Case-specific potentiation of glioblastoma drugs by pterostilbene

// Linnéa Schmidt 1 , Sathishkumar Baskaran 1 , Patrik Johansson 1 , Narendra Padhan 1 , Damian Matuszewski 2 , Lydia C Green 3 , Ludmila Elfineh 1 , Shimei Wee 4 , Maria Häggblad 5 , Ulf Martens 5 , Bengt Westermark 1 , Karin Forsberg-Nilsson 1 , Lene Uhrbom 1 , Lena Claesson-Welsh 1 , Michael Andäng 4 , Ida-Maria Sintorn 2 , Bo Lundgren 5 , Ingrid Lönnstedt 1 , Cecilia Krona 1 , Sven Nelander 1 1 Life Laboratory, Uppsala University, Uppsala Sweden 2 Centre for Image Analysis, Department of Information Technology, Uppsala University, Uppsala, Sweden 3 Sahlgrenska Cancer Center, Institute of Medicine, Gothenburg, Sweden 4 Department of Physiology and Pharmacology, Karolinska Institute, Sweden 5 Cell Screening Facility, Science for Life Laboratory Stockholm, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden Correspondence to: Sven Nelander, email: sven.nelander@igp.uu.se Keywords: glioblastoma, glioblastoma initiating cells, stilbenoids, drug repurposing, cancer therapeutics Received: March 12, 2016 Accepted: September 16, 2016 Published: September 28, 2016 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.