A cathepsin K inhibitor reduces breast cancer induced osteolysis and skeletal tumor burden.
Osteoclasts mediate bone destruction in breast cancer skeletal metastases. Cathepsin K is a proteinase that is secreted by osteoclasts and degrades bone. Here, immunohistochemistry 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 microg/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.
Le Gall
Céline
C
Institut National de la Santé et de la Recherche Médicale, UMR 664, IFR62, Lyon, France.
Bellahcène
Akeila
A
Bonnelye
Edith
E
Gasser
Jürg A
JA
Castronovo
Vincent
V
Green
Jonathan
J
Zimmermann
Johann
J
Clézardin
Philippe
P
D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000517:prevention & control / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D010014:Osteolysis / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse