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Halofuginone inhibits multiple myeloma growth in vitro and in vivo and enhances cytotoxicity of conventional and novel agents
Author(s) -
Leiba Merav,
Jakubikova Jana,
Klippel Steffen,
Mitsiades Constantine S.,
Hideshima Teru,
Tai YuTzu,
Leiba Adi,
Pines Mark,
Richardson Paul G.,
Nagler Ar,
Anderson Kenneth C.
Publication year - 2012
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2012.09120.x
Subject(s) - cancer research , cytotoxicity , apoptosis , in vivo , bortezomib , multiple myeloma , medicine , pharmacology , chemistry , immunology , in vitro , biology , biochemistry , microbiology and biotechnology
Summary Multiple M yeloma ( 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 CD 40 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 M cl‐1 and X ‐ IAP . Multiplex analysis of phosphorylation of diverse components of signalling cascades revealed that HF induced changes in P 38 MAPK 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 .