Scientists stop colon cancer growth in mice by blocking just one enzyme

October 01, 2006

GALVESTON, Texas -- Texas researchers have discovered what may become a potent new weapon in the fight against colon cancer.

In cell culture experiments, scientists from the University of Texas Medical Branch at Galveston (UTMB) and the University of Texas at Arlington determined that stopping the activity of a single enzyme called aldose reductase could shut down the toxic network of biochemical signals that promotes inflammation and colon cancer cell growth.

In a dramatic demonstration of the potential of this discovery, they followed up this work with animal studies showing that blocking the production of aldose reductase halted the growth of human colon cancer cells implanted in laboratory mice.

"By inhibiting aldose reductase we were able to completely stop the further growth of colorectal cancer tumor cells," said UTMB professor Satish K. Srivastava, senior author of a paper about the discovery to be published Oct. 1 in the journal Cancer Research.

According to the federal Centers for Disease Control and Prevention, colon cancer is the country's second leading cancer killer. In 2002, the most recent year for which statistics are available, 70,651 men and 68,883 women were diagnosed with colon cancer in the United States; 28,471 men and 28,132 women died from the disease.

In a series of cell-culture experiments, Srivastava and his colleagues--including lead author and postdoctoral fellow Ravinder Tammali, assistant professor Kota V. Ramana, and Sharad S. Singhal and Sanjay Awasthi of the University of Texas at Arlington-- investigated aldose reductase's role in colon cancer cell growth. First they stimulated colon cancer cells with growth factors, chemicals known to kick-start inflammatory chain reactions that encourage colon cancer cells to proliferate; this proliferation process then itself produces even more inflammation and cancer cell growth. (Chronic inflammation is strongly linked to the development of colon and other cancers.)

The researchers then blocked aldose reductase activity and checked the responses of known molecular links in the chain of colon cancer cell growth.

"In a nutshell, when we inhibited aldose reductase by using pharmacological inhibitors or genetic manipulations, all the inflammatory players were significantly blocked," Srivastava said. "We really understand this toxic signaling pathway much better now."

In their mouse experiments, the researchers implanted human colon cancer cells beneath the skin of "nude mice"--a hairless and immune-deficient variety commonly used in medical research. Tumor progression stopped completely in the mice treated with genetic material known as small interfering RNA (or "siRNA") that was engineered to prevent cells from making the aldose reductase enzyme.

The treated mice seemed unharmed by the procedure. In contrast, the untreated "control" animals experienced uncontrolled tumor growth.

As exciting as such results are, Srivastava pointed out, the distance between a brand-new procedure that works in nude mice and one that works in humans is considerable.

However, substantial research has already been done on developing drugs that inhibit aldose reductase in people, because the enzyme is also involved in causing such complications of diabetes as blindness and nerve damage.

Aldose reductase inhibitors might be in use against human colon cancer in a relatively short time, Srivastava said, since one candidate is already in phase 3 clinical trials in the United States for prolonged use in diabetes, and an aldose reductase inhibitor is already available for clinical use in Japan. Such drugs would likely be used after surgery as a "chemo-preventive" measure to keep cancer cells missed by surgery in check. "As far as I am aware, there is no other chemo-preventive agent that has been shown to be so effective in laboratory animals," the researcher said.
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University of Texas Medical Branch at Galveston

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