Synthetic Triterpenoids Show Promise in Preventing Colitis-Associated Colon Cancer

Researchers from Case Western Reserve and Dartmouth universities have shown that a class of small antioxidant molecules carries enormous promise for supressing colon cancer associated with colitis. These findings, published in an early June edition of the Journal of Clinical Investigation, offer hope that physicians ultimately will be able to reduce dramatically the number of sufferers of this inflammatory bowel disease (IBD) who go on to develop colon cancer.

The molecules, known as synthetic triterpenoids, appear to achieve their positive effect in two ways. First, they impede inflammation, often a flashpoint that contributes to the development of colon cancer. Second, they increase 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a gene product that is known at high levels to protect against colon cancer. The oral administration of synthetic triterpenoids showed such success in mice that the researchers believe that clinical trials could demonstrate their efficacy in chemoprevention - that is, the administration of medicine to stop or delay the onset of cancer, rather than treat it.

“Patients with inflammatory bowel disease have a 10-fold greater risk of colon cancer, placing it among the top three high-risk conditions for colorectal cancer,” said senior 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, University Hospitals Rainbow Babies & Children’s Hospital. “Common epithelial cancers develop over a period of years, even decades, in populations at high risk due to genetic predisposition, so chemoprevention strategies could delay, or even halt, onset of clinically evident colon cancer.”

Joining Letterio in this investigation was Michael B. Sporn, MD, professor of pharmacology and toxicology, Dartmouth Medical School, who first coined the term “chemoprevention” nearly four decades ago and has investigated synthesized triterpenoids since 1995, demonstrating their effectiveness against epithelial cancers.

Sporn collaborates in scientific investigation with leading physicians throughout the country, and Letterio’s collaboration with Sporn was a natural because the two worked together when Letterio was a post-doctoral fellow. Colleague Sanford Markowitz, MD, PhD, Ingalls Professor of Cancer Genetics at Case Western Reserve School of Medicine, served an important role in this investigation because of his expertise as the innovator who first characterized 15-PGDH, an important tumor suppressor and natural anti-inflammatory.

“We have been intrigued by recent findings that inflammatory cytokines, such as TNF-alpha, hinder the expression of 15-PGDH,” Letterio said. “We found that triterpenoids could reverse the inflammatory process by allowing 15-PGDH expression to resume. Triterpenoids also impede expression of the cyclooxygenase-2 (COX-2), an enzyme known to fuel inflammation. Between reversing the effects of TNF-alpha and of COX-2, this class of small molecules might suppress colitis-associated colon cancer.”