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Experimental Drug Stops Cancer Growth by Activating Integrin-Based Apoptosis

By LabMedica International staff writers
Posted on 13 Jun 2016
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Image: ProAgio (green) binding to integrin v3 (Photo courtesy of Georgia State University).
Image: ProAgio (green) binding to integrin v3 (Photo courtesy of Georgia State University).
An experimental drug blocks tumor growth by binding to a novel site on the surface receptor integrin alphavbeta3, which activates the apoptotic factor caspase 8 and leads to the death of the cancer cells.

Expression of the integrin alphavbeta3 is altered in various diseases and has been proposed as a drug target. Integrins are transmembrane receptors that mediate the attachment between a cell and the tissues that surround it, such as other cells or the extracellular matrix (ECM). Integrin molecules do not adhere to their appropriate ligands until cells are activated by chemotactic agents or other stimuli. Only then do the integrins undergo the conformational change necessary to confer high binding affinity for the endothelial adhesion molecules.

Investigators at Georgia State University (Atlanta, USA) used a rational design approach to develop a therapeutic protein, which they called ProAgio. This protein was shown to bind to integrin alphavbeta3 outside the classical ligand-binding site.

Results published in the May 31, 2016, online edition of the journal Nature Communications revealed that ProAgio induced apoptosis of integrin alphavbeta3-expressing cells by recruiting and activating caspase 8 to the cytoplasmic domain of integrin alphavbeta3. Caspases (cysteine-aspartic proteases) are a family of protease enzymes playing essential roles in programmed cell death (including apoptosis, pyroptosis, and necroptosis) and inflammation. Activation of caspases ensures that the cellular components are degraded in a controlled manner, carrying out cell death with minimal effect to surrounding tissues.

ProAgio was also found to express potent anti-angiogenic activity and strongly inhibited growth of tumor xenografts in mice, but did not affect the established vasculature. Toxicity analyses demonstrated that ProAgio was not toxic to mice.

"This integrin pair, alphavbeta3, is not expressed in high levels in normal tissue," said senior author Dr. Zhi-Ren Liu, professor of biology at Georgia State University. "In most cases, it is associated with a number of different pathological conditions. Therefore, it constitutes a very good target for multiple disease treatment. We took a unique angle. We designed a protein that binds to a different site. Once the protein binds to the site, it directly triggers cell death. When we are able to kill pathological cells, then we are able to kill the disease."

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