Structure-based design of specific cathepsin inhibitors and their application to protection of bone metastases of cancer cells.

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.

• Authors: N Katunuma, H Tsuge, M Nukatsuka, T Asao, M Fukushima
• Journal: Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 397 Issue 2 Pg. 305-11 (Jan 15 2002) ISSN: 0003-9861 [Print] United States
• PMID: 11795887 (Publication Type: Journal Article)
• Copyright: (c)2002 Elsevier Science.

Chemical References

• Antineoplastic Agents
• CLIK 148
• Cysteine Proteinase Inhibitors
• Epoxy Compounds
• Pyridines
• Collagen
• Cathepsins

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Bone Neoplasms (drug therapy, secondary)
• Bone Resorption (drug therapy)
• Cathepsins (antagonists & inhibitors)
• Collagen (metabolism)
• Colonic Neoplasms (drug therapy)
• Cysteine Proteinase Inhibitors (therapeutic use)
• Drug Design
• Epoxy Compounds (chemistry, therapeutic use)
• Femur (pathology)
• Humans
• Hypercalcemia (drug therapy)
• Melanoma (drug therapy)
• Mice
• Neoplasm Metastasis
• Pyridines (chemistry, therapeutic use)