Case-specific potentiation of glioblastoma drugs by pterostilbene
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Linnéa Schmidt1, Sathishkumar Baskaran1, Patrik Johansson1, Narendra Padhan1, Damian Matuszewski2, Lydia C Green3, Ludmila Elfineh1, Shimei Wee4, Maria Häggblad5, Ulf Martens5, Bengt Westermark1, Karin Forsberg-Nilsson1, Lene Uhrbom1, Lena Claesson-Welsh1, Michael Andäng4, Ida-Maria Sintorn2, Bo Lundgren5, Ingrid Lönnstedt1, Cecilia Krona1, Sven Nelander1
1Life Laboratory, Uppsala University, Uppsala Sweden
2Centre for Image Analysis, Department of Information Technology, Uppsala University, Uppsala, Sweden
3Sahlgrenska Cancer Center, Institute of Medicine, Gothenburg, Sweden
4Department of Physiology and Pharmacology, Karolinska Institute, Sweden
5Cell Screening Facility, Science for Life Laboratory Stockholm, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden
Sven Nelander, email: [email protected]
Keywords: glioblastoma, glioblastoma initiating cells, stilbenoids, drug repurposing, cancer therapeutics
Received: March 12, 2016 Accepted: September 16, 2016 Published: September 28, 2016
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.
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