Temozolomide-induced autophagy enhances Glioblastoma Multiforme cell death in combination with inhibitors of the PI3K/AKT pathway

Patients diagnosed with GBM, a highly migratory, heterogeneous, rapidly growing primary adult brain tumor are faced with a dismal prognosis. Recent research has shed light on cell-survival pathways that are induced after the DNA-damage response induced by TMZ. Autophagy, a major catabolic process meant to degrade damaged organelles and large misfolded proteins, has recently been shown to be activated by TMZ. However, a precise mechanism has not yet been determined. T98G cells treated with TMZ showed significant induction of unfolded protein response (UPR) markers such as GRP78, and LC3-II expression, indicating increased autophagosome formation. Additional experiments have used the autophagic inhibitor Bafilomycin A1 (Baf) to determine that autophagic flux is induced, supporting the conclusion that UPR induction by TMZ induces autophagy. Combination treatments with PI3K inhibitors PX-866 and BEZ235 with Baf as a means to shut down two critical mechanisms of GBM cell survival were explored in this research. PX-866 was found to inhibit autophagy, while BEZ235, was found to induce autophagy. The differential modulation of autophagy by these PI3K inhibitors offers new knowledge for utilizing more effective drug combinations to treat GBM and improve patient survival.