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Lv H.-Y.,Hebei Medical University | Hao J.-S.,Research Center for Cancer Immunotherapy | Hu X.-D.,Research Center for Cancer Immunotherapy | Meng J.-B.,Hebei Medical University | And 2 more authors.
Chinese Traditional and Herbal Drugs

Objective: To investigate the effects and mechanisms of norcantharidin (NCTD) combined with melphalan (Mel) on proliferation and apoptosis of multiple myeloma (MM) cells. Methods: Human MM cell line U266 cells were treated with NCTD alone or in combination with Mel. MTT and Annexin V/PI flow cytometry were used to determine the rates of cell viability and apoptosis. The protein expression of nuclear factor-κB P65 (NF-κB P65), NF-κB P65 inhibitor IkBα, phosphorylated IκBα (p-IκBα), survivin, Bcl-2, and Bax was determined by Western blotting. The model of mice with MM was established, and the inhibition of combination of NCTD and Mel on tumor growth was observed. Results: NCTD potentiated the cytotoxicity and pro-apoptotic effects induced by Mel. Compared with the group treated with Mel alone, the expression levels of NF-κB P65 in U266 nucleus and p-IκBα in cytoplasm in NCTD and Mel combination group decreased from 1.13 ± 0.08 and 0.83 ± 0.08 to 0.26 ± 0.02 and 0.090 ± 0.002, respectively. Mel showed no effect on IκBα expression, but NCTD could enhance its expression, and the combination of NCTD and Mel could obviously enhance the expression. The expression of survivin and Bcl-2 decreased from 1.03 ± 0.10 and 0.72 ± 0.05 to 0.52 ± 0.04 and 0.06 ± 0.01, while the expression of Bax increased from 0.29 ± 0.03 to 0.75 ± 0.06 respectively. In vivo results also demonstrated that NCTD could increase the antitumor effects of Mel. Conclusion: The results suggest that NCTD could potentialize the anti-MM effects through inhibiting NF-κB/p-IκBα signal pathway and regulating the espression of survivin, Bcl-2, and Bax. Source

Nguyen-Pham T.-N.,Research Center for Cancer Immunotherapy | Nguyen-Pham T.-N.,Chonnam National University | Jung S.-H.,Research Center for Cancer Immunotherapy | Jung S.-H.,Chonnam National University | And 8 more authors.
Journal of Immunotherapy

We investigated the efficacy of lenalidomide (LEN) in combination with dendritic cell (DC) vaccination in the MOPC-315 murine myeloma model. After tumor growth, LEN was injected intraperitoneally for 4 consecutive days in combination with DC vaccination. The combination of LEN and vaccination efficiently inhibited tumor growth compared with the single agents alone. A cytotoxic assay revealed that the anticancer effects of DC vaccination plus LEN involved not only generation of antigen-specific cytotoxic T lymphocytes but also NK cells. Vaccinated mice had reduced numbers of suppressor cells, including both myeloid-derived suppressor cells and regulatory T cells, in the spleen. The proportions of CD4 + and CD8 + T cells increased in the spleen, and a Th1 cytokine (interferon-γ) rather than a Th2 cytokine (interleukin-10) was synthesized in response to tumor antigens. LEN enhanced the innate immune response by modulating NK cell numbers and function. In addition, LEN reduced the production levels of angiogenesis-inducing factors in tumor-bearing mice. Together, these results suggest that a combination of LEN and DC vaccination may synergistically enhance anticancer immunity in the murine myeloma model, by inhibiting immunosuppressor cells and stimulating effector cells, as well as effectively polarizing the Th1/Th2 balance in favor of a Th1-specific immune response. © Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

Lee H.J.,Research Center for Cancer Immunotherapy | Lee H.J.,Chonnam National University | Hong C.Y.,Research Center for Cancer Immunotherapy | Hong C.Y.,Chonnam National University | And 13 more authors.
Experimental and Molecular Medicine

Anterior gradient-2 (AGR2) promotes tumor growth, cell migration, and cellular transformation, and is one of the specific mRNA markers for circulating tumor cells in patients with gastrointestinal cancer. We investigated the feasibility of AGR2 as a potent antigen for tumor immunotherapy against colorectal cancer (CRC) cells using dendritic cells (DCs) transduced with a recombinant adenovirus harboring the AGR2 gene (AdAGR2). DCs transduced with a recombinant adenovirus encoding the AGR2 gene (AdAGR2/DCs) were characterized. These genetically-modified DCs expressed AGR2 mRNA as well as AGR2 protein at a multiplicity of infection of 1,000 without any significant alterations in DC viability and cytokine secretion (IL-10 and IL-12p70) compared with unmodified DCs as a control. In addition, AdAGR2 transduction did not impair DC maturation, but enhanced expression of HLA-DR, CD80, and CD86. AdAGR2/DCs augmented the number of IFN-γ-secreting T-cells and elicited potent AGR2-specific cytotoxic T lymphocytes capable of lysing AGR2-expressing CRC cell lines. These results suggest that AGR2 act as a potentially important antigen for immunotherapy against CRC in clinical applications. Source

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