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Medicineworld.org: How NSAIDs Halt Cancer Growth

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How NSAIDs Halt Cancer Growth

How NSAIDs Halt Cancer Growth
Researchers have discovered that induction of a gene known as MDA-7/IL-24 is the molecular mechanism that enables nonsteroidal anti-inflammatory drugs (NSAIDs) to halt the growth of cancer cells, a finding that could eventually lead to the development of targeted cancer therapys.

Led by scientists at Beth Israel Deaconess Medical Center (BIDMC), in collaboration with researchers at Columbia University Medical Center, the new findings provide the answer to the long-puzzling question: How does this popular class of pain killers protect people from developing this deadly disease" The study appears in the Dec. 15 issue of the journal Cancer Research.

"Eventhough findings based on observation had previously demonstrated that NSAIDs [such as aspirin, ibuprofen and sulindac] might be effective in the prevention and therapy 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 many 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.

As per Libermann, it was these observations that originally prompted clinical and epidemiological scientists 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 ovary cancer.

"Since then, studies have indeed shown that at clinically relevant concentrations, NSAIDs may be effective in the prevention and therapy 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, MDA-7/IL-24 was already familiar to the researchers as a novel tumor suppressor gene, says Libermann. "Viral delivery of MDA-7/IL-24 is currently being reviewed 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".

Following their identification of this cytokine, the researchers 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 prior 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 especially 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".


Posted by: Janet    Source




Did you know?
Researchers have discovered that induction of a gene known as MDA-7/IL-24 is the molecular mechanism that enables nonsteroidal anti-inflammatory drugs (NSAIDs) to halt the growth of cancer cells, a finding that could eventually lead to the development of targeted cancer therapys.

Medicineworld.org: How NSAIDs Halt Cancer Growth

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