Inhibitors of the PI3-kinase/Akt pathway induce mitotic catastrophe in non-small cell lung cancer cells

Int J Cancer. 2006 Sep 1;119(5):1028-38. doi: 10.1002/ijc.21927.


Non-small cell lung cancer cells (NSCLC) are more resistant to anticancer treatment as compared with other types of cancer cells. Recently (Hemström et al., Exp Cell Res 2005;305:200-13) we showed that apoptosis of U1810 NSCLC cells induced by the staurosporine analog PKC 412 correlated with inhibition of Akt and ERK1/2, suggesting the involvement of these kinases in cell survival. Here we investigated the contribution of the PI3-kinase/Akt and MEK/ERK pathways to survival of NSCLC cells. The two signaling pathways were studied by using different combinations of the PI3-kinase inhibitors LY-294002 and wortmannin, the Akt activator Ro 31-8220, the MEK inhibitor PD 98059 and PKC 412. PI3-kinase inhibitors induced apoptosis-like death in U1810 cells. H157 cells in general were relatively resistant to PI3 kinase/Akt inhibitors yet these compounds sensitized cells to the DNA-damaging drug VP-16, while Ro 31-8220 could not. PD 98059 only had a sensitizing effect on H157 cells when combined with PI3-kinase inhibition and VP-16. Morphological data indicated that LY-294002 and PKC 412 induced cell death at anaphase and metaphase, respectively, suggesting death by mitotic catastrophe. Analyzes of cells blocked in G2/M-phase by nocodazol revealed that LY-294002 increased, while PKC 412 decreased histone H3 phosphorylation, suggesting that LY-294002 allowed, while PKC 412 inhibited cells to leave M-phase. Flow cytometric analysis of cell cycle distribution demonstrated that LY-294002 allowed cells to leave G2/M phase, while PKC 412 inhibited cytokinesis, resulting in formation of multinucleated cells. These results indicate that sensitization of NSCLC cells by PI3-kinase inhibition involves interplay between cell cycle regulation, mitotic catastrophe and apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Cell Cycle / drug effects
  • Cell Survival / drug effects
  • Chromones / pharmacology
  • Enzyme Inhibitors / pharmacology*
  • Etoposide / pharmacology
  • Flavonoids / pharmacology
  • Flow Cytometry
  • Humans
  • Indoles / pharmacology
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism*
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Kinase Kinases / metabolism
  • Mitosis / drug effects*
  • Morpholines / pharmacology
  • Nocodazole / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Proto-Oncogene Proteins c-akt / drug effects*
  • Signal Transduction / drug effects
  • Staurosporine / analogs & derivatives
  • Staurosporine / pharmacology
  • Wortmannin


  • Androstadienes
  • Antineoplastic Agents
  • Chromones
  • Enzyme Inhibitors
  • Flavonoids
  • Indoles
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Etoposide
  • Proto-Oncogene Proteins c-akt
  • MAP Kinase Kinase Kinases
  • Staurosporine
  • midostaurin
  • Nocodazole
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • Ro 31-8220
  • Wortmannin