Resveratrol induces apoptosis in K562 (chronic myelogenous leukemia)
cells by targeting a key survival protein, heat shock protein 70
Authors: Chakraborty, Prabir K.1; Mustafi, Soumyajit Banerjee1;
Ganguly, Sudipto2; Chatterjee, Mitali2; Raha, Sanghamitra
Source: Cancer Science, Volume 99, Number 6, June 2008 , pp.
1109-1116(8)
Publisher: Blackwell Publishing
Abstract:
Chronic myelogenous leukemia (CML) is a myeloproliferative disease
associated with a characteristic chromosomal translocation called the
Philadelphia chromosome.
This results in the expression of the Bcr-Abl fusion protein, a
constitutively active protein tyrosine kinase.
Although there are a few treatment options with Bcr-Abl kinase
inhibitors, drug resistance is often encountered.
One of the major obstacles in overcoming drug resistance in CML is the
high endogenous levels of heat shock protein 70 (Hsp70). Resveratrol
is a phytoalexin produced by several plants.
We studied the chemotherapeutic effects and mode of action of
resveratrol on K562 (CML) cells.
Resveratrol induced apoptosis in K562 cells in a time-dependent
manner.
This was established by increased annexin V binding, corroborated with
an enhanced caspase-3 activity and a rise in the sub-G0/G1
population.
Resveratrol treatment also caused suppression of Hsp70 both in mRNA
and protein levels.
The downregulation of Hsp70 by resveratrol exposure was correlated
with a diminished presence of heat shock factor 1 (HSF1) in the
nucleus, and the downregulation of transcriptional activity of HSF1.
High endogenous levels of Hsp70 have been found to be a deterrent for
sensitivity to chemotherapy.
We show here that resveratrol could considerably enhance the apoptosis
induction in K562 cells by 17-allylamino-17-demethoxygeldanamycin, an
anticancer agent that inhibits Hsp90 but augments Hsp70 levels.
We conclude that resveratrol significantly downregulated Hsp70 levels
through inhibition of HSF1 transcriptional activity and appreciably
augmented the pro-apoptotic effects of 17-allylamino-17-
demethoxygeldanamycin. (Cancer Sci 2008; 99: 1109-1116)
Document Type: Research article
DOI: 10.1111/j.1349-7006.2008.00809.x
Affiliations: 1: Crystallography and Molecular Biology Division, Saha
Institute of Nuclear Physics, 1/AF Bidhan Nagar, Kolkata-700064; 2:
Department of Pharmacology, Institute of Post Graduate Medical
Education and Research, 244B Acharya JC Bose Road, Kolkata-700020,
India
-----------------
Researchers Show Resveratrol
Works In The Brain By Metal Chelating Effects
Researchers now convincingly show that, via its iron-chelating
effects, resveratrol is able to cross barriers that protect the brain
from entry of toxins (blood/brain barrier) and reduce oxidation
(spoilage) of fats and increase the activity of protective
antioxidant
enzymes in the brain of healthy rodents.
The research has application for age-related brain disorders such as
Alzheimer's and Parkinson's disease.
Resveratrol decreased malondialdehyde (an end product of oxidation of
fats) in brain tissues by -300%. Doses ranging (in human equivalents)
from 87.5 to 875 milligrams were effective in this regard.
Higher doses were not more effective.
Resveratrol also significantly increased the activity of antioxidant
enzymes superoxide dismutase, catalase and peroxidase by 160%, 270%
and 210% (see above chart).
The forms of most of these protective enzymes were iron-controlling
proteins, confirming that resveratrol's primary action is via its
ability to control metallic metals.
Loose (free) iron causes tissue damage in all forms of age-related
brain disease.
While a relatively high dose of resveratrol was shown to be
most effective (875 milligrams human equivalent dose), this was only a
7-day study.
It is expected that a life-long accumulation of iron in
brain tissues will require a high loading dose and a lower maintenance
dose.
The current fad of ultra-high dose resveratrol supplementation
may be beneficial initially, but lead to anemias over longer term
use. -Resveratrol News April 2007
http://www.resveratrolnews.com/page77.htm
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