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
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Baumann, Philipp, Hagemeier, Hilke, Mandl-Weber, Sonja, Franke, Daniel and Schmidmaier, Ralf (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). pp. 259-266. ISSN 0959-4973
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.
| Item Type: | Article |
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| Additional Information: | Author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used |
| Keywords: | Akt; mammalian target of rapamycin; multiple myeloma; NVP-AEW541; phosphatidylinositol 3 kinase; Rad001 |
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| Date Deposited: | 13 Oct 2015 13:16 |
| Last Modified: | 13 Oct 2015 13:16 |
| URI: | https://oak.novartis.com/id/eprint/2547 |