The combination of Endostatin (ES) and Herpes Simplex Virus thymidine kinase (HSV‐TK) gene therapy is known to have antitumor activity in bladder cancer. The potential effect of ES and TK therapy in glioma has not yet been investigated. In this study, pTK‐internal ribosome entry site (IRES), pIRES‐ES, and pTK‐IRES‐ES plasmids were constructed; pIRES empty vector served as the negative control. The recombinant constructs were transfected into human umbilical vein endothelial cells (HUVECs) ECV304 and C6 rat glioma cell line. Ganciclovir (GCV) was used to induce cell death in transfected C6 cells. We found that ECV304 cells expressing either ES or TK‐ES showed reduced proliferation, decreased migration capacity, and increased apoptosis, as compared to untransfected cells or controls. pTK‐IRES‐ES/GCV or pTK‐IRES/GCV significantly suppressed cell proliferation and induced cell apoptosis in C6 cells, as compared to the control. In addition, the administration of pIRES‐ES, pTK‐IRES/GCV, or pTK‐IRES‐ES/GCV therapy improved animal activity and behavior; was associated with prolonged animal survival, and a lower microvessel density (MVD) value in tumor tissues of C6 glioma rats. In comparison to others, dual gene therapy in form of pTK‐IRES‐ES/GCV had a significant antitumor activity against C6 glioma. These findings indicate combined TK and ES gene therapy was associated with a superior antitumor efficacy as compared to single gene therapy in C6 glioma.
Overexpression of leukemia/lymphoma-related factor (LRF), which is an erythroid myeloid ontogenic factor protein, occurs in different cancers, including glioma. LRF is also reported to have an oncogenic activity in various human cancers. This study investigated the effect of LRF knockdown on the regulation of glioma growth. LRF short hairpin RNA (shRNA) suppressed the expression of LRF protein in a glioma cell line (GL261-EGFP) compared to the negative control vector-transfected glioma cells. LRF knockdown also reduced glioma cell viability and enhanced cisplatin-induced apoptosis in glioma cells. AKT activation and the expression of various cell cycle-related genes were inhibited following LRF knockdown. The effect on growth and migration is related to dose response results of AKT and nuclear factor-kappa B (NF-κB) inhibitors. These data demonstrate that LRF may play a role in glioma progression, suggesting that inhibition of LRF expression using LRF shRNA should be further evaluated as a novel target for the control of glioma.
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