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Cellular stress response in Eca-109 cells inhibits apoptosis during early exposure to isorhamnetin.

Abstract
The flavonol aglycone isorhamnetin shows anti-proliferative activity in a variety of cancer cells. Previous work, from our laboratory showed that isorhamnetin inhibits the proliferation of human esophageal squamous carcinoma Eca-109 cells in vitro, but only after 72 h of exposure. This led us to propose that isorhamnetin exposure induces a cellular stress response that inhibits the antiproliferative and apoptotic effects of the compound during early exposure. To test this hypothesis, the present study examined the effects of isorhamnetin on Eca-109 cells during the first 72 h of exposure. Cell growth was assessed using the trypan blue exclusion assay, and expression of IκBα, NF-κB/p65, NF-κB/p50, phospho-Akt, Bcl-2, COX-2, Mcl-1, Bax, p53 and Id-1 were analyzed by Western blot. During the first 72 h of exposure, NF-κB/p65 and NF-κB/p50 accumulated in nuclei and expression of COX-2, Bcl-2 and Mcl-1 increased. In contrast, expression of IκBα and Bax fell initially but later increased. Expression of phospho-Akt and p53 showed no detectable change during the first 48 h. Pretreatment with the NF-κB inhibitor MG132 before exposure to isorhamnetin blocked the nuclear accumulation of p50 and p65, thereby inhibiting cell proliferation. These results show that during early exposure of Eca-109 cells to isorhamnetin, the NF-κB signaling pathway is activated and COX-2 expression increases, and this increase in expression partially inhibits isorhamnetin-induced apoptosis. Beyond 72 h of exposure, however, the apoptotic effect of isorhamnetin dominates, leading to inhibition of the NF-κB pathway and of cellular proliferation. These results will need to be taken into account when exploring the use of isorhamnetin against cancer in vivo.
AuthorsC Shi, L Y Fan, Z Cai, Y Y Liu, C L Yang
JournalNeoplasma (Neoplasma) Vol. 59 Issue 4 Pg. 361-9 ( 2012) ISSN: 0028-2685 [Print] Slovakia
PMID22489690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • NF-kappa B
  • 3-methylquercetin
  • Quercetin
  • Cyclooxygenase 2
  • PTGS2 protein, human
Topics
  • Apoptosis (drug effects)
  • Blotting, Western
  • Carcinoma, Squamous Cell (drug therapy, metabolism, pathology)
  • Cell Nucleus (metabolism)
  • Cell Proliferation (drug effects)
  • Cyclooxygenase 2 (metabolism)
  • Esophageal Neoplasms (drug therapy, metabolism, pathology)
  • Gene Expression (drug effects)
  • Humans
  • NF-kappa B (metabolism)
  • Phosphorylation (drug effects)
  • Quercetin (analogs & derivatives, pharmacology)
  • Tumor Cells, Cultured

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