The Quinoline Imidoselenocarbamate EI201 Blocks the AKT/mTOR Pathway and Targets Cancer Stem Cells Leading to a Strong Antitumor Activity

E.      Ibanez; A.      Agliano; C.      Prior; P.      Nguewa; M.      Redrado; I.      Gonzalez-Zubeldia; D.      Plano; J.      A. Palop; C.      Sanmartin; A.      Calvo

Abstract

Methylimidoselenocarbamates have previously proven to display potent antitumor activities. In the present study we show that these compounds act as multikinase inhibitors. We found that the most effective compound, quinoline imidoselenocarbamate EI201, inhibits the PI3K/AKT/mTOR pathway, which is persistently activated and contributes to malignant progression in various cancers. EI201 blocked the phosphorylation of AKT, mTOR and several of its downstream regulators (p70S6K and 4E-BP1) and ERK1/2 in PC-3, HT-29 and MCF-7 cells in vitro, inducing both autophagy and apoptosis. EI201 also contributes to the loss of maintenance of the selfrenewal and tumorigenic capacity of cancer stem cells (CSCs). 0.1 μmol/L EI201 triggered a reduction in size and number of tumorspheres in PC-3, HT-29 and MCF-7 cells and 4 μmol/L induced the elimination of almost all the tumorspheres in the three studied cell lines. In addition, EI201 suppressed almost 80% prostate tumor growth in vivo (p < 0.01) compared to controls at a relatively low dose (10 mg/kg) in a mouse xenograft model. There was a significant decrease in the subcutaneous primary tumor [18F]-FDG uptake (76.5% reduction, p < 0.05) and in the total tumor burden (76.8% reduction, p < 0.05) after EI201 treatment compared to vehicle control, without causing toxicity in mice. Taken together, our results support further development of EI201 as a novel multi-kinase inhibitor that may be useful against cancers with aberrant upregulation of PI3K/AKT and MAPK signaling pathways.

Keywords: AKT, angiogenesis, antitumor, autophagy, cancer stem cells, ERK1/2, HIF-1α, imidoselenocarbamate, microPET, mTOR, selenium