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Neuro Oncol.2013 Nov;15(11):1469-78. doi: 10.1093/neuonc/not111. Epub 2013 Oct 6.

Comparative drug pair screening across multiple glioblastoma cell lines reveals novel drug-drug interactions.

Schmidt L1,Kling T, Monsefi N, Olsson M, Hansson C, Baskaran S, Lundgren B, Martens U, Häggblad M, Westermark B, Forsberg Nilsson K, Uhrbom L, Karlsson-Lindahl L, Gerlee P, Nelander S.

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BACKGROUND: Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults, and despite state-of-the-art treatment, survival remains poor and novel therapeutics are sorely needed. The aim of the present study was to identify new synergistic drug pairs for GBM. In addition, we aimed to explore differences in drug-drug interactions across multiple GBM-derived cell cultures and predict such differences by use of transcriptional biomarkers.

METHODS: We performed a screen in which we quantified drug-drug interactions for 465 drug pairs in each of the 5 GBM cell lines U87MG, U343MG, U373MG, A172, and T98G. Selected interactions were further tested using isobole-based analysis and validated in 5 glioma-initiating cell cultures. Furthermore, drug interactions were predicted using microarray-based transcriptional profiling in combination with statistical modeling.

RESULTS: Of the 5 × 465 drug pairs, we could define a subset of drug pairs with strong interaction in both standard cell lines and glioma-initiating cell cultures. In particular, a subset of pairs involving the pharmaceutical compounds rimcazole, sertraline, pterostilbene, and gefitinib showed a strong interaction in a majority of the cell cultures tested. Statistical modeling of microarray and interaction data using sparse canonical correlation analysis revealed several predictive biomarkers, which we propose could be of importance in regulating drug pair responses.

CONCLUSION: We identify novel candidate drug pairs for GBM and suggest possibilities to prospectively use transcriptional biomarkers to predict drug interactions in individual cases.

KEYWORDS: drug combination responses; glioblastoma stem cell cultures; glioblastoma therapy; predictive medicine

PMID: 24101737

J Nutr Biochem.2015 May;26(5):466-75. doi: 10.1016/j.jnutbio.2014.11.015. Epub 2015 Jan 19.

Pterostilbene suppressed irradiation-resistant glioma stem cells by modulating GRP78/miR-205 axis.

Huynh TT1,Lin CM2, Lee WH3, Wu AT4, Lin YK5, Lin YF6, Yeh CT7, Wang LS8.

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Glioblastoma multiforme (GBM) is the most aggressive type characterized by relapse and resistance even with the combination of radio- and chemotherapy. The presence of glioma stem cells (GSCs) has been shown to contribute to tumorigenesis, recurrence and treatment resistance. Particularly, CD133-positive glioma cells have been shown to represent the subpopulation that confers glioma radioresistance and suggested to be the source of tumor recurrence after radiation. Thus, a better understanding and the development of agents which target GSCs could potentially lead to a significant improvement in treating GBM patients. Here, we demonstrated that GRP78 (an antistress protein) was highly expressed in GBM cells along with β-catenin and Notch and correlated to the development of GSCs. CD133+ GSCs exhibited enhanced migration/invasion and self-renewal abilities. When GRP78 was silenced, GSC properties were suppressed and the sensitivity towards irradiation increased. In addition, the level of microRNA 205 appeared to be negatively associated with GRP78 expression. Our previous study indicated that pterostilbene(PT) possessed anticancer stem cell properties in hepatocellular carcinoma. Thus, we examined whether PT is also effective against GSCs. We found that PT-treated GSCs exhibited suppressed self-renewal and irradiation-resistant abilities. PT-mediated effects were associated with an increase of miR-205. Finally, we showed that PT treatment suppressed tumorigenesis in GSC xenograft mice. In conclusion, we provided evidence that GRP78/miR-205 axis played an important role in GSC maintenance and irradiation resistance. PT treatment suppressed GSC development via negatively modulating GRP78 signaling. PT may be considered for combined therapeutic agent to enhance irradiation efficacy in GBM patients.

Copyright © 2015 Elsevier Inc. All rights reserved.

KEYWORDS: CD133+ glioma stem cells; Glucose-regulated protein, 78 kDa (GRP78); Irradiation resistance; Pterostilbene; miR-205

PMID: 25736407

CancerRes.2016 Sep 1;76(17):4970-80. doi: 10.1158/0008-5472.CAN-15-3541. Epub 2016 Jun 30.

