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Archive - Oct 29, 2009

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Convergent Evolution of Toxins Seen in Shrew and Lizard

Biologists at Harvard University and Massachusetts General Hospital have shown that independent, but similar, molecular changes turned a harmless digestive enzyme into a toxin in two unrelated species--a shrew and a lizard--giving each a venomous bite. "The venom is essentially an overactivation of the original digestive enzyme, amplifying its effects," said Dr. Yael T. Aminetzach, lead author of the study. "What had been a mild anticoagulant in the salivary glands of both species has become a much more extreme compound that causes paralysis and death in prey that is bitten." In the first part of the study, Dr. Aminetzach and her colleagues compared a toxin found in the salivary glands of the insectivorous North American shrew (Blarina brevicauda) to its closely related digestive enzyme kallikrein. Dr. Aminetzach found that the specific molecular differences between kallikrein and its toxic descendent are highly localized around the enzyme's active site. "Catalysis is fostered by three specific changes that increase enzyme activity," Dr. Aminetzach said. "The active site is physically opened up, and the loops surrounding it become more flexible. The area around the active site also becomes positively charged, serving to better guide the substrate directly into the active site." To further demonstrate that these molecular changes to kallikrein are related to the evolution of toxicity, Aminetzach explored the evolution of another kallikrein-like toxin in the Mexican beaded lizard (Helodermata horridum) (male and female shown in photo). She found that this toxin, while distinct from the analogous toxin in the shrew, nonetheless exhibits the same catalytic enhancement relative to the original kallikrein enzyme.

Drug-Radiation Combination Eradicates Lung Cancer in Mice

Combination of an investigative drug (BEZ235) and low-dose radiation eliminates non-small cell lung cancer (NSCLC) in mice, according to results of a recent study conducted by researchers at the University of Texas Southwestern Medical Center, and collaborators including Novartis Pharma. NSCLC is a leading cause of cancer-related deaths worldwide. The researchers found that if they administered BEZ235 before they damaged the DNA of tumor cells with otherwise nontoxic radiation, the drug blocked the pro-survival actions of a protein called PI3K, which normally springs into action to keep tumor cells alive while they repair DNA damage. The researchers tested their novel therapeutic strategy in mice transplanted with NSCLC cells obtained from patients. They found that tumors in the mice treated with BEZ235 alone were significantly smaller than those in mice not given the drug. Although the tumors stopped growing, they did not die. By contrast, tumors were completely eradicated in mice treated with a combination of BEZ235 and radiation. “These early results suggest that the drug-radiation combination might be an effective therapy in lung cancer patients,” said Dr. Pier Paolo Scaglioni, senior author of the study. The report was published in the October 1 issue of Cancer Research. [Press release] [Cancer Research abstract]