Investigating Programmed Cell Death and Tumor Invasion in a Three-Dimensional (3D) Microfluidic Model of Glioblastoma

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dc.contributor.author Samiei, Ehsan
dc.contributor.author Seyfoori, Amir
dc.contributor.author Toyota, Brian
dc.contributor.author Ghavami, Saeid
dc.contributor.author Akbari, Mohsen
dc.date.accessioned 2020-07-06T17:04:46Z
dc.date.available 2020-07-06T17:04:46Z
dc.date.copyright 2020 en_US
dc.date.issued 2020
dc.identifier.citation Samiei, E., Seyfoori, A., Toyota, B., Ghavami, S., & Akbari, M. (2020). Investigating programmed cell death and tumor invasion in a three-dimensional (3D) microfluidic model of glioblastoma. International Journal of Molecular Sciences, 21(9). https://doi.org/10.3390/ijms21093162 en_US
dc.identifier.uri https://doi.org/10.3390/ijms21093162
dc.identifier.uri http://hdl.handle.net/1828/11902
dc.description.abstract Glioblastoma multiforme (GBM) is a rapidly progressive and deadly form of brain tumor with a median survival rate of ~15 months. GBMs are hard to treat and significantly affect the patient’s physical and cognitive abilities and quality of life. Temozolomide (TMZ)—an alkylating agent that causes DNA damage—is the only chemotherapy choice for the treatment of GBM. However, TMZ also induces autophagy and causes tumor cell resistance and thus fails to improve the survival rate among patients. Here, we studied the drug-induced programmed cell death and invasion inhibition capacity of TMZ and a mevalonate cascade inhibitor, simvastatin (Simva), in a three-dimensional (3D) microfluidic model of GBM. We elucidate the role of autophagy in apoptotic cell death by comparing apoptosis in autophagy knockdown cells (Atg7 KD) against their scrambled counterparts. Our results show that the cells were significantly less sensitive to drugs in the 3D model as compared to monolayer culture systems. An immunofluorescence analysis confirmed that apoptosis is the mechanism of cell death in TMZ- and Simva-treated glioma cells. However, the induction of apoptosis in the 3D model is significantly lower than in monolayer cultures. We have also shown that autophagy inhibition (Atg7 KD) did not change TMZ and Simva-induced apoptosis in the 3D microfluidic model. Overall, for the first time in this study we have established the simultaneous detection of drug induced apoptosis and autophagy in a 3D microfluidic model of GBM. Our study presents a potential ex vivo platform for developing novel therapeutic strategies tailored toward disrupting key molecular pathways involved in programmed cell death and tumor invasion in glioblastoma. en_US
dc.description.sponsorship Funding: This research was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC), grant number RGPIN-2016-04024, the BC Cancer Foundation, the Research Manitoba New Investigator Operating Grant, grant number 43873 and the National Institute for Medical Research Development of Iran (NIMAD) operating grant, grant number 943267. Acknowledgments: Authors would like to acknowledge the support of the Canadian Foundation for Innovation (CFI) and the B.C. Knowledge Development Fund (BCKDF) for supporting the equipment used in this research by providing funding to M.A. They also appreciate the support from the Centre for Advanced Materials and Related Technology (CAMTEC) at the University of Victoria for providing imaging facility. en_US
dc.language.iso en en_US
dc.publisher International Journal of Molecular Sciences en_US
dc.subject tumor on a chip en_US
dc.subject blioblastoma en_US
dc.subject apoptosis en_US
dc.subject autophagy en_US
dc.subject cell phenotype en_US
dc.subject invasion en_US
dc.title Investigating Programmed Cell Death and Tumor Invasion in a Three-Dimensional (3D) Microfluidic Model of Glioblastoma en_US
dc.type Article en_US
dc.description.scholarlevel Faculty en_US
dc.description.reviewstatus Reviewed en_US

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