title: Myeloma cell growth inhibition is augmented by synchronous inhibition of the insulin-like growth factor-1 receptor by NVP-AEW541 and inhibition of mammalian target of rapamycin by Rad001.
abstract: Multiple myeloma is still incurable. Myeloma cells become resistant to common drugs and patients eventually die of tumour progression. Therefore, new targets and drugs are needed immediately. NVP-AEW541 is a new, orally bioavailable small molecule inhibitor of the insulin-like growth factor-1 receptor (IGF-1R). Here, we show that NVP-AEW541 inhibits cell growth in myeloma cells at low concentrations in a time-dependent and a dose-dependent manner. Further experiments using the annexin-V-fluorescein isothiocyanate/propidium iodide assay revealed induction of apoptosis in common myeloma cell lines, but not in peripheral blood mononuclear cell from healthy donors. Stimulation of myeloma cells with IGF-1 led to a vast increase of cell growth and this was blocked by low doses of NVP-AEW541. Stimulation of myeloma cells with conditioned medium obtained from a 48-h-old HS-5 stromal cell culture was only partly blocked by NVP-AEW541. Western blotting experiments revealed that NVP-AEW541 decreased the phosphorylation status of P70S6 kinase and 4E-BP-1 but not of mammalian target of rapamycin (mTOR). Combined inhibition of IGF-1R and mTOR using the novel mTOR inhibitor Rad001 led to additive/synergistic increase of cell growth inhibition in multiple myeloma cells, which was accompanied by a stronger dephosphorylation of P70S6 kinase and 4E-BP-1. Taken together, we show that the combined inhibition of IGF-1R and mTOR by combining NVP-AEW541 and Rad001 is highly effective in multiple myeloma and might represent a potential new treatment strategy.
authors.affiliation: Department of Hematology and Oncology, Medizinische Klinik Innenstadt, Klinikum der Universität München, Germany. Philipp.Baumann@med.uni-muenchen.de
authors.forename: Philipp
authors.initials: P
authors.lastname: Baumann
authors.forename: Hilke
authors.initials: H
authors.lastname: Hagemeier
authors.forename: Sonja
authors.initials: S
authors.lastname: Mandl-Weber
authors.forename: Daniel
authors.initials: D
authors.lastname: Franke
authors.forename: Ralf
authors.initials: R
authors.lastname: Schmidmaier
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004357:Drug Synergism; D000068338:Everolimus; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors
chemical_list: C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus