Inhibition of adenosine monophosphate-activated protein kinase induces apoptosis in multiple myeloma cells.
In this study, we show that adenosine monophosphate-activated protein kinase (AMPK) is expressed and activated in multiple myeloma cells. The inhibition of AMPK induced growth arrest and reduction of cell viability in the cell viability assay using the water-soluble tetrazolium salt 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate (WST-1 assay). Induction of apoptosis was determined by annexin-V and propidium iodide staining. The prevention of apoptosis using the pancaspase inhibitor ZVAD-fmk and caspase-3 cleavage upon incubation with the AMPK inhibitor (AMPKI) is shown. Furthermore, incubation of myeloma cells with AMPKI resulted in the downregulation of pAMPK, Mcl-1 and Bcl-xL. Coincubation of AMPKI and melphalan led to a strong additional increase of apoptosis in myeloma cells. We conclude that AMPKI has a strong antimyeloma activity in vitro and represents a new targeted strategy in the treatment of multiple myeloma.
Baumann
Philipp
P
Department of Hematology and Oncology, Medizinische Klinik Innenstadt, Klinikum der Universität München, Germany. Philipp.Baumann@med.uni-muenchen.de
Mandl-Weber
Sonja
S
Emmerich
Bertold
B
Straka
Christian
C
Schmidmaier
Ralf
R
D017302:Annexins / Q000096:biosynthesis; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D008558:Melphalan / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051020:bcl-X Protein / Q000096:biosynthesis
D017302:Annexins; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D017868:Cyclic AMP-Dependent Protein Kinases; D008558:Melphalan