Inhibition of autophagy enhances apoptosis induced by the PI3K/AKT/mTor inhibitor NVP-BEZ235 in renal cell carcinoma cells

Cell Biochem Funct. 2013 Jul;31(5):427-33. doi: 10.1002/cbf.2917. Epub 2012 Oct 22.

Abstract

The PI3K/AKT/mTOR pathway plays a key role in the development of the hypervascular tumor renal cell carcinoma (RCC). NVP-BEZ235 (NVP), a novel dual PI3K/mTOR inhibitor, showed great antitumor benefit and provided a treatment strategy in RCC. In this study, we test the effect of NVP on survival rate, apoptosis and autophagy in the RCC cell line, 786-0. We also explore the hypothesis that NVP, in combination with autophagy inhibitors, leads to apoptosis enhancement in 786-0 cells. The results showed that the PI3K/AKT/mTOR pathway proteins p-AKT and p-P70S6K were highly expressed in RCC tissue. We also showed that NVP inhibited cell growth and induced apoptosis and autophagy in RCC cells. The combination treatment of NVP with autophagy inhibitors enhanced the effect of NVP on suppressing 786-0 growth and induction of apoptosis. This study proposes a novel treatment paradigm where combining PI3K/AKT/mTOR pathway inhibitors and autophagy inhibitors lead to enhanced RCC cell apoptosis.

Keywords: AKT; BEZ235; apoptosis; autophagy; renal cell carcinoma.

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Apoptosis / drug effects*
  • Autophagy / drug effects*
  • Carcinoma, Renal Cell / drug therapy
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • Chloroquine / pharmacology
  • Drug Synergism
  • Drug Therapy, Combination
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Imidazoles / pharmacology*
  • Kidney Neoplasms / drug therapy
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quinolines / pharmacology*
  • Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Imidazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Quinolines
  • 3-methyladenine
  • Chloroquine
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases
  • Adenine
  • dactolisib