism)
  • Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
  • NF-kappa B (metabolism)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Reactive Oxygen Species (metabolism)
  • Signal Transduction (drug effects)
  • Tumor Cells, Cultured

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