f rmiges pattern. Autophagy glicht erm L Between the cell and recycle proteins and organelles, to support the metabolism and can be detected in part by the formation of LC3 II punctae. The inhibition of autophagy f F Promotes death of cancer cells survive and potentiates various cancer treatments with autophagy as a mechanism for tumor cells antineoplastics. MPC-3100 Chloroquine inhibits autophagy glioma cells and malaria tested as an antineoplastic agent in a small clinical study. Hydroxychloroquine related molecule is subject to a phase II and a much discussed option for patients who can not be treated even K for the treatment of glioma. Although chloroquine advise on the use of glioma s is not on the basis of their R Necessary ability, F, autophagic degradation of this compound, such as hydroxychloroquine, lysosomal function blocks Justified for the final stages of autophagy. Here we have shown that dual inhibitors of PI3K and mTOR in autophagy signaling via gliomas, and inhibition of two different protein complexes of mTOR, mTOR complex 1 and 2 induces a complex of mTOR autophagy fa An additive. Since mTORC1 rapamycin induces autophagy allosteric inhibitor, we were surprised that. No inhibition of autophagosome maturation in the presence of rapamycin f Rdern apoptosis In contrast, apoptosis was induced normal only if rapamycin with inhibitors of PI3K and autophagosome maturation.
To understand why the blockade of PI3K itself induce apoptosis at all, but it was necessary for the induction of apoptosis by the combination of rapamycin and inhibitors of the maturation autophagosome, we examined the F Ability of F rapamycin induces autophagy and simultaneously activate real We found that rapamycin induces both autophagy and Akt phosphorylation as a distinct survival signals. The combination of rapamycin with PI3K inhibitors blocked autophagy, or one of them, so that the cells survive. In contrast, the combination of rapamycin AT7867 with inhibitors of PI3K and autophagy Bl Press the signals of survival and apoptosis. In addition, we have shown that NVP BEZ235, which inhibits both PI3K and mTOR signaling and is currently in Phase II clinical trials in solid tumors, I worked with chloroquine. Apoptosis in glioma promotion Since F PI3K inhibitors, mTOR and autophagosome maturation in clinical trials or clinical use of this combination of drugs is a promising approach, and the results for the treatment of cancer. RESULTS a dual inhibitor of PI3K and mTOR induces the formation of glioma cells autophagosome We found that PI 103, a small molecule that induces measured as a direct inhibitor of PI3K and mTOR two acts, the formation of autophagosome broken, fluorescent GFP protein LC3 wild-type PTEN-and PTEN-deficient glioma cell lines. The immunoblot analysis showed that PI-induced 103 by the reaction of II LC3 LC3 depende I in a dose