Cathepsin K inhibitors as treatment of bone metastasis.
OBJECTIVE
Cancer cells that metastasize to the skeleton are, on their own, rarely able to destroy bone. Instead, they stimulate the function of bone-degrading cells, the osteoclasts, leading to the formation of osteolytic lesions. The purpose of this review is to consider cathepsin K, a cysteine protease produced by osteoclasts, as a therapeutic target for the treatment of patients with osteolytic bone metastases.


RESULTS
Cathepsin K plays a key role in osteoclast-mediated bone degradation. It is also produced by cancer cells that metastasize to bone where it functions in proteolytic pathways that promote cancer cell invasion. Highly selective and potent cathepsin K inhibitors have been recently developed and shown to be useful antiresorptive agents to treat osteoporosis. Moreover, preclinical studies show that cathepsin K inhibitors reduce breast cancer-induced osteolysis and skeletal tumor burden. This reduction of skeletal tumor burden is due to the antiresorptive activity of cathepsin K inhibitors, which in turn, deprive cancer cells of bone-derived growth factors that are required for tumor growth.


CONCLUSIONS
Cathepsin K inhibitors are appropriate drugs to treat diseases associated with increased bone loss. However, their chronic use in treating osteoporosis may result in adverse effects because basic nitrogen-containing cathepsin K inhibitors accumulate within acidic organelles such as lysosomes, thereby inhibiting the activity of other cathepsins. These adverse effects should not, however, preclude the use of these drugs in life-threatening diseases such as bone metastasis.
Le Gall
Céline
C
Institut National de la Santé et de la Recherche Médicale, Lyon, France.
Bonnelye
Edith
E
Clézardin
Philippe
P
D001381:Azepines / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D016723:Bone Remodeling; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000473:pathology; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008297:Male; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000473:pathology; D013450:Sulfones / Q000627:therapeutic use; D013844:Thiazoles / Q000627:therapeutic use
D001381:Azepines; D001549:Benzamides; D001713:Biphenyl Compounds; C507712:CRA 013783; D010879:Piperazines; D013450:Sulfones; D013844:Thiazoles; C509706:relacatib; C529767:balicatib; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C527128:odanacatib