MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts

• Published in: Blood 2007-11, Vol.110 (10), p.3744-3752
• Main Authors: Vallet, Sonia, Raje, Noopur, Ishitsuka, Kenji, Hideshima, Teru, Podar, Klaus, Chhetri, Shweta, Pozzi, Samantha, Breitkreutz, Iris, Kiziltepe, Tanyel, Yasui, Hiroshi, Ocio, Enrique M., Shiraishi, Norihiko, Jin, Janice, Okawa, Yutaka, Ikeda, Hiroshi, Mukherjee, Siddhartha, Vaghela, Nileshwari, Cirstea, Diana, Ladetto, Marco, Boccadoro, Mario, Anderson, Kenneth C.
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Cell Adhesion - drug effects; Cell Communication - drug effects; Cell Differentiation - drug effects; Cell Fusion; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Chemokine CCL3 - metabolism; Down-Regulation - drug effects; Drug Evaluation, Preclinical; General aspects; Genes, fos; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Medical sciences; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Neoplasia; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteoclasts - physiology; Pharmacology. Drug treatments; Receptors, CCR1 - antagonists & inhibitors
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-05-093294

The interaction between osteoclasts (OCs) and multiple myeloma (MM) cells plays a key role in the pathogenesis of MM-related osteolytic bone disease (OBD). MM cells promote OC formation and, in turn, OCs enhance MM cell proliferation. Chemokines are mediators of MM effects on bone and vice versa; in particular, CCL3 enhances OC formation and promotes MM cell migration and survival. Here, we characterize the effects of MLN3897, a novel specific antagonist of the chemokine receptor CCR1, on both OC formation and OC-MM cell interactions. MLN3897 demonstrates significant impairment of OC formation (by 40%) and function (by 70%), associated with decreased precursor cell multinucleation and down-regulation of c-fos signaling. OCs secrete high levels of CCL3, which triggers MM cell migration; conversely, MLN3897 abrogates its effects by inhibiting Akt signaling. Moreover, MM cell-to-OC adhesion was abrogated by MLN3897, thereby inhibiting MM cell survival and proliferation. Our results therefore show novel biologic sequelae of CCL3 and its inhibition in both osteoclastogenesis and MM cell growth, providing the preclinical rationale for clinical trials of MLN3897 to treat OBD in MM.