title: Simultaneous targeting of PI3K and mTOR with NVP-BGT226 is highly effective in multiple myeloma.
abstract: Multiple myeloma is still uncurable. Myeloma cells become resistant to common drugs and patients eventually die of tumour progression. Therefore, new targets and drugs are urgently needed. NVP-BGT226 is a novel, orally bioavailable small-molecule inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin. Here, we show that NVP-BGT226 inhibits growth in common myeloma cell lines and primary myeloma cells at nanomolar concentrations in a time-dependent and dose-dependent manner. Western blots for the detection of caspase 3 cleavage and annexin-V-fluorescein isothiocyanate/propidium iodide assays revealed induction of apoptosis in common myeloma cells lines. Induction of apoptosis was accompanied by upregulation of proapoptotic Bim and a moderate upregulation of Mcl-1 and Bad and a downregulation of Bcl-2, Bax and Bcl-Xl. Inhibition of cell growth was mainly due to inhibition of myeloma cell proliferation, as shown by the 5-bromo-2'-deoxyuridine assay. Cell cycle analysis revealed induction of cell cycle arrest in the G1 phase, which was due to downregulation of cyclin D1, cyclin D2, pRb and cdc25a. NVP-BGT226 inhibited phosphorylation of protein kinase B (Akt), P70S6k and 4E-BP-1 in a time-dependent and dose-dependent manner. Furthermore, we show that the stimulatory effect of insulin-like growth factor 1, interleukin-6 and conditioned medium of HS-5 stromal cells on myeloma cell growth is completely abrogated by NVP-BGT226. Overall, inhibition of phosphoinositol-3-kinase/mammalian target of rapamycin by NVP-BGT226 is highly effective, and NVP-BGT226 represents a potential new candidate for targeted therapy in multiple myeloma.
authors.affiliation: Abteilung Hämatologie und Onkologie, Medizinische Klinik, Campus Innenstadt, Klinikum der Universität München, München, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Baumann
authors.forename: Laura
authors.initials: L
authors.lastname: Schneider
authors.forename: Sonja
authors.initials: S
authors.lastname: Mandl-Weber
authors.forename: Fuat
authors.initials: F
authors.lastname: Oduncu
authors.forename: Ralf
authors.initials: R
authors.lastname: Schmidmaier
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003470:Culture Media / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000737:chemistry; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C570852:8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo(4,5-c)quinolin-2-one; D000970:Antineoplastic Agents; D003470:Culture Media; D007093:Imidazoles; D015850:Interleukin-6; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D007334:Insulin-Like Growth Factor I; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases