Dual PI3K/Akt/mTOR Pathway Inhibitor Potentiate Cytarabine Cytotoxicity For Acute Myeloid Leukemia

Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signal transduction pathway integrating signals from multiple receptor tyrosine kinases has been firmly established as a major determinant for cell growth, proliferation, and survival in a wide array of solid cancers. PI3K/Akt/mTOR pathway is frequently activated in acute myeloid leukemia (AML) cells and contributes to survival and drug-resistance of AML through various mechanisms. BEZ235 is one of the most promising dual inhibitor of PI3K and mTOR currently under clinical development in solid tumor area. In this study, the potential of BEZ235 was investigated as antileukemic agent using alone or with cytarabinearabinoside (AraC) as combination regimen.

AML cell lines KG-1, MV 4-11, THP-1 and HL60 were treated with AraC, BEZ235 and combination regimen with various mixed ratio. BEZ235 effectively inhibited leukemic cell growth with similar range of half maximal inhibitory concentration (IC50) values among different cell lines. Apoptosis was induced gradually as BEZ235 concentration increased, but significant level of apoptosis was not shown even at higher concentration beyond IC50 value. Then, AraC-resistant MV4-11 and THP-1 cell lines were chosen to investigate interaction between BEZ235 and AraC. Using CalcuSyn software based on Chou and Talalay analysis, Combination Index (CI) value was calculated in each combination regimen. Moderate to strong synergism was shown and it was well maintained as combination ratio of AraC versus BEZ235 gradually decreased from 20:1 to 1,000:1. BEZ235 reduced resistance to AraC when it was added as combination regimen, and significance of combination effect changed according to AraC concentration. When antileukemic effect was compared among combination regimens with different schedules, synergism was maximized when BEZ235 was pretreated before AraC administration. This means BEZ235 sensitizes leukemic cells to apoptotic effect of AraC.

Genetic alteration in PI3K/Akt/mTOR pathway is an attractive target to investigate and dual pathway inhibitor BEZ235 has potential to maximize AML treatment through sensitization of leukemic cells to conventional drug. The results of this experiment suggest the possibility of designing early clinical trials for the therapy - AraC administration after dual inhibitor BEZ administration. An effective control of a signal transmission system using innovate new drugs along with an accurate understanding of a signal transmission system which is the target of therapy will establish a foothold for the development of AML therapy.