odanacatib and Prostatic-Neoplasms

It has been long recognized that skeleton represents one of the most favored metastatic sites for common cancers like breast and prostate. During the last decade the molecular mechanisms that are responsible for the development of bone metastasis have been gradually illuminated. It appears that the bone microenvironment has a pivotal role in this process. Metastatic tumor cells interact with bone triggering a cascade of molecular events that produce osteolytic and/or osteoblastic phenomena. In this review, we summarize and discuss the most significant factors and signaling pathways implicated in bone colonization. Moreover, based on the recent literature and data, we foresee the need for designing novel agents that will efficiently disrupt these interactions among cancer cells and bone microenvironment, bringing hope for more effective treatments.

Topics: Animals; beta Catenin; Biphenyl Compounds; Bone Neoplasms; Bone Remodeling; Breast Neoplasms; Cathepsin K; Chemokine CXCL12; Diphosphonates; Endothelin-1; Female; Humans; Hypoxia; Male; Neoplastic Stem Cells; Osteoblasts; Osteoclasts; Osteolysis; Parathyroid Hormone-Related Protein; Prostatic Neoplasms; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, CXCR4; Signal Transduction; Urokinase-Type Plasminogen Activator; Wnt Proteins

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