Structure-based design of specific cathepsin inhibitors and their application to protection of bone metastases of cancer cells.
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.
Katunuma
N
N
Institute for Health Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima-city 770-8514, Japan. katunuma@tokushima.bunri-u.ac.jp
Tsuge
H
H
Nukatsuka
M
M
Asao
T
T
Fukushima
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D001862:Bone Resorption / Q000188:drug therapy; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003094:Collagen / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D015195:Drug Design; D004852:Epoxy Compounds / Q000737:chemistry / Q000627:therapeutic use*; D005269:Femur / Q000473:pathology; D006801:Humans; D006934:Hypercalcemia / Q000188:drug therapy*; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D009362:Neoplasm Metastasis; D011725:Pyridines / Q000737:chemistry / Q000627:therapeutic use*
D000970:Antineoplastic Agents; C402823:CLIK 148; D015853:Cysteine Proteinase Inhibitors; D004852:Epoxy Compounds; D011725:Pyridines; D003094:Collagen; D002403:Cathepsins