A cathepsin K inhibitor reduces breast cancer-induced osteolysis and skeletal tumor burden
A cathepsin K inhibitor reduces breast cancer-induced osteolysis and skeletal tumor burden
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DOI：
10.1158/0008-5472.can-06-3940
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Clezardin, Philippe
中科院分区：
文献类型：
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作者：
Le Gall, Celine;Bellahcene, Akeila;Clezardin, Philippe
破骨细胞介导乳腺癌骨骼转移的骨破坏。组织蛋白酶K是一种由破骨细胞分泌并降解骨的蛋白酶。免疫组化结果显示，组织蛋白酶K不仅在破骨细胞中表达，在转移至骨的乳腺癌细胞中也表达。在胫骨内注射表达组织蛋白酶K的人BT474乳腺癌细胞后，用组织蛋白酶K抑制剂（CKI, 50mg /kg，每日两次）临床给药方案治疗的荷瘤小鼠出现的溶骨病变比用载药剂治疗的荷瘤小鼠小79%。CKI的影响也在小鼠模型中进行了研究，在小鼠模型中，静脉接种表达组织蛋白酶K的人B02乳腺癌细胞导致骨转移形成。在发生溶骨性病变之前（预防方案）或之后（治疗方案）开始给药。在治疗方案中，CKI （50 mg/kg，每日两次）或单次临床剂量100 μ g/kg唑来膦酸（破骨细胞抑制剂）可使溶骨病变的进展减少59%至66%。与对照组相比，CKI治疗还减少了62%的骨骼肿瘤负担，而唑来膦酸没有减少肿瘤负担。CKI在抑制骨骼肿瘤负荷方面的疗效在治疗和预防方案上相似。相比之下，CKI没有阻断s.c.b 02肿瘤异种移植动物的生长。因此，CKI可能通过抑制骨吸收而使骨成为不利于肿瘤生长的微环境。这些发现提高了组织蛋白酶K可能成为骨转移治疗的治疗靶点的可能性。
Osteoclasts mediate bone destruction in breast cancer skeletal metastases. Cathepsin K is a proteinase that is secreted by osteoclasts and degrades bone. Here, immohistochemistry revealed that cathepsin K was expressed not only by osteoclasts but also by breast cancer cells that metastasize to bone. Following intratibial injection with cathepsin K-expressing human BT474 breast cancer cells, tumor-bearing mice treated with a clinical dosing regimen of cathepsin K inhibitor (CKI; 50 mg/kg, twice daily) had osteolytic lesions that were 79% smaller than those of tumor-bearing mice treated with the vehicle. The effect of CKI was also studied in a mouse model in which the i.v. inoculation of human B02 breast cancer cells expressing cathepsin K leads to bone metastasis formation. Drug administration was started before (preventive protocol) or after (treatment protocol) the occurrence of osteolytic lesions. In treatment protocols, CKI (50 mg/kg, twice daily) or a single clinical dose of 100 mu g/kg zoledronic acid (osteoclast inhibitor) reduced the progression of osteolytic lesions by 59% to 66%. CKI therapy also reduced skeletal tumor burden by 62% compared with vehicle, whereas zoledronic acid did not decrease the tumor burden. The efficacy of CKI at inhibiting skeletal tumor burden was similar in the treatment and preventive protocols. By contrast, CKI did not block the growth of s.c. B02 tumor xenografts in animals. Thus, CKI may render the bone a less favorable microenvironment for tumor growth by inhibiting bone resorption. These findings raise the possibility that cathepsin K could be a therapeutic target for the treatment of bone metastases.