Case-specific potentiation of glioblastoma drugs by pterostilbene.
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.
Life Laboratory, Uppsala University, Uppsala Sweden.
Linnéa
L
Schmidt
Life Laboratory, Uppsala University, Uppsala Sweden.
Sathishkumar
S
Baskaran
Life Laboratory, Uppsala University, Uppsala Sweden.
Patrik
P
Johansson
Life Laboratory, Uppsala University, Uppsala Sweden.
Narendra
N
Padhan
Centre for Image Analysis, Department of Information Technology, Uppsala University, Uppsala, Sweden.
Damian
D
Matuszewski
Sahlgrenska Cancer Center, Institute of Medicine, Gothenburg, Sweden.
Lydia C
LC
Green
Life Laboratory, Uppsala University, Uppsala Sweden.
Ludmila
L
Elfineh
Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden.
Shimei
S
Wee
Cell Screening Facility, Science for Life Laboratory Stockholm, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden.
Maria
M
Häggblad
Cell Screening Facility, Science for Life Laboratory Stockholm, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden.
Ulf
U
Martens
Life Laboratory, Uppsala University, Uppsala Sweden.
Bengt
B
Westermark
Life Laboratory, Uppsala University, Uppsala Sweden.
Karin
K
Forsberg-Nilsson
Life Laboratory, Uppsala University, Uppsala Sweden.
Lene
L
Uhrbom
Life Laboratory, Uppsala University, Uppsala Sweden.
Lena
L
Claesson-Welsh
Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden.
Michael
M
Andäng
Centre for Image Analysis, Department of Information Technology, Uppsala University, Uppsala, Sweden.
Ida-Maria
IM
Sintorn
Cell Screening Facility, Science for Life Laboratory Stockholm, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden.
Bo
B
Lundgren
Life Laboratory, Uppsala University, Uppsala Sweden.
Ingrid
I
Lönnstedt
Life Laboratory, Uppsala University, Uppsala Sweden.
Cecilia
C
Krona
Life Laboratory, Uppsala University, Uppsala Sweden.
Sven
S
Nelander
D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056915:DNA Copy Number Variations; D004357:Drug Synergism; D005260:Female; D000077156:Gefitinib; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use; D059467:Transcriptome
D000972:Antineoplastic Agents, Phytogenic; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013267:Stilbenes; C107773:pterostilbene; D000077156:Gefitinib
cancer therapeutics; drug repurposing; glioblastoma; glioblastoma initiating cells; stilbenoids
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