Antitumor effect of IL-12 gene-modified bone marrow mesenchymal stem cells combined with Fuzheng Yiliu decoction in an in vivo glioma nude mouse model

Abstract

Background Glioma is a complex cancer with a high morbidity and high mortality. Bone marrow mesenchymal stem cells (BMSCs) have shown promise as an excellent cell/drug delivery vehicle for gene-targeted therapy; however, maintaining genetic stability and biological activity remains difficult. Furthermore, whether BMSCs support or inhibit tumor growth remains debated. This study investigated whether a traditional Chinese medicine fomular, Fuzheng Yiliu decoction (FYD) had a synergistic antitumor effect with IL-12 gene-modified BMSCs in glioma-bearing nude mice Methods The lentivirus-mediated IL-12 gene was transfected into primarily cultured BMSCs. A total of 72 BALB/c nude mice were used to establish xenograft models with glioma U251 cells and were divided into groups (n = 12) including blank control group, nude mouse model group (model group), lentiviral transfection of BMSC group with no gene loading (BMSC group), IL-12 lentivirus-transfected BMSC group (IL-12 + BMSC group), FYD treatment group (FYD group), and FYD treatment in IL-12 lentivirus-transfected BMSC group (FYD + IL-12 + BMSC group).. After treatment for 14 days, all mice were sacrificed to collect tumor tissue and serum for more detection, such as distribution of BMSCs, cell apoptosis in xenograft tumors, serum IL-12 and INF-γ levels, mouse weight and tumor volume were measured Results There were significantly more apoptotic cells in tumor tissue in IL-12 gene transfected group, FYD treatment group and FYD combining with IL-12 gene transfected group than that in the model group (P < 0.05). The FYD + IL-12 + BMSC group showed significantly higher Bax and lower Bcl-2 expression (P < 0.05), and serum IL-12 and INF-γ levels (P < 0.05) were higher than that in all other groups. After the intervention, this group also showed a strong inhibitory effect against tumor growth (P < 0.05) Conclusions This study suggested FYD treatment combined with IL-12 gene-modified BMSCs shows synergistic antitumor effect in glioma-bearing nude mice.

RETRACTED: Mesenchymal Stem/Stromal Cells as a Vehicle for Cytokine Delivery: An Emerging Approach for Tumor Immunotherapy

“…Meanwhile, glioma U251 cell-bearing BALB/c nude mice experienced robust decreases in tumor volume upon treatment with FYD plus MSC-IL-12. Moreover, a combine treatment of FYD and MSC-IL-12 induced higher Bax and lower Bcl-2 expression and also supported higher serum IL-12 and INF-γ levels compared with monotherapy with FYD or MSC-IL-12 (67). Besides, intramural injection of genetically modified MSCs co-expressing IL-12 and IL-7 caused a marked inversion of the CD4+/CD8+ T-cell ratio with an intricate antitumor response mainly mediated by CD8+ effector T cells in glioma tumor-bearing mice (68).…”

“…In another study, injection of MSC-IL-12 into Ast11.9-2 glioma cell-bearing C57/B16 mice caused enhanced NK cell infiltration in brain tissue, and thereby exerted an improvement in non-specific cell lysis, while could not induce significant promotion in overall survival rates of the treated mice compared with control mice (66). Nonetheless, it was demonstrated that treatment with Fuzheng Yiliu decoction (FYD), a traditional Chinese medicine, in combination with MSC-IL-12 therapy could elicit synergistic antitumor effects in glioma-bearing nude mice (67). Meanwhile, glioma U251 cell-bearing BALB/c nude mice experienced robust decreases in tumor volume upon treatment with FYD plus MSC-IL-12.…”

Effects of INF-γ-modified bone marrow mesenchymal stem cells on the distribution and inhibition of tumours in vivo in a glioma nude mouse model

“…Human glioma U251 cell culture U251 cells were cultured as described previously [21] at saturated humidity in Roswell Park Memorial Institute (RPMI) 1640 medium, which was changed every 2-3 days.…”

“…The mouse feed was not supplemented with foetal bovine serum in this study. Mice were handled post mortem as described previously [21]. The cell surface molecular markers CD44, CD105, CD34, CD45, and CD11b were detected by ow cytometry [5,22,23].…”

“…The primers used in this study were described previously [21]. The INF-γ overexpression sequence was ampli ed by polymerase chain reaction (PCR).…”