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Z-Phe-Gly-NHO-Bz, an Inhibitor of Cysteine Cathepsins, Induces Apoptosis in Human Cancer Cells

Departments of Immunology [D-M. Z.], Experimental Oncology [F. M. U.], and Drug Discovery Program [F. M. U.], Parker Hughes Cancer Center, Parker Hughes Institute, Roseville, Minnesota 55113

An increasing number of studies indicate that cysteine cathepsins contribute to cancer progression, invasion, and metastasis. Here we provide experimental evidence that the cathepsin inhibitor Z-Phe-Gly-NHO-Bz induces rapid apoptotic death in human cancer cell lines. Notably, the Z-Phe-Gly-NHO-Bz-induced apoptosis exhibited independence of p53, caspases, and mitogen-activated protein (MAP) kinases. Taken together, our results prompt the hypothesis that cysteine cathepsin(s) is a universal survival factor for cancer cells, and its inhibition leads to cancer cell apoptosis. The exquisite sensitivity of human cancer cells to CATI-1 indicates that this compound and its derivatives may provide the basis for new treatment programs against a broad spectrum of malignancies.

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