Multikinase inhibitor sorafenib exerts cytocidal efficacy against Non‐Hodgkin lymphomas associated with inhibition of MAPK14 and AKT phosphorylation

• Published in: British journal of haematology 2011-02, Vol.152 (4), p.401-412
• Main Authors: Chapuy, Bjoern, Schuelper, Nikolai, Panse, Melanie, Dohm, Andrea, Hand, Elisabeth, Schroers, Roland, Truemper, Lorenz, Wulf, Gerald G.
• Format: Article
• Language: English
• Subjects: AKT; AKT protein; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Benzenesulfonates - pharmacology; Biological and medical sciences; Cell Cycle - drug effects; Cell Death - drug effects; Cell Proliferation - drug effects; Cell survival; Cell suspensions; Cytotoxicity; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical - methods; Extracellular signal-regulated kinase; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; lymphoma; Lymphoma, Non-Hodgkin - drug therapy; Lymphoma, Non-Hodgkin - metabolism; Lymphoma, Non-Hodgkin - pathology; MAP kinase; MAPK14; Medical sciences; Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 14 - metabolism; multikinase inhibition; Niacinamide - analogs & derivatives; Phenylurea Compounds; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Pyridines - pharmacology; Raf protein; Signal transduction; Signal Transduction - drug effects; sorafenib; T-cell lymphoma; Tumor Cells, Cultured; Tumor Stem Cell Assay - methods
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2010.08526.x

Summary Intracellular signal transduction by kinase‐mediated phosphorylation is essential for the survival and growth of lymphoma cells. This study analysed the multikinase inhibitor sorafenib for its cytotoxic activity against lymphoma cells. We found that sorafenib reduced cell viability at low micromolar concentrations in a time‐dependent manner in cell lines and primary cell suspensions representing major types of aggressive B‐ and T‐cell lymphomas. In cells surviving short term exposure, proliferative arrest occurred leading to complete loss of in vitro clonogenicity. Previously described sorafenib targets within the RAF kinase family were found to be expressed and phosphorylated in all cell lines, and sorafenib perturbed the activation of classical RAF/MEK/ERK pathway targets. However, using a global phoshoprotein array, the most consistent downstream effect of sorafenib in NHL cells was the inhibition of mitogen‐activated protein kinase 14 (MAPK14) and panAKT phosphorylation. In conclusion, sorafenib has significant in vitro efficacy against aggressive B‐ and T‐cell lymphoma cells, associated with inhibition of MAPK14 and panAKT.