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Potent in vitro and in vivo activity of sorafenib in multiple myeloma: induction of cell death, CD 138‐downregulation and inhibition of migration through actin depolymerization
Author(s) -
Udi Josefina,
Schüler Julia,
Wider Dagmar,
Ihorst Gabriele,
Catusse Julie,
Waldschmidt Johannes,
Schnerch Dominik,
Follo Marie,
Wäsch Ralph,
Engelhardt Monika
Publication year - 2013
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/bjh.12226
Subject(s) - sorafenib , bortezomib , cancer research , downregulation and upregulation , chemistry , in vivo , microbiology and biotechnology , pharmacology , biology , immunology , multiple myeloma , biochemistry , hepatocellular carcinoma , gene
Summary Despite considerable advances, multiple myeloma ( MM ) remains incurable and the development of novel therapies targeting the interplay between plasma cells ( PC s) and their bone marrow (BM) microenvironment remains essential. We investigated the effect of various agents in vitro on the proliferation, phenotype, morphology, actin polymerization and migration of MM cells and, in vivo, the tumour growth of L363‐bearing non‐obese diabetic severe combined immunodeficient mice with a deficient interleukin‐2 receptor gamma chain ( NSG ). In vitro , we observed a dose‐dependent cytotoxicity with bortezomib and sorafenib. Using RPMI8226 cells co‐expressing histone 2B‐ mC herry and cytochrome c‐ GFP , bortezomib‐ and sorafenib‐induced apoptosis was confirmed, and both agents combined showed synergism. Sorafenib induced CD138‐downregulation and abolished CXCL12‐induced actin polymerization. L363 cells expressed CCR4 and CCR5 and migrated to their common ligand CCL5. Chemotaxis to BM stroma cells was notable and significantly reduced by sorafenib. Downregulation of phospho‐ ERK appeared relevant for the inhibition of actin polymerization and chemotaxis. Sorafenib alone, and combined with bortezomib, showed substantial antitumour activity in L363‐bearing NSG . Correspondingly, sorafenib induced clinical responses in MM ‐/ AL ‐amyloidosis patients. We conclude that, in addition to the cytotoxic and anti‐angiogenic effects of sorafenib, blocking of MM cell migration and homing represent promising mechanisms to interrupt the interplay between PC s and their supportive microenvironment.