Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells.
Multiple myeloma is still an incurable disease; therefore, new therapeutics are urgently needed. A771726 is the active metabolite of the immunosuppressive drug leflunomide, which is currently applied in the treatment of rheumatoid arthritis, BK virus nephropathy, and cytomegaly viremia. Here, we show that dihydroorotate dehydrogenase (DHODH) is commonly expressed in multiple myeloma cell lines and primary multiple myeloma cells. The DHODH inhibitor A771726 inhibits cell growth in common myeloma cell lines at clinically achievable concentrations in a time- and dose-dependent manner. Annexin V-FITC/propidium iodide staining revealed induction of apoptosis of multiple myeloma cell lines and primary multiple myeloma cells. The 5-bromo-2'-deoxyuridine cell proliferation assay showed that inhibition of cell growth was partly due to inhibition of multiple myeloma cell proliferation. A771726 induced G(1) cell cycle arrest via modulation of cyclin D2 and pRb expression. A771726 decreased phosphorylation of protein kinase B (Akt), p70S6K, and eukaryotic translation initiation factor 4E-binding protein-1 as shown by Western blotting experiments. Furthermore, we show that the stimulatory effect of conditioned medium of HS-5 bone marrow stromal cells on multiple myeloma cell growth is completely abrogated by A771726. In addition, synergism studies revealed synergistic and additive activity of A771726 together with the genotoxic agents melphalan, treosulfan, and doxorubicin as well as with dexamethasone and bortezomib. Taken together, we show that inhibition of DHODH by A771726/leflunomide is effective in multiple myeloma. Considering the favorable toxicity profile and the great clinical experience with leflunomide in rheumatoid arthritis, this drug represents a potential new candidate for targeted therapy in multiple myeloma.
Baumann
Philipp
P
Department of Hematology and Oncology, Medizinische Klinik Innenstadt, Klinikum der Universität München, München, Germany. Philipp.Baumann@med.uni-muenchen.de
Mandl-Weber
Sonja
S
Völkl
Andreas
A
Adam
Christian
C
Bumeder
Irmgard
I
Oduncu
Fuat
F
Schmidmaier
Ralf
R
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003470:Culture Media; D000090722:Dihydroorotate Dehydrogenase; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D000077339:Leflunomide; D009101:Multiple Myeloma / Q000201:enzymology* / Q000473:pathology*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects; D014529:Uridine / Q000172:deficiency
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D003470:Culture Media; D000090722:Dihydroorotate Dehydrogenase; C087000:EIF4EBP1 protein, human; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018121:Receptors, Cytokine; D044925:Oxidoreductases Acting on CH-CH Group Donors; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D000077339:Leflunomide; D014529:Uridine