Source: Oxford Journals
A component of snake venom has demonstrated its ability to inhibit cancer cell migration in two different cancer models. The protein, called contortrostatin, seems to block cell migration in a novel way.
Francis S. Markland, Ph.D., professor of biochemistry and molecular biology at the University of Southern California Keck School of Medicine, Los Angeles, was examining venom from the southern copperhead Agkistrodon contortrix contortrix for its clot-busting properties when he learned that a group in Taiwan had found disintegrins—integrin antagonists—in the venom of another snake.?
“I thought it would be interesting to see if a similar protein was present in southern copperhead venom,” recalled Markland in an interview. “But our initial studies showed no activity. The problem was that we were looking at its ability to inhibit platelet aggregation, and in the crude venom there are also platelet aggregating agents.” After purifying the venom, Markland and his colleagues found a minor component of the venom that worked as a disintegrin, and this is the protein they named contortrostatin.
The integrins are a family of transmembrane receptor proteins that bind to components of the extracellular matrix. One of their functions is to grip the extracellular matrix, providing traction and allowing cells to migrate from one place to another. Researchers in a number of laboratories are focusing on one integrin in particular, called ?v?3. This integrin is present on the surface of cancer cells and is thought to be critical in metastasis.
Contortrostatin appears to block cell migration both by binding to a cell-surface protein in the integrin family, preventing it from gripping the extracellular matrix, and by scrambling signals to the cytoskeleton.
“We knew on the basis of contortrostatin’s ability to inhibit platelet aggregation that it was interacting with integrins, and we also knew that there are integrins on the surface of cancer cells,” noted Markland. “Therefore we reasoned that it might be fruitful to look at its anticancer activity.”
The group found that contortrostatin had very effective inhibitory properties on adhesion to several extracellular matrix proteins such as fibronectin and vitronectin. They also found that it was effective in inhibiting tumor cell invasion. Using human breast cancer cells and human ovarian cancer cells in immunodeficient mice given daily intratumor injections of contortrostatin, they discovered that it inhibited tumor dissemination and angiogenesis.
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