PDK1 inhibitor GSK2334470 synergizes with proteasome inhibitor MG‑132 in multiple myeloma cells by inhibiting full AKT activity and increasing nuclear accumulation of the PTEN protein

Oncol Rep. 2018 Jun;39(6):2951-2959. doi: 10.3892/or.2018.6369. Epub 2018 Apr 12.


Phosphoinositide‑dependent kinase 1 (PDK1) is generally active in multiple myeloma (MM) and higher expression than other hematopoietic cells, which is associated with the drug resistance and the disease progression. Previous studies have demonstrated that PDK1 can be targeted therapeutically in MM. In the present study, we examined the combination effect of GSK2334470 (GSK‑470), a novel and highly specific inhibitor of PDK1, with proteasome inhibitor MG‑132 in MM cell lines. GSK‑470 monotherapy significantly inhibited growth of MM cell lines and induced apoptosis that was associated with the activation of both the intrinsic mitochondrial pathway and the extrinsic death receptor pathway. Moreover, GSK‑470 demonstrated synergistic growth inhibitory effects with MG‑132. Notably, treatment with these inhibitors resulted in an almost complete inhibition of phosphorylation of mammalian target of rapamycin on Ser2448 and Ser2481 and full activation of AKT. The combination therapy also caused an upregulation of PTEN and an increased nuclear accumulation of PTEN protein. Collectively, our results provide the rationale for novel combination treatment with PDK1 inhibitor and proteasome inhibitors to improve outcomes in patients with MM.

MeSH terms

  • Cell Line, Tumor
  • Cell Nucleus / metabolism*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Indazoles / pharmacology*
  • Leupeptins / pharmacology*
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / metabolism*
  • PTEN Phosphohydrolase / metabolism*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pyrimidines / pharmacology*
  • TOR Serine-Threonine Kinases / metabolism


  • GSK 2334470
  • Indazoles
  • Leupeptins
  • Pyrimidines
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde