Structure-based design of specific cathepsin inhibitors and their application to protection of bone metastases of cancer cells. |
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Authors: | N Katunuma H Tsuge M Nukatsuka T Asao M Fukushima |
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Affiliation: | Institute for Health Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima-city 770-8514, Japan. katunuma@tokushima.bunri-u.ac.jp |
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Abstract: | We report the antihypercalcemic and antimetastatic effects of CLIK-148 in vivo, which is a specific inhibitor of cathepsin L. The decalcification during bone absorption is followed by the degradation of type-1 collagen by osteoclastic cathepsins. Tumor-bearing osteoclasts or TNF-alpha-activated osteoclasts secrete large amounts of cysteine proteases, especially procathepsin L, which powerfully degrade type-1 collagen leading to tumor-associated bone absorption and release of bone calcium. The bone pit formations in vitro, which are caused by osteoclasts derived from human bone marrow cells activated by RANKL and M-CSF and also by mice osteoclasts activated by TNF-alpha, are significantly prevented by CLIK-148 treatment. We evaluated the in vivo inhibitory effect of malignant hypercalcemia induced by LJC-1 human mandibular cancer inoculation by CLIK-148 treatment, and the CLIK-148 treatment significantly protected against the tumor-induced hypercalcemia. On the protection of bone metastasis of colon 26 PMF-15 implanted to mouse calvaria, CLIK-148 treatment significantly inhibited calvaria bone absorption (direct metastasis). The CLIK-148 treatment also reduced distant bone metastasis to the femur and tibia of melanoma A375 tumors implanted into the left ventricle of the heart. |
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Keywords: | cathepsin L cathepsin inhibitor bone metastasis malignant hypercalcemia |
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