title: Induction of apoptosis in multiple myeloma cells by a statin-thalidomide combination can be enhanced by p38 MAPK inhibition.
abstract: The mechanisms involved in anti-myeloma activity of statins combined with thalidomide were studied in multiple myeloma (MM) cells. In addition, the effect of p38 MAPK inhibition on the induction of apoptosis in MM cells by the combination of thalidomide and simvastatin was investigated. Thalidomide was observed to significantly potentiate the antiproliferative activity of statins and enhance the proapoptotic effect of simvastatin and lovastatin. What is more, the combination of thalidomide with statins inhibited cell migration and decreased the production of VEGF and MMP-9 in MM cells more effectively than each of these drugs used separately. The combination of simvastatin and thalidomide augmented caspase 8 and 3 activation, and the additional application of p38 MAPK inhibitor resulted in enhanced apoptosis of MM cells concomitant with increased caspase 9 and 3 activation, as well as JNK phosphorylation. The results suggest that p38 inhibitors together with the combination of simvastatin and thalidomide have the potential to be used in MM treatment.
authors: Department of Cell Biology, Maria Curie-Sklodowska University, Lublin, Poland.
authors: Adrianna
authors: A
authors: Slawinska-Brych
authors: Barbara
authors: B
authors: Zdzisinska
authors: Magdalena
authors: M
authors: Mizerska-Dudka
authors: Martyna
authors: M
authors: Kandefer-Szerszen
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000096:biosynthesis; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019821:Simvastatin / Q000494:pharmacology*; D013792:Thalidomide / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013792:Thalidomide; D019821:Simvastatin; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020169:Caspases