Activation of the c-Met Pathway Mobilizes an Inflammatory Network in the Brain Microenvironment to Promote Brain Metastasis of Breast Cancer.

Xing F1, Liu Y2, Sharma S2, Wu K2, Chan MD3, Lo HW2, Carpenter RL2, Metheny-Barlow LJ3, Zhou X4, Qasem SA5, Pasche B2, Watabe K1.

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Brain metastasis is one of the chief causes of mortality in breast cancer patients, but the mechanisms that drive this process remain poorly understood. Here, we report that brain metastatic cells expressing high levels of c-Met promote the metastatic process via inflammatory cytokine upregulation and vascular reprogramming. Activated c-Met signaling promoted adhesion of tumor cells to brain endothelial cells and enhanced neovascularization by inducing the secretion of IL8 and CXCL1. Additionally, stimulation of IL1β secretion by activation of c-Met induced tumor-associated astrocytes to secrete the c-Met ligand HGF. Thus, a feed-forward mechanism of cytokine release initiated and sustained by c-Met fed a vicious cycle that generated a favorable microenvironment for metastatic cells. Reinforcing our results, we found that pterostilbene, a compound that penetrates the blood-brain barrier, could suppress brain metastasis by targeting c-Met signaling. These findings suggest a potential utility of this natural compound for chemoprevention. Cancer Res; 76(17); 4970-80. ©2016 AACR.

©2016 American Association for Cancer Research.

PMID: 27364556

Oncotarget.2016 Nov 8;7(45):73200-73215. doi: 10.18632/oncotarget.12298.

Case-specific potentiation of glioblastoma drugs by pterostilbene.

Schmidt L1,Baskaran S1, Johansson P1, Padhan N1, Matuszewski D2, Green LC3, Elfineh L1, Wee S4, Häggblad M5, Martens U5, Westermark B1, Forsberg-Nilsson K1,Uhrbom L1, Claesson-Welsh L1,Andäng M4, Sintorn IM2, Lundgren B5, Lönnstedt I1, Krona C1, Nelander S1.

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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.

KEYWORDS: cancer therapeutics; drug repurposing; glioblastoma; glioblastoma initiating cells; stilbenoids

PMID: 27689322

Toxicol In Vitro.2017 Sep;43:69-75. doi: 10.1016/j.tiv.2017.06.004. Epub 2017 Jun 6.

The effect of resveratrol, its naturally occurring derivatives and tannic acid on the induction of cell cycle arrest and apoptosis in rat C6 and human T98G glioma cell lines.

Zielińska-Przyjemska M1,Kaczmarek M2, Krajka-Kuźniak V1,Łuczak M3, Baer-Dubowska W4.

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Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a potent chemopreventive and potentially cancer therapeutic agent. Since rapid metabolism limits resveratrol bioavailability, derivatives less prone to metabolic transformation are being sought and tested. We evaluated the effect of resveratrol, and its analogs (pterostilbene and 3,5,4′-trimethoxystilbene) along with tannic acid, on cell cycle and apoptosis in rat C6 and human T98G glioma cells. At concentration ranges both lower and higher than IC50calculated based on MTT assay, all these polyphenols affected the cell cycle distribution. However, resveratrol and pterostilbene increased the percentage of the cells in S phase, while trimethoxystilbene (TMS) caused a massive accumulation of cells at the G2/M phase of the cell cycle. Tannic acid had no effect on cell cycle distribution in C6 cells, but increased the number of dead cells in both glioma cell lines. The ability to induce apoptosis by tannic acid and stilbenes was confirmed by phosphatidylserine externalization, the loss of mitochondrial membrane potential and the level of cleaved caspase-3. The apoptosis rate was most significantly increased by TMS and this was related to p53 induction. These results indicate that methoxylated stilbenes are efficient inhibitors of glioma cell proliferation and apoptosis inducers and might be considered adjuvants in glioma therapy.

Copyright © 2017. Published by Elsevier Ltd.

KEYWORDS: Apoptosis; Cell cycle; Human T98G glioblastoma cells; Rat C6 glioma cells; Stilbene derivatives; Tannic acid

PMID: 28595835