Everolimus shows synergistic antimyeloma effects with bortezomib via the AKT/mTOR pathway

J Investig Med. 2019 Jan;67(1):39-47. doi: 10.1136/jim-2018-000780. Epub 2018 Jul 11.

Abstract

Multiple myeloma (MM) is characterized by the proliferation of malignant plasma cells and a subsequent overabundance of monoclonal paraproteins (M proteins). Everolimus works similarly to sirolimus as a mammalian target of rapamycin (mTOR) inhibitor. Bortezomib was the first therapeutic proteasome inhibitor to be tested in humans with MM. However, the combination of these two drugs for the treatment of MM has been rarely reported. In this study, we compared the therapeutic effects of everolimus and bortezomib, as well as those of a combination of everolimus and bortezomib, using an in vitro MM cell line model and in vivo xenograft mouse model. Our results showed that the synergistic antitumor effects of everolimus and bortezomib have significant inhibitory effect through inhibition of the AKT/mTOR pathway in both the MM cell lines and MM-bearing mice model. Our results provided evidence that the mTOR inhibitor, everolimus, will be a potential drug in MM therapy.

Keywords: cell cycle; cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects
  • Bortezomib / pharmacology
  • Bortezomib / therapeutic use*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Synergism
  • Everolimus / pharmacology
  • Everolimus / therapeutic use*
  • Mice, Nude
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / metabolism*
  • Multiple Myeloma / pathology
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction* / drug effects
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Bortezomib
  • Everolimus
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases