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Senior Citizen Health & Medicine
How NSAIDs Halt Cancer Growth Determined in New
Study
MDA-7/IL-24 already known as a novel tumor
suppressor gene
December 15, 2006 – Researchers have earlier found
that nonsteroidal anti-inflammatory drugs (NSAIDs), like aspirin,
ibuprofen and sulindac, appear effective in preventing and treating some
common cancers. But, they could not explain why. Now, however, a new
study says it is the induction of a gene known as MDA-7/IL-24 that stops
the growth of cancer cells.
The discovery of this molecular mechanism could
eventually lead to the development of targeted cancer treatments.
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This study was led by researchers at Beth Israel
Deaconess Medical Center (BIDMC), in collaboration with scientists at
Columbia University Medical Center, and appears in the Dec. 15 issue of
the journal Cancer Research.
“Although observational studies had previously
demonstrated that NSAIDs might be effective in the prevention and
treatment of several common cancers, it wasn’t at all clear how this was
happening,” explains the study’s senior author Towia Libermann, PhD,
Director of the BIDMC Genomics Center and Associate Professor of
Medicine at Harvard Medical School (HMS).
“Now, after treating a number of different types of
cancer cells in culture with a whole set of NSAIDs, we can point to this
single gene which, when upregulated, kills cancer cells while sparing
normal, healthy cells.”
In recent years, a great deal of attention has
focused on the link between inflammation and cancer. As the body’s
immune response to tissue damage, acute inflammation serves as a natural
defense to guard against injury or infection.
However, in cases of chronic inflammation – for
example, inflammatory bowel disease – certain signaling pathways that
modulate the inflammatory processes become “stuck” in an activated
state. Among other outcomes, this course of events leads to the release
of molecules that enhance carcinogenesis and tumor progression at the
site of the damage.
According to Libermann, it was these observations
that originally prompted clinical and epidemiological researchers to
begin examining whether routine use of anti-inflammatory agents had any
effect on a person’s risk of developing several types of cancer,
including colorectal cancer, breast cancer and ovarian cancer.
“Since then, studies have indeed shown that at
clinically relevant concentrations, NSAIDs may be effective in the
prevention and treatment of common cancers,” he says.
These anti-cancer effects have been attributed, in
large part, to NSAIDs’ potential to induce cell death, which appears to
stem from the drugs’ inhibition of the COX (cyclooxygenase) enzymes, the
primary mechanism by which NSAIDs guard against pain.
“However,” adds Libermann, “COX inhibition did not
appear to be the only anti-cancer pathway being targeted by the
compounds. We, therefore, undertook a comprehensive review of NSAIDs in
order to decipher the precise molecular mechanisms that were at work.”
Using whole genome microarray analysis, Libermann
and first author Luiz Zerbini, PhD, a researcher in the BIDMC Genomics
Center and Instructor of Medicine at HMS, examined more than 20,000
genes to identify potential mechanisms for cell death induction.
“When we analyzed the genes that were upregulated
by NSAIDS, one in particular stood out from the rest,” says Zerbini.
“And that was MDA-7/IL-24.”
A cancer specific cytokine (a protein secreted by
cells of the lymph system that affects the activity of other cells and
is important in controlling inflammatory responses), MDA-7/IL-24 was
already familiar to the investigators as a novel tumor suppressor gene,
says Libermann.
“Viral delivery of MDA-7/IL-24 is currently being
evaluated in several clinical trials as a therapeutic agent against
various cancers, and enhanced levels of the gene have also been
correlated with prolonged survival in patients with non-small lung
cancer,” he said.
Following their identification of this cytokine,
the investigators used an interfering RNA approach to block MDA-7/IL-24
gene expression in cancer cells, thereby demonstrating the necessity of
NSAID-mediated induction of the gene to destroy cancer cells. They also
used a mouse model of prostate cancer to demonstrate that when
MDA-7/IL-24 was blocked, the anti-cancer effects of the NSAIDs were
diminished.
Finally, building on their earlier work
demonstrating the relevance of GADD45 (Growth Arrest DNA Damage) family
members to cancer cell death (as well as previous work by study coauthor
Paul Fisher, MPh, PhD, of Columbia University Medical Center) Libermann
and Zerbini identified GADD45 alpha and gamma as the critical mediators
of this course of events, showing that the ability of NSAIDs to induce
apoptosis was dependent on their abilities to induce MDA-7/IL-24
expression, leading to enhanced GADD45 alpha and gamma expression.
“Current clinical trials are evaluating a range of
NSAIDs for a variety of cancers without any clear vision of the best way
to use them,” notes Libermann.
“The fact that upregulation of this single gene –
MDA-7/IL-24 -- correlated not only with cell death induction of numerous
types of cancer but also among various diverse classes of NSAIDs, makes
this discovery particularly exciting.
"The level of MDA-7/IL-24 gene expression in cancer
patients may emerge as a new biomarker for monitoring patients’
responses to certain therapies, and may help determine whether drugs
such as NSAIDs are hitting their intended targets.”
Editor's Notes:
In addition to Libermann, Zerbini and Fisher,
study coauthors include BIDMC investigators Akos Czibere, MD, Yihong
Wang, MD, Hasan Otu, PhD, Marie Joseph, Yuko Takayasu, MD, Moriah
Silver, Xuesong Gu, PhD, Kriangsak Ruchusatsawat, PhD, Linglin Li, MSc,
and Jin-Rong Zhou, PhD; Ricardo Correa, PhD, of The Salk Institute for
Biological Studies in La Jolla, California; and Devanand Sarkar, PhD, of
the Columbia University Medical Center, College of Physicians and
Surgeons, New York.
This study was funded, in part, by grants from
the National Institutes of Health, the U.S. Department of Defense, the
Hershey Foundation, the Samuel Waxman Cancer Research Foundation and the
Chernow Endowment.
Beth Israel Deaconess Medical Center is a major
patient care, teaching and research affiliate of Harvard Medical School
and ranks third in National Institutes of Health funding among
independent hospitals nationwide. BIDMC is clinically affiliated with
the Joslin Diabetes Center and is a research partner of the
Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the
Boston Red Sox.
For more information, visit
http://www.bidmc.harvard.edu.
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