Leiba, M., Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, United States, Division of Haematology and Bone Marrow Transplantation, Chaim Sheba Medical Centre, Tel-Hashomer, Israel
Jakubikova, J., Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, United States, Department of Tumour Immunology, Cancer Research Institute, Bratislava, Slovakia
Klippel, S., Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, United States
Mitsiades, C.S., Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, United States
Hideshima, T., Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, United States
Tai, Y.-T., Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, United States
Leiba, A., Harvard Medical School, Boston, MA, United States
Pines, M., Institute of Animal Science, Agricultural Research Organization, The Volcani Centre, Bet Dagan, Israel
Richardson, P.G., Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, United States
Nagler, A., Division of Haematology and Bone Marrow Transplantation, Chaim Sheba Medical Centre, Tel-Hashomer, Israel
Anderson, K.C., Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, United States

Multiple Myeloma (MM), a malignancy of plasma cells, remains incurable despite the use of conventional and novel therapies. Halofuginone (HF), a synthetic derivative of quinazolinone alkaloid, has recently been shown to have anti-cancer activity in various preclinical settings. This study demonstrated the anti-tumour activity of HF against a panel of human MM cell lines and primary patient-derived MM cells, regardless of their sensitivity to conventional therapy or novel agents. HF showed anti-MM activity in vivo using a myeloma xenograft mouse model. HF suppressed proliferation of myeloma cells alone and when co-cultured with bone marrow stromal cells. Similarly, HF induced apoptosis in MM cells even in the presence of insulin-like growth factor 1 or interleukin 6. Importantly, HF, even at high doses, did not induce cytotoxicity against CD40 activated peripheral blood mononuclear cells from normal donors. HF treatment induced accumulation of cells in the G 0/G 1 cell cycle and induction of apoptotic cell death associated with depletion of mitochondrial membrane potential; cleavage of poly (ADP-ribose) polymerase and caspases-3, 8 and 9 as well as down-regulation of anti-apoptotic proteins including Mcl-1 and X-IAP. Multiplex analysis of phosphorylation of diverse components of signalling cascades revealed that HF induced changes in P38MAPK activation; increased phosphorylation of c-jun, c-jun NH(2)-terminal kinase (JNK), p53 and Hsp-27. Importantly, HF triggered synergistic cytotoxicity in combination with lenalidomide, melphalan, dexamethasone, and doxorubicin. Taken together, these preclinical studies provide the preclinical framework for future clinical studies of HF in MM. © 2012 Blackwell Publishing Ltd.