Case-specific potentiation of glioblastoma drugs by pterostilbene

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.

Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages

“… 4 In brain tumor research, these primary GC cultures have emerged as a standard model to study drug sensitivity and identify new molecular targets. 5 , 27–30 Considerable effort has been invested in supporting the representivity of primary GC cultures and comparing cell cultures isolated from the same tumor. 2–4 By comparison, we have relatively little information on the temporal evolution of GC cultures.…”

“… 2 Compared with traditional tissue culture models, GC cultures retain cells transcriptionally similar to the tumor of origin, and retain properties important for the study of tumor regeneration. 3 One promising application of GCs is based on their potential to facilitate functional studies on cells across a population of patients 4 , 5 (eg, to determine biomarkers of drug response). For such studies to be efficient, however, it is necessary to consider the stability of the GC cultures, and the possible impact of time-dependent fluctuations in clonal substructure.…”

Pterostilbene Attenuates Astrocytic Inflammation and Neuronal Oxidative Injury After Ischemia-Reperfusion by Inhibiting NF-κB Phosphorylation

“…In a previous study, we explored the benefits of PTE in attenuating inflammation and oxidative injury following subarachnoid hemorrhage and reducing mitochondrial oxidative stress after cerebral IR (11, 12). Other studies have also demonstrated the potent neuromodulatory effect of PTE on aging, Alzheimer's disease, and glioblastoma (13, 14). However, the role of PTE in modulating astrocyte-mediated inflammatory injury following cerebral IR has not been previously investigated.…”

A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma

“…After 72h incubation alamarBlueâ cell viability reagent (Thermo Fisher Scientific) was added and fluorescent readout made by Wallac 1420 Victor2 (Perkin Elmer). The resulting viability data was used to compute Combination Index scores as previously described (Schmidt et al, 2016). For further validation in a 3D tumor model over an extended time period, combinations of bortezomib with navitoclax or milciclib were selected for treatment of one bortezomib sensitive and one bortezomib resistant cell culture over 10 days.…”