title: Sorafenib has potent antitumor activity against multiple myeloma in vitro, ex vivo, and in vivo in the 5T33MM mouse model.
abstract: Multiple myeloma (MM) is a B-cell malignancy characterized by the expansion of clonal plasma blasts/plasma cells within the bone marrow that relies on multiple signaling cascades, including tyrosine kinase activated pathways, to proliferate and evade cell death. Despite emerging new treatment strategies, multiple myeloma remains at present incurable. Thus, novel approaches targeting several signaling cascades by using the multi-tyrosine kinase inhibitor (TKI), sorafenib, seem a promising treatment approach for multiple myeloma. Here, we show that sorafenib induces cell death in multiple myeloma cell lines and in CD138(+)-enriched primary multiple myeloma patient samples in a caspase-dependent and -independent manner. Furthermore, sorafenib has a strong antitumoral and -angiogenic activity in the 5T33MM mouse model leading to increased overall survival. Multiple myeloma cells undergo autophagy in response to sorafenib, and inhibition of this cytoprotective pathway potentiated the efficacy of this TKI. Mcl-1, a survival factor in multiple myeloma, is downregulated at the protein level by sorafenib allowing for the execution of cell death, as ectopic overexpression of this protein protects multiple myeloma cells. Concomitant targeting of Mcl-1 by sorafenib and of Bcl-2/Bcl-xL by the antagonist ABT737 improves the efficacy of sorafenib in multiple myeloma cell lines and CD138(+)-enriched primary cells in the presence of bone marrow stromal cells. Altogether, our data support the use of sorafenib as a novel therapeutic modality against human multiple myeloma, and its efficacy may be potentiated in combination with ABT737.
authors.affiliation: Department of Oncology-Pathology, Cancer Centre Karolinska, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Pedram
authors.initials: P
authors.lastname: Kharaziha
authors.forename: Hendrik
authors.initials: H
authors.lastname: De Raeve
authors.forename: Charlotte
authors.initials: C
authors.lastname: Fristedt
authors.forename: Qiao
authors.initials: Q
authors.lastname: Li
authors.forename: Astrid
authors.initials: A
authors.lastname: Gruber
authors.forename: Per
authors.initials: P
authors.lastname: Johnsson
authors.forename: Georgia
authors.initials: G
authors.lastname: Kokaraki
authors.forename: Maria
authors.initials: M
authors.lastname: Panzar
authors.forename: Edward
authors.initials: E
authors.lastname: Laane
authors.forename: Anders
authors.initials: A
authors.lastname: Osterborg
authors.forename: Boris
authors.initials: B
authors.lastname: Zhivotovsky
authors.forename: Helena
authors.initials: H
authors.lastname: Jernberg-Wiklund
authors.forename: Dan
authors.initials: D
authors.lastname: Grandér
authors.forename: Fredrik
authors.initials: F
authors.lastname: Celsing
authors.forename: Magnus
authors.initials: M
authors.lastname: Björkholm
authors.forename: Karin
authors.initials: K
authors.lastname: Vanderkerken
authors.forename: Theocharis
authors.initials: T
authors.lastname: Panaretakis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001483:Base Sequence; D001557:Benzenesulfonates / Q000627:therapeutic use*; D017931:DNA Primers; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000627:therapeutic use*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D017931:DNA Primers; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib