Structure-based design of specific cathepsin inhibitors and their application to protection of bone metastases of cancer cells
Structure-based design of specific cathepsin inhibitors and their application to protection of bone metastases of cancer cells
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DOI：
10.1006/abbi.2001.2709
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发表时间：
2002-01-15
影响因子：
3.9
通讯作者：
Fukushima, M
中科院分区：
文献类型：
--
作者：
Katunuma, N;Tsuge, H;Fukushima, M
我们报告了CLIK-148的体内抗高钙血症和抗转移作用，CLIK-148是组织蛋白酶L的特异性抑制剂。骨吸收过程中的脱钙作用之后是破骨细胞组织蛋白酶对1型胶原蛋白的降解。携带肿瘤的破骨细胞或TNF-α激活的破骨细胞分泌大量的半胱氨酸蛋白酶，特别是组织蛋白酶原L，其有力地降解1型胶原，导致肿瘤相关的骨吸收和骨钙的释放。CLIK-148治疗可显著预防体外骨陷窝形成，该骨陷窝形成由RANKL和M-CSF激活的人骨髓细胞衍生的破骨细胞以及TNF-α激活的小鼠破骨细胞引起。我们评估了CLIK-148治疗对由LJC-1人下颌骨癌接种诱导的恶性高钙血症的体内抑制作用，并且CLIK-148治疗显著地防止了肿瘤诱导的高钙血症。在对植入到小鼠颅骨的结肠26 PMF-15的骨转移的保护上，CLIK-148处理显著抑制颅骨骨吸收（直接转移）。CLIK-148治疗还减少了植入心脏左心室的黑色素瘤A375肿瘤的股骨和胫骨的远端骨转移。(C)2002年，Elsevier Science。
We report the antihypercalcemic and antimeta-static 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. (C) 2002 Elsevier Science.