CURCUMIN--MECHANISMS OF CHEMOPREVENTION

Project: Research project

Project Details

Description

The mechanism by which curcumin inhibits gastrointestinal tumorigenesis
appears to be similar to that of sulindac, a NSAID chemopreventive agent
which is highly effective in causing regression of polyps in familial
polyposis patients. However, the advantage of curcumin is that it is
a safe dietary component, with minimal to no toxic affects, unlike
sulindac. Both curcumin and sulindac stimulate p21 expression, cell
cycle arrest and apoptosis, which are likely fundamental to their
mechanisms of action. This is related to, but distinctly different
from, mechanisms we have investigated underlying the effect of short
chain fatty acids on apoptosis of colonic epithelial cells, which also
involves mitochondrial function as a critical event in the entry of
cells into this pathway.

The goal of this application is to determine in detail the molecular and
cellular events responsible for the mechanism of action of curcumin, and
to compare that to sulindac, an established, effective chemopreventive
agent. We will do this both in colonic carcinoma cells in culture, and
in novel mouse genetic models we have available. Studies will focus on
components of the cell cycle machinery (eg. P21/waf1/cip1, cyclin D1
levels and activity) and how they are related to release of cytochrome
C from the mitochondria, the dissipation of the mitochondrial membrane
potential, and cleavage of caspase-3 in the apoptotic pathway. These
preclinical data on mechanism and efficacy of curcumin will help
determine the nature of future clinical intervention studies with
curcumin: if the mechanisms appear identical to that by which sulindac
functions, then a clinical study design in which curcumin is compared
to sulindac, or other NSAIDs would be warranted. On the other hand,
differences in mechanism could suggest a study design in which curcumin
was combined with sulindac or to other NSAIDs in a prevention trial to
test whether the two agents give additive, or synergistic, effects.
StatusFinished
Effective start/end date5/1/982/28/99

Funding

  • National Cancer Institute

ASJC

  • Molecular Medicine
  • Biochemistry
  • Cancer Research
  • Pharmacology
  • Histology

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