Combination of an allosteric AKT inhibitor MK-2206 with etoposide or rapamycin enhances the antitumor growth effect in neuroblastoma
Clinical Cancer Research, 06/01/2012
Li Z et al. – Akt inhibition by MK-2206 increased the efficacy of etoposide or rapamycin.Methods
- The anticell proliferation effect of MK-2206 was tested in eight neuroblastoma cell lines by MTS assay.
- Caspase-3/7 activity, cell-cycle analysis, and reactive oxygen species (ROS) production were determined.
- Effect of MK-2206 combined with etoposide or rapamycin was evaluated in vitro and in vivo.
- Akt phosphorylation was measured by Western blotting in neuroblastoma cells and tumors.
- In vitro, MK-2206 treatment inhibited neuroblastoma cell proliferation, which was accompanied by a cell line selective G1 arrest of cell cycle or production of ROS.
- A synergistic effect between MK-2206 and etoposide was detected in four tested neuroblastoma cell lines via caspase-dependent apoptosis, whereas increased inhibition of cell growth induced by combination of MK-2206 and rapamycin was mediated by ROS production.
- In vivo, MK-2206 alone decreased tumor growth and increased murine survival at dose that inhibited Akt phosphorylation in tumors.
- MK-2206, in combination with etoposide or rapamycin, caused a significant decrease in tumor growth and increase of murine survival compared with MK-2206 alone.