Phosphorothioate modification of the TLR9 ligand CpG ODN inhibits poly(I:C)-induced apoptosis of hepatocellular carcinoma by entry blockade

Zhang, Yuyi; Lin, Ang; Sui, Qiangjun; Zhang, Cai; Tian, Zhigang; Zhang, Jian

doi:10.1016/j.canlet.2014.09.013

Cited by 23 publications

(24 citation statements)

References 28 publications

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“…4). In a study, lipofectamine mixed phosphorothioate-modified CpG ODN plus poly(I:C) was demonstrated to block uptake of poly(I:C) by tumor cells [34]. Here, since our ligands are encapsulated rather than complexed with the nanocarrier, we did not observe any blockage of wither of the ligand uptake.…”

Section: Discussionmentioning

confidence: 51%

Encapsulation of two different TLR ligands into liposomes confer protective immunity and prevent tumor development

Bayyurt

Tincer

Almacioglu

et al. 2017

Journal of Controlled Release

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Nucleic acid-based Toll-like receptor (TLR) ligands are promising adjuvants and immunotherapeutic agents. Combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory. However, their short circulation time due to nuclease attack hampers their clinical performance. Liposomes offer inclusion of protein and nucleic acid-based drugs with high encapsulation efficiency and drug loading. Furthermore, they protect cargo from enzymatic cleavage while providing stability, and enhancing biological activity. Herein, we aimed to develop a liposomal carrier system co-encapsulating TLR3 (polyinosinic-polycytidylic acid; poly(I:C)) and TLR9 (oligodeoxynucleotides (ODN) expressing unmethylated CpG motifs; CpG ODN) ligands as immunoadjuvants together with protein antigen. To demonstrate that this depot system not only induce synergistic innate immune activation but also boost antigen-dependent immune response, we analyzed the potency of dual ligand encapsulated liposomes in long-term cancer protection assay. Data revealed that CpG ODN and poly(I:C) co-encapsulation significantly enhanced cytokine production from spleen cells. Activation and maturation of dendritic cells as well as bactericidal potency of macrophages along with internalization capacity of ligands were elevated upon incubation with liposomes co-encapsulating CpG ODN and poly(I:C). Immunization with co-encapsulated liposomes induced OVA-specific Th1-biased immunity which persisted for eight months post-booster injection. Subsequent challenge with OVA-expressing tumor cell line, E.G7, demonstrated that mice immunized with liposomes co-encapsulating dual ligands had significantly slower tumor progression. Tumor clearance was dependent on OVA-specific cytotoxic memory T-cells. These results suggest that liposomes co-encapsulating TLR3 and TLR9 ligands and a specific cancer antigen could be developed as a preventive cancer vaccine.

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Section: Discussionmentioning

confidence: 51%

Encapsulation of two different TLR ligands into liposomes confer protective immunity and prevent tumor development

Bayyurt

Tincer

Almacioglu

et al. 2017

Journal of Controlled Release

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“…As previously described [61], One-Step TUNEL Apoptosis Assay Kit (Beyotime, Jiangsu, China) was applied in TUNEL assay according to the manuscript. Nuclei were stained with 4′, 6-diamidino-2-phenylindole (DAPI).…”

Section: Methodsmentioning

confidence: 99%

Targeting hyperactivated DNA-PKcs by KU0060648 inhibits glioma progression and enhances temozolomide therapy via suppression of AKT signaling

Lan

Zhao

et al. 2016

Oncotarget

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The overall survival remains undesirable in clinical glioma treatment. Inhibition of DNA-PKcs activity by its inhibitors suppresses tumor growth and enhances chemosensitivity of several tumors to chemotherapy. However, whether DNA-PKcs could be a potential target in glioma therapy remains unknown. In this study, we reported that the hyperactivated DNA-PKcs was profoundly correlated with glioma malignancy and observe a significant association between DNA-PKcs activation and survival of the glioma patients. Our data also found that inhibition of DNA-PKcs by its inhibitor KU0060648 sensitized glioma cells to TMZ in vitro. Specifically, we demonstrated that KU0060648 interrupted the formation of DNA-PKcs/AKT complex, leading to suppression of AKT signaling and resultantly enhanced TMZ efficacy. Combination of KU0060648 and TMZ substantially inhibited downstream effectors of AKT. The in vivo results were similar to those obtained in vitro. In conclusion, this study indicated that inhibition of DNA-PKcs activity could suppress glioma malignancies and increase TMZ efficacy, which was mainly through regulation of the of AKT signaling. Therefore, DNA-PKcs/AKT axis may be a promising target for improving current glioma therapy.

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“…These findings demonstrated that CpG-ODN enhanced immune function in the tumor-bearing mice. CpG-ODN can activate the NF-κB signaling pathway and induce immuno-stimulation in vivo by binding with toll-like receptor 9 to enter into immune cells [13]. Previouse studies also showed that CpG-ODN might induce cytokines, such as IFN-γ and IL-12, by activating JNK1/2 and p38 pathways [14,15].…”

Section: Discussionmentioning

confidence: 99%

Investigation of nedaplatin and CpG oligodeoxynucleotide combination therapy in a mouse model of lung cancer

Quan¹,

Zhao²

2018

Trop. J. Pharm Res

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Purpose: To investigate the anti-tumor effects of nedaplatin (NDP) and CpG oligodeoxynucleotide (CpG-ODN) combination therapy in a mouse-modeled lung cancer. Methods: To evaluate the anti-tumor effects of NDP and CpG-ODN combination therapy, a lung cancer xenograft mouse model was established by subcutaneous injection of LA-795 cells. BALB/c mice were divided into four groups as follows: NDP, CpG-, NDP + CpG-ODN and untreated control group. The sections of lung cancer tissue were stained with hematoxylin and eosin (H&E) and morphologically examined. Spleen, body weight, and spleen index were measured. Flow cytometry was used to determine the proportions of CD3 + , CD8 + , CD4 + and CD4 + /CD8 + in mice blood cells. Serum levels of interferon-γ (IFN-γ) and interleukin-12 (IL-12) were measured by enzyme-linked immunosorbent assay (ELISA). Results: NDP + CpG-ODN therapy significantly reduced tumor volume and prolonged the survival time of tumor-bearing mice. NDP + CpG-ODN induced a change in cancer cell morphology, including large areas of necrosis which correlated with a reduction in tumor size. NDP + CpG-ODN significantly increased spleen weight/index and dramatically enhanced immune cell activation. This was evident in the increase serum levels of IFN-γ and IL-12. Conclusion: NDP and CpG-ODN combination therapy inhibits the growth of lung cancer and prolongs the survival time of tumor-bearing mice. This may result from the activation of immune cells and increased expression of IFN-γ and IL-12.

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Phosphorothioate modification of the TLR9 ligand CpG ODN inhibits poly(I:C)-induced apoptosis of hepatocellular carcinoma by entry blockade

Cited by 23 publications

References 28 publications

Encapsulation of two different TLR ligands into liposomes confer protective immunity and prevent tumor development

Encapsulation of two different TLR ligands into liposomes confer protective immunity and prevent tumor development

Targeting hyperactivated DNA-PKcs by KU0060648 inhibits glioma progression and enhances temozolomide therapy via suppression of AKT signaling

Investigation of nedaplatin and CpG oligodeoxynucleotide combination therapy in a mouse model of lung cancer

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