relacatib and Bone-Neoplasms

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.. 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.. 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.

Topics: Azepines; Benzamides; Biphenyl Compounds; Bone Neoplasms; Bone Remodeling; Bone Resorption; Breast Neoplasms; Cathepsin K; Cathepsins; Female; Humans; Male; Osteoclasts; Piperazines; Prostatic Neoplasms; Sulfones; Thiazoles

Bone metastases of prostate cancer usually have an underlying osteoclastic component. Bone metastasis is incurable and contributes significantly to disease-specific morbidity and mortality. Management of bone metabolism in patients is a clinically significant issue. Several key factors have been found to be important in tumor-induced promotion of osteoclast activity. Receptor activator of nuclear factor-kappa B ligand (RANKL) is produced by bone metastasis of prostate cancer, enabling these metastasis to induce osteolysis through osteoclast activation. Matrix metalloproteinases (MMPs) are secreted by prostate cancer cells and promote osteolysis primarily through degradation of bone matrix. In this way, many factors derived from prostate cancer metastases can promote osteolysis, and these factors may serve as therapeutic targets. The new agents are targeted to osteoclasts (i.e.: zoledronic acid, anti-RANKL monoclonal antibody, cathepsin K inhibitor, and anti-PTHrP monoclonal antibody), are considered to be standard management in the care of bone metastasis patients in combination with chemotherapy and hormone therapy. In this review, we summarized the current understanding and therapy of bone metastasis in prostate cancer.

Topics: Antibodies, Monoclonal; Azepines; Bone Neoplasms; Cathepsin K; Cathepsins; Diphosphonates; Enzyme Inhibitors; Humans; Imidazoles; Male; Matrix Metalloproteinases; Osteoclasts; Osteolysis; Osteoporosis; Parathyroid Hormone-Related Protein; Prostatic Neoplasms; RANK Ligand; Sulfones; Zoledronic Acid