Abstract
Hypoxia is a key driver of tumor adaptation promoting tumor progression and resistance to therapy. Hypoxia related pathways might represent attractive targets for the treatment of Glioblastoma Multiforme (GBM), that up to date is characterized by a poor prognosis. Primary aim of this study was to investigate the role of hypoxia and hypoxia-related modifications in the effect of temozolomide (TMZ) given alone or in association with the antidiabetic agent Metformin (MET) or the PI3K/mTOR blocker, BEZ235. The study was conducted in the TMZ responsive U251 and resistant T98 GBM cells. Our results showed that during hypoxia, TMZ plus MET reduced viability of U251 cells affecting also CD133 and CD90 expressing cells. This effect was associated with a reduction of HIF-1α activity, VEGF release and AKT activation. In T98 TMZ-resistant cells, TMZ plus MET exerted similar effects on HIF-1α. However, in this cell line, TMZ plus MET failed to reduce CD133 positive cells and AKT phosphorylation. Nevertheless, the administration of the dual PI3K/mTOR inhibitor BEZ235 potentiated the effect of TMZ plus MET on cell viability, inducing a pro-apoptotic phenotype during hypoxic condition also in T98 cells, suggesting the block of the PI3K/AKT/mTOR pathway as a complementary target to further overcome GBM resistance during hypoxia. In conclusion, we proposed TMZ plus MET as suitable treatment to revert TMZ-resistance also during hypoxia, an effect potentiated by the inhibition of PI3K/mTOR axis.
Highlights
In Glioblastoma Multiforme (GBM), the “international gold standard” therapy includes surgery, radiotherapy, and chemotherapy with Temozolomide (TMZ) [1], but the prognosis remains poor
In this study we initially investigated the role of hypoxia and hypoxia-related modifications on the effect of Temozolomide given alone or in association with drug targeting cell metabolism such as Metformin
First we investigated the effect of MET as a TMZadjuvant agent in hypoxia in GBM cell lines
Summary
In Glioblastoma Multiforme (GBM), the “international gold standard” therapy includes surgery, radiotherapy, and chemotherapy with Temozolomide (TMZ) [1], but the prognosis remains poor. The glycolytic switch and hypoxia-induced factors influence tumor progression and resistance to therapy [2, 3]. Hypoxia and hypoxia-related factors are associated with pseudopalisading necrotic regions that protect stem cells niche, contributing to the aggressive profile of these tumors [3, 4]. Hypoxia effect on tumor malignancy involves hypoxia-inducible factors [5], stem population [6], negative modulation of apoptotic axis [7] and molecular pathways related to regulation of cell metabolism including PI3K/AKT/mTOR pathway [8]. Metformin and AKT Role in Hypoxia TMZ-Resistance. Metformin (MET), a modulator of cell metabolism acting on 5′ adenosine monophosphate-activated protein kinase (AMPK) and mitochondrial respiration, potentiates the activity of TMZ in glioblastoma models [9, 10]. Despite the various hypothesis suggested including ours [11,12,13], the precise mechanism of action of MET remains elusive regarding its activity under hypoxic condition
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