Abstract
Glioblastoma multiforme (GBM, astrocytoma grade IV) is the most common malignant primary brain tumor in adults. Addressing the shortage of effective treatment options for this cancer, we explored repurposing of existing drugs into combinations with potent activity against GBM cells. We report that the phytoalexin pterostilbene is a potentiator of two drugs with previously reported anti-GBM activity, the EGFR inhibitor gefitinib and the antidepressant sertraline. Combinations of either of these two compounds with pterostilbene suppress cell growth, viability, sphere formation and inhibit migration in tumor GBM cell (GC) cultures. The potentiating effect of pterostilbene was observed to a varying degree across a panel of 41 patient-derived GCs, and correlated in a case specific manner with the presence of missense mutation of EGFR and PIK3CA and a focal deletion of the chromosomal region 1p32. We identify pterostilbene-induced cell cycle arrest, synergistic inhibition of MAPK activity and induction of Thioredoxin interacting protein (TXNIP) as possible mechanisms behind pterostilbene's effect. Our results highlight a nontoxic stilbenoid compound as a modulator of anticancer drug response, and indicate that pterostilbene might be used to modulate two anticancer compounds in well-defined sets of GBM patients.
Highlights
The dismal outcome for glioblastoma (GBM) patients with current therapies [1] strongly motivates the exploration for new therapeutic approaches
We report that the phytoalexin pterostilbene is a potentiator of two drugs with previously reported anti-GBM activity, the EGFR inhibitor gefitinib and the antidepressant sertraline
We first investigated the effect of pterostilbene, gefitinib and sertraline (Supplementary Figure S1A) in a set of four glioblastoma cell (GC) cultures (U3017MG, U3037MG, U3047MG and U3065MG)
Summary
The dismal outcome for glioblastoma (GBM) patients with current therapies [1] strongly motivates the exploration for new therapeutic approaches. Amounting evidence suggests that GBM cells can be inhibited by synergistically acting pairs of compounds [2,3,4,5], such as tricyclic antidepressants together with inhibitors of the P2Y12 receptor family of purinergic G protein coupled receptors, or antidepressants with sigma receptor inhibitors [4, 6] Such repurposed combinations of approved drugs offer a faster route to clinical evaluation and it is a priority objective to determine which pathways are relevant for combinatorial targeting of GBM. Pterostilbene (trans-3, 5-dimethoxy-4′hydroxystilbene) is chemically classified as a stilbenoid and biologically as a phytoalexin (a class of low molecular weight compounds synthesized by plants as www.impactjournals.com/oncotarget part of their antimicrobial defense) It is considered a safe compound with no reported toxicities, and is found naturally in berries [8,9,10,11,12,13]. Pterostilbene is relevant for glioma treatment due to its high bioavailability and its ability to pass the blood brain barrier [8, 11]
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