Parathyroid hormone receptor mediates the anti-myeloma effect of proteasome inhibitors

• Published in: Bone (New York, N.Y.) Vol. 61; pp. 39 - 43
• Main Authors: Zangari, Maurizio, Berno, Tamara, Yang, Ye, Zeng, Ming, Xu, Hongwei, Pappas, Lisa, Tricot, Guido, Kamalakar, Archana, Yoon, Donghoon, Suva, Larry J
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.04.2014; Elsevier
• Subjects: Animals; Biological and medical sciences; Boronic Acids - pharmacology; Bortezomib; Cell Line, Tumor; Cell Proliferation - drug effects; Disease Models, Animal; Female; Fundamental and applied biological sciences. Psychology; Hematologic and hematopoietic diseases; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Mice; Multiple myeloma; Multiple Myeloma - metabolism; Oligopeptides - pharmacology; Orthopedics; Proteasome inhibition; Proteasome Inhibitors - pharmacology; PTH receptor; Pyrazines - pharmacology; Receptor, Parathyroid Hormone, Type 1 - metabolism; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Proteasome inhibition; Multiple myeloma; PTH receptor; Immunopathology; Multicatalytic endopeptidase complex; Enzyme; Malignant hemopathy; Myeloma; Peptidases; Immunoglobulinopathy; Parathyroid hormone; Lymphoproliferative syndrome; Morphology; Hydrolases; Cancer
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2013.12.025

Abstract Clinically significant serum parathyroid hormone (PTH) variations have been reported in multiple myeloma (MM) patients treated with proteasome inhibitors. To elucidate the association between serum PTH variations and proteasome inhibition in MM, the effect of PTH and PTHR1 ligands on the proteasome inhibitors bortezomib and carfilzomib in vitro and in vivo was determined. The MM cell lines ARP1, OC1 and 5TGM1 expressed mRNA and protein encoding PTH receptor 1 (PTHR1). Treatment of 5TGM1 cells with either PTH(1–34), bortezomib or carfilzomib alone dose-dependently inhibited 5TGM1 cell proliferation. However, treatment with the potent PTHR1 antagonist [TYR34]PTH(7–34) (PTH(7–34)) had no significant effect on myeloma cell proliferation and cell viability. In contrast, when used in combination with bortezomib or carfilzomib, PTH(7–34) treatment significantly reduced the bortezomib or carfilzomib-associated decrease in cell proliferation. Treatment of the C57BL/KaLwRij mouse myeloma model with either bortezomib or carfilzomib provided a significantly prolonged survival benefit compared to controls ( p = 0.04; p = 0.01 respectfully). This potent anti-myeloma effect was completely abrogated by concomitant treatment with PTH(7–34). These results suggest an important role of the PTHR1 in the anti-myeloma effect of proteosome inhibition.