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. doi: 10.1097/CAD.0b013e328328d18b.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Delivery Systems
  • Drug Synergism
  • Everolimus
  • Humans
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / pathology
  • Phosphorylation / drug effects
  • Protein Kinases / drug effects*
  • Protein Kinases / metabolism
  • Pyrimidines / administration & dosage
  • Pyrroles / administration & dosage
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Sirolimus / administration & dosage
  • Sirolimus / analogs & derivatives
  • TOR Serine-Threonine Kinases
  • Time Factors

Substances

  • NVP-AEW541
  • Pyrimidines
  • Pyrroles
  • Everolimus
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Receptor, IGF Type 1
  • Sirolimus