title: Sorafenib inhibits lymphoma xenografts by targeting MAPK/ERK and AKT pathways in tumor and vascular cells.
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.
authors.affiliation: Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milano, Italy. carmelo.carlostella@unimi.it
authors.forename: Carmelo
authors.initials: C
authors.lastname: Carlo-Stella
authors.forename: Silvia L
authors.initials: SL
authors.lastname: Locatelli
authors.forename: Arianna
authors.initials: A
authors.lastname: Giacomini
authors.forename: Loredana
authors.initials: L
authors.lastname: Cleris
authors.forename: Elena
authors.initials: E
authors.lastname: Saba
authors.forename: Marco
authors.initials: M
authors.lastname: Righi
authors.forename: Anna
authors.initials: A
authors.lastname: Guidetti
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Gianni
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D020286:Pericytes / Q000187:drug effects / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases