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Apicularen A induces cell death through Fas ligand up-regulation and microtubule disruption by tubulin down-regulation in HM7 human colon cancer cells.

AbstractPURPOSE:
Apicularen A has been shown to cause growth inhibition and apoptosis in several cancer cell lines. However, the mechanisms of apicularen A-induced cell death and in vivo effects remain unclear. In this study, we investigated the molecular mechanisms of apicularen A-induced cell death in HM7 human colon cancer cells in vitro and anticancer activity in vivo.
EXPERIMENTAL DESIGN:
We tested cytotoxicity with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, apoptosis with DNA fragmentation assay, mitochondrial membrane potential, and cell cycle with fluorescence-activated cell sorting. Caspase activation was done by fluorometry. Alterations of microtubule structure, tubulin protein, and mRNA level were assessed by immunofluorescence, Western blot, and reverse transcription-PCR. In vivo studies were assessed using nude mice tumor cell growth in xenograft model and liver colonization assay.
RESULTS:
Apicularen A treatment of HM7 cells inhibited cell growth and this inhibition was partially rescued by z-VAD-fmk. Apicularen A caused accumulation of sub-G(1)-G(0), DNA fragmentation, Fas ligand induction, and activation of caspase-8 and caspase-3, but mitochondrial membrane potential was not changed. Furthermore, beta-tubulin protein and mRNA were decreased by apicularen A, but in vitro polymerization of tubulin was not affected. Concurrently, apicularen A-treated cell showed disruption of microtubule architecture. In in vivo studies, apicularen A reduced tumor volume by approximately 72% at the end of a 15-day treatment. Moreover, apicularen A reduced liver colonization as much as 95.6% (50 microg/kg/d).
CONCLUSION:
Apicularen A induces cell death of HM7 cells through up-regulating Fas ligand and disruption of microtubule architecture with down-regulation of tubulin level. These findings indicate that apicularen A is a promising new microtubule-targeting compound.
AuthorsJong-Seok Kim, Young-Chul Lee, Ho-Tak Nam, Ge Li, Eun-Jin Yun, Kyoung-Sub Song, Kang-Sik Seo, Ji-Hoon Park, Jong-Woong Ahn, Okpyo Zee, Jong-Il Park, Wan-Hee Yoon, Kyu Lim, Byung-Doo Hwang
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 21 Pg. 6509-17 (Nov 01 2007) ISSN: 1078-0432 [Print] United States
PMID17975164 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Bridged Bicyclo Compounds, Heterocyclic
  • Fas Ligand Protein
  • Tubulin
  • apicularen A
  • Caspase 3
  • Caspase 8
Topics
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
  • Caspase 3 (metabolism)
  • Caspase 8 (metabolism)
  • Cell Death
  • Cell Line, Tumor
  • Colonic Neoplasms (metabolism, pathology)
  • DNA Fragmentation
  • Enzyme Activation
  • Fas Ligand Protein (metabolism)
  • Gene Expression Regulation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Liver (metabolism)
  • Membrane Potential, Mitochondrial
  • Mice
  • Mice, Nude
  • Microtubules (metabolism)
  • Tubulin (metabolism)

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