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Snake Venom Protein Paralyzes Cancer Cells

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Snake Venom Protein Paralyzes Cancer Cells | 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 School of Medicine in Los Angeles, was examining the poison of the southern copper head Agkistrodon contortrix contortrix for its properties anticoagulants when he learned that a group in Taiwan had found disintegrins-integrin antagonists-in the venom of another snake.

"I thought it was interesting to see if a protein was similar in the southern venom of copperhead," Markland recalled in an interview. "But the initial studies were not better known, the problem was that we were studying their ability to inhibit platelet aggregation, and in the crude venom there were also platelet-aggregating agents." After purifying the poison, Markland and his colleagues were a minor component of the poison that functioned as a disintegrin, and this is the protein they called contortrostatin.

Integrins are a family of transmembrane receptor proteins that bind to the components of the extracellular matrix. One of its functions is to grab the extracellular matrix, provide traction and allow cells to migrate from one place to another. Researchers in several laboratories are focusing on a particular integrin, called αvβ3. This integrin is present on the surface of cancer cells and is thought to be critical in metastasis.

Contortrostatin appears to block cell migration by binding to a cell surface protein in the integrin family, which prevents it from adhering to the extracellular matrix and confusing signals with the cytoskeleton.

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"We knew on the basis of the ability of contortrostatin to inhibit platelet aggregation that interacted with integrins, and we also knew that there are integrins on the surface of cancer cells," Markland said. "Therefore, we reason that it could be fruitful to observe its activity against cancer."

The group found that contortrostatin had very effective inhibitory properties on adhesion to several extracellular matrix proteins, such as fibronectin and vitronectin. He also discovered that it was effective in inhibiting the invasion of tumor cells. Using breast cancer cells and human ovarian cancer cells in immunodeficient mice that received daily intratumoral injections of contortrostatin, they discovered that they inhibited tumor spread and angiogenesis.

Also, said Markland. "There's a little oozing next to the injections in mom's cancer model." And in the ovarian cancer model we have seen some petechiae [hemorrhagic spots], which is an antiplatelet effect. In addition to its effect on platelets, it has minimal side effects and no evidence of internal bleeding has been seen. "

Recently, Matthew R. Ritter, a graduate student in the Markland lab, tried to unravel the exact mechanism of action of contortrostatin. What he found was a surprise, Markland said. The researchers expected that contortrostatin functioned in the same way as other disintegrins, that is, by interfering with the binding of αvβ3 to extracellular matrix proteins. But contortrostatin apparently does more.

Integrins can bind to extracellular proteins only when they are grouped into groups known as focal adhesions. Normally, integrins spread diffusely on the cell membrane, but when a molecule binds to its ligand, it sends an intracellular signal that leads to the formation of focal adhesion. In a poster session at the 40th Annual Meeting of the American Society of Cellular Biology, Ritter and Markland (along with their colleague Qing Zhou) reported that by cross-linking integrins αvβ3, contortrostatin caused intracellular signals that are spatial and inappropriate thematics. These faulty signals interrupt both focal adhesions and the actin cytoskeleton.

David A. Cheresh, Ph.D., professor in the departments of immunology and vascular biology at the Scripps Research Institute, La Jolla, California, who works on integrins in angiogenesis and neoplasia, is intrigued by Markland's work , but in an interview. He expressed skepticism. In particular Cheresh, Markland argues that contortrostatin acts as an antagonist, which blocks the binding of αvβ3 to the matrix proteins, and as an agonist, which makes αvβ3 a defective signal.

"It's a very interesting molecule," said Cheresh. "It's a very exciting observation, I'm not sure, however, what the mechanism is, and I'm not sure what part of the biological activity that you see in the vitro is due to the antagonistic effects, I'm not sure I can not get a similar effect with just a decent antagonist Are the signaling properties really critical for their biological activity?

Cheresh said there are two monoclonal antibodies to the integrin αvβ3 currently in phase II clinical trials. Vitaxin is being developed by MedImmune Inc., Gaithersburg, Md., And Cilengitide is being developed by Merck KgaA, Darmstadt, Germany. Markland said that although several pharmaceutical companies have expressed interest in contortrostatin, he has not yet developed an association with any for clinical development.

And Cheresh warned that it can be a long way from the laboratory to the clinic. "Certainly, in culture it is an interesting molecule, the question is, can it be developed for cancer? One has to worry about the pharmacodynamic properties, and of course, those are the best pitfalls of an interesting cell phone, since these people have made, a possible drug candidate. "

Snake Venom Protein Paralyzes Cancer Cells.

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