Small antioxidant molecules suppress colon cancer associated with colitis -
Researchers at Case Western Reserve University and Dartmouth showed that a class of small antioxidant molecules carries a huge potential for suppressing cancer associated colitis colon. These results, published in early June edition of Journal of Clinical Investigation offers hope that eventually doctors will be able to significantly reduce the number of people suffering from this inflammatory disease of intestine (IBD) who will develop colon cancer.
The molecules, called synthetic triterpenoids, appear to reach their positive effect in two ways. Firstly, they prevent inflammation, often a flash point which contributes to the development of colon cancer. On the other hand, they increase 15 hydroxyprostaglandin dehydrogenase (15-PGDH), a gene product that is known for a high level of protection against colon cancer. Oral administration of synthetic triterpenoids has shown such success in mice that researchers believe that clinical trials could demonstrate their efficacy in chemoprevention -. That is, the administration of drugs to stop or delay the onset of cancer rather than treat
"Patients with inflammatory bowel disease were 10 times more risk of cancer colon, placing it among the top three high-risk conditions for colorectal cancer, "said lead author and hematologist / oncologist John Letterio, MD, Professor of Pediatrics, Case Western Reserve University school of Medicine and director of the Angie Fowler adolescent and young adult Cancer Institute, Rainbow Babies & Hospital Hospitals University children. 'common epithelial cancers develop over a period of years or decades, in populations at high risk because of genetic predisposition, of so that chemoprevention strategies could delay or even halt the onset of clinically evident colon cancer. "
Join Letterio in this survey was Michael B. Sporn, MD, Professor of pharmacology and toxicology, Dartmouth Medical School, who first coined the term "chemoprevention" there almost four decades and investigated triterpenoids synthesized since 1995, demonstrating their effectiveness against epithelial cancers. Sporn collaborating on scientific research with leading physicians around the country, and collaboration with Letterio Sporn was natural because the two worked together when Letterio was a postdoctoral researcher. Colleague Sanford Markowitz, MD, PhD, Genetics Ingalls Professor of Cancer Case Western Reserve School of Medicine, served an important role in the investigation because of its expertise as the innovator who first characterized 15-PGDH, significant tumor suppressor and anti-inflammatory natural.
"We were intrigued by recent results that inflammatory cytokines, such as TNF-alpha, inhibit the expression of 15-PGDH" Letterio said. "We found that the triterpenoids may reverse inflammatory process by allowing the expression 15-PGDH to resume. Triterpenoids also inhibit the expression of cyclooxygenase-2 (COX-2), an enzyme known to feed inflammation. Between reverse the effects of TNF-alpha and COX-2, this class of small molecules could remove the colon cancer associated colitis. "
In genetically modified to proneness to inflammation-driven mouse on intestinal neoplasia, triterpenoids administered orally increased the survival of mice. triterpenoid molecules also deleted neoplasia intestinal epithelial reducing production of inflammatory mediators and increase the expression of the colon, the suppression of cancer 15 -PGDH.
the investigators also found that the triterpenoids administered to normal mice prevented their development of inflammation and colon cancer, despite their exposure to carcinogens known to cause both conditions. in addition, they discovered that triterpenoids trigger responses of epithelial cells to TGF-beta, a signaling pathway known to activate the 15-PGDH.
"Two points are particularly important in this study," said Letterio. "First of all, our studies in mice showed a cancer chemopreventive effect with triterpenoids. Second, our data also show that the production of 15-PGDH in mice was dependent on the presence of a signaling pathway intact TGF-beta. This path ensures that internal conditions remain relatively constant in the intestinal mucosa, both in the regulation of epithelial cell differentiation and development of inducible regulatory T cells to repel cancer. "
The following research team will focus on assessing the effect of triterpenoids for models of IBD and colon cancer that are not related to colitis. Investigators also want to explore whether triterpenoids natural plant derivatives with similar properties to synthetic triterpenoids laboratory products might offer a comparable benefit.
"the argument is strong for further human trials in cancer chemoprevention with triterpenoids," said Letterio . "There are many questions about safety, effectiveness, intermittent versus continuous administration, and synthetic vs. triterpenoid natural. clinical trials designed with care and a collaborative approach between industry and academia are needed to answer these questions. "
Markowitz agrees and further discusses the importance of the findings in the latter investigation.
"colon cancer is among the most feared consequences of ulcerative colitis in the long term," he said. "Even with intense monitoring of the colon by colonoscopy and random biopsies, cancer development are not always taken in time. The conclusion that synthetic triterpenoids can prevent colon cancer in the mouse model is the first breakthrough in this area and opens a novel opportunity to develop new drugs for use in human patients. "
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