Double-Edged Sword of Novel Anti-Cancer Treatment: Proteasome Inhibition in the Growth Plate Causes Impairment of Longitudinal Bone Growth

Farasat      Zaman; Bengt      Fadeel; Lars      Savendahl

doi:10.2174/157339611796892319

Abstract

Longitudinal bone growth is a complex and tightly regulated process. A precise balance between proliferation, differentiation and cell death in growth plate chondrocytes is a key to normal bone growth in children. Indeed, decrease in proliferation/differentiation and increase in undesired cell death in growth plate cartilage are directly associated with impaired bone growth. Proteasome inhibitors are currently undergoing phase I and II clinical trials to evaluate their efficacy in the treatment of various childhood cancers. Effects of proteasome inhibitors on bone growth in children have not yet been reported. However, recent preclinical observations suggest that proteasome inhibitors may selectively target essential cell populations in growth plate cartilage, causing significant growth failure; an effect associated with increased apoptosis and decreased proliferation of chondrocytes. The observed effects on apoptosis and proliferation in growth plate chondrocytes appear to be mediated by several proteins including p53, apoptosis inducing factor (AIF), caspases, NF-κB and β-catenine. These observations could have important implications for the use of proteasome inhibitors in the treatment of childhood diseases.

Keywords: Growth Plate, chondrocytes, bone, Apoptosis, proteasome inhibitors, Autophagy, cell death, apoptosis inducing factor (AIF), bortezomib, anti-cancer agents