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

Abstract

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.

• Authors: Bjoern Chapuy, Nikolai Schuelper, Melanie Panse, Andrea Dohm, Elisabeth Hand, Roland Schroers, Lorenz Truemper, Gerald G Wulf
• Journal: British journal of haematology (Br J Haematol) Vol. 152 Issue 4 Pg. 401-12 (Feb 2011) ISSN: 1365-2141 [Electronic] England
• PMID: 21689083 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Blackwell Publishing Ltd.

Chemical References

• Antineoplastic Agents
• Benzenesulfonates
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Pyridines
• Niacinamide
• Sorafenib
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 14

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzenesulfonates (pharmacology)
• Cell Cycle (drug effects)
• Cell Death (drug effects)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical (methods)
• Humans
• Lymphoma, Non-Hodgkin (drug therapy, metabolism, pathology)
• Mitogen-Activated Protein Kinase 14 (antagonists & inhibitors, metabolism)
• Niacinamide (analogs & derivatives)
• Phenylurea Compounds
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Pyridines (pharmacology)
• Signal Transduction (drug effects)
• Sorafenib
• Tumor Cells, Cultured
• Tumor Stem Cell Assay (methods)