Fluoxetine enhances the antitumor effect of olfactory ensheathing cell‐thymidine kinase/ganciclovir gene therapy in human glioblastoma multiforme cells through upregulation of Connexin43 levels

Fluoxetine enhances the antitumor effect of olfactory ensheathing cell‐thymidine kinase/ganciclovir gene therapy in human glioblastoma multiforme cells through upregulation of Connexin43 levels

Glioblastoma multiforme (GBM) is the most invasive form of primary brain astrocytoma, resulting in poor clinical outcomes. Herpes simplex virus thymidine kinase/ganciclovir (HSV‐TK/GCV) gene therapy is considered a promising strategy for GBM treatment. Since Connexin43 (Cx43) expression is reduced i...

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Published in:Drug development research Vol. 84; no. 8; pp. 1739 - 1750
Main Authors: Hosseindoost, Saereh, Dehpour, Ahmad R., Dehghan, Samaneh, Javadi, Seyed A. H., Arjmand, Babak, Fallah, Ali, Hadjighassem, Mahmoudreza
Format: Journal Article
Language:English
Published: United States Wiley Subscription Services, Inc 01-12-2023
Subjects:
Anticancer properties
Antitumor activity
Apoptosis
Astrocytes
Astrocytoma
BAX protein
Bcl-2 protein
Caspase
Connexin 43
Connexin43
Flow cytometry
Fluoxetine
Ganciclovir
Gene therapy
Glioblastoma
glioblastoma multiforme
Herpes simplex
Kinases
Olfactory ensheathing cells
Thymidine
Thymidine kinase
Viruses
glioblastoma multiforme
gene therapy
Connexin43
fluoxetine
olfactory ensheathing cells
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Summary:Glioblastoma multiforme (GBM) is the most invasive form of primary brain astrocytoma, resulting in poor clinical outcomes. Herpes simplex virus thymidine kinase/ganciclovir (HSV‐TK/GCV) gene therapy is considered a promising strategy for GBM treatment. Since Connexin43 (Cx43) expression is reduced in GBM cells, increasing Cx43 levels could enhance the effectiveness of gene therapy. The present study aims to examine the impact of fluoxetine on HSV‐TK/GCV gene therapy in human GBM cells using human olfactory ensheathing cells (OECs) as vectors. The effect of fluoxetine on Cx43 levels was assessed using the western blot technique. GBM‐derived astrocytes and OECs‐TK were Cocultured, and the effect of fluoxetine on the Antitumor effect of OEC‐TK/GCV gene therapy was evaluated using MTT assay and flow cytometry. Our results showed that fluoxetine increased Cx43 levels in OECs and GBM cells and augmented the killing effect of OECs‐TK on GBM cells. Western blot data revealed that fluoxetine enhanced the Bax/Bcl2 ratio and the levels of cleaved caspase‐3 in the coculture of OECs‐TK and GBM cells. Moreover, flow cytometry data indicated that fluoxetine increased the percentage of apoptotic cells in the coculture system. This study suggests that fluoxetine, by upregulating Cx43 levels, could strengthen the Antitumor effect of OEC‐TK/GCV gene therapy on GBM cells.
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ISSN:0272-4391
1098-2299
DOI:10.1002/ddr.22119