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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.
Anticancer Drugs. 2009 Apr; 20(4):259-66.AD

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+Show Affiliations

Department of Hematology and Oncology, Medizinische Klinik Innenstadt, Klinikum der Universität München, Germany. Philipp.Baumann@med.uni-muenchen.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19240643

Citation

Baumann, Philipp, et al. "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." Anti-cancer Drugs, vol. 20, no. 4, 2009, pp. 259-66.
Baumann P, Hagemeier H, Mandl-Weber S, et al. 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. Anticancer Drugs. 2009;20(4):259-66.
Baumann, P., Hagemeier, H., Mandl-Weber, S., Franke, D., & Schmidmaier, R. (2009). 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. Anti-cancer Drugs, 20(4), 259-66. https://doi.org/10.1097/CAD.0b013e328328d18b
Baumann P, et al. 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. Anticancer Drugs. 2009;20(4):259-66. PubMed PMID: 19240643.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Baumann,Philipp, AU - Hagemeier,Hilke, AU - Mandl-Weber,Sonja, AU - Franke,Daniel, AU - Schmidmaier,Ralf, PY - 2009/2/26/entrez PY - 2009/2/26/pubmed PY - 2009/5/16/medline SP - 259 EP - 66 JF - Anti-cancer drugs JO - Anticancer Drugs VL - 20 IS - 4 N2 - 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. SN - 1473-5741 UR - https://www.unboundmedicine.com/medline/citation/19240643/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_ L2 - https://doi.org/10.1097/CAD.0b013e328328d18b DB - PRIME DP - Unbound Medicine ER -