Abstract
The anti-lymphoma activity and mechanism(s) of action of the multikinase inhibitor sorafenib were investigated using a panel of lymphoma cell lines, including SU-DHL-4V, Granta-519, HD-MyZ, and KMS-11 cell lines. In vitro, sorafenib significantly decreased cell proliferation and phosphorylation levels of MAPK and PI3K/Akt pathways while increased apoptotic cell death. In vivo, sorafenib treatment resulted in a cytostatic rather than cytotoxic effect on tumor cell growth associated with a limited inhibition of tumor volumes. However, sorafenib induced an average 50% reduction of tumor vessel density and a 2-fold increase of necrotic areas. Upon sorafenib treatment, endothelial and tumor cells from SU-DHL-4V, Granta-519, and KMS-11 nodules showed a potent inhibition of either phospho-ERK or phospho-AKT, whereas a concomitant inhibition of phospho-ERK and phospho-AKT was only observed in HD-MyZ nodules. In conclusion, sorafenib affects the growth of lymphoid cell lines by triggering antiangiogenic mechanism(s) and directly targeting tumor cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / pharmacology
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Angiogenesis Inhibitors / therapeutic use
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Animals
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Apoptosis / drug effects
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Cell Count
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Endothelial Cells / drug effects
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Endothelial Cells / enzymology
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Endothelial Cells / pathology
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Humans
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Lymphoma / drug therapy*
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Lymphoma / enzymology*
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Lymphoma / pathology
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MAP Kinase Signaling System* / drug effects
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Mice
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Mice, SCID
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Necrosis
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Neovascularization, Pathologic / drug therapy*
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Neovascularization, Pathologic / enzymology
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Neovascularization, Pathologic / pathology
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Niacinamide / analogs & derivatives*
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Niacinamide / pharmacology
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Niacinamide / therapeutic use
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Pericytes / drug effects
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Pericytes / pathology
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Phenylurea Compounds / pharmacology
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Phenylurea Compounds / therapeutic use*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Proto-Oncogene Proteins c-akt / metabolism*
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Sorafenib
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Xenograft Model Antitumor Assays
Substances
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Angiogenesis Inhibitors
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Phenylurea Compounds
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Protein Kinase Inhibitors
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Niacinamide
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Sorafenib
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
Grants and funding
The work was supported in part by grants from the Ministry of Education, University and Research (Rome, Italy), the Ministry of Health (Ricerca Finalizzata 2008 and 2010 to C.C.-S.), and the Italian Association for Cancer Research (MCO - 9998 to A.M.G. and C.C.-S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.