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

作者：Chapuy Bjoern; Schuelper Nikolai; Panse Melanie; Dohm Andrea; Hand Elisabeth; Schroers Roland; Truemper Lorenz; Wulf Gerald G^*

来源：British Journal of Haematology, 2011, 152(4): 401-412.

DOI：10.1111/j.1365-2141.2010.08526.x

• sorafenib
• lymphoma
• AKT
• MAPK14
• multikinase inhibition

P>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.

• 出版日期2011-2