Combining MPDL3280A with adoptive cell immunotherapy exerts better antitumor effects against cervical cancer

Abstract Background Cervical cancer is a type of the most common gynecology tumor in women of the whole world. Accumulating data have shown that icariin (ICA), a natural compound, has anti-cancer activity in different cancers, including cervical cancer. The study aimed to reveal the antitumor effects and the possible underlying mechanism of ICA in U14 tumor-bearing mice and SiHa cells. Methods The antitumor effects of ICA were investigated in vivo and in vitro. The expression of TLR4/MyD88/NF-κB and Wnt/β-catenin signaling pathways were evaluated. Results We found that ICA significantly suppressed tumor tissue growth and SiHa cells viability in a dose-dependent manner. Also, ICA enhanced the anti-tumor humoral immunity in vivo. Moreover, ICA significantly improved the composition of the microbiota in mice models. Additionally, the results clarified that ICA significantly inhibited the migration, invasion capacity, and expression levels of TGF-β1, TNF-α, IL-6, IL-17A, IL-10 in SiHa cells. Meanwhile, ICA was revealed to promote the apoptosis of cervical cancer cells by down-regulating Ki67, survivin, Bcl-2, c-Myc, and up-regulating P16, P53, Bax levels in vivo and in vitro. For the part of mechanism exploration, we showed that ICA inhibits the inflammation, proliferation, migration, and invasion, as well as promotes apoptosis and immunity in cervical cancer through impairment of TLR4/MyD88/NF-κB and Wnt/β-catenin pathways. Conclusions Taken together, ICA could be a potential supplementary agent for cervical cancer treatment.

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Antitumor effects of internal iliac arterial infusion of platinum compounds in a rabbit cervical cancer model

Obstetrics and Gynecology ◽

10.1016/s0029-7844(96)00480-2 ◽

1997 ◽

Vol 89 (2) ◽

pp. 286-290 ◽

Cited By ~ 10

Author(s):

H ITAMOCHI ◽

J KIGAWA ◽

Y MINAGAWA ◽

X CHENG ◽

M OKADA ◽

...

Keyword(s):

Cervical Cancer ◽

Platinum Compounds ◽

Cancer Model ◽

Antitumor Effects ◽

Arterial Infusion ◽

Internal Iliac

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Strategies to Improve the Antitumor Effect of γδ T Cell Immunotherapy for Clinical Application

International Journal of Molecular Sciences ◽

10.3390/ijms22168910 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8910

Author(s):

Masatsugu Miyashita ◽

Teruki Shimizu ◽

Eishi Ashihara ◽

Osamu Ukimura

Keyword(s):

T Cells ◽

T Cell ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Γδ T Cells ◽

Target Cells ◽

Γδ T Cell ◽

Antitumor Effects ◽

Cell Immunotherapy ◽

T Cell Immunotherapy

Human γδ T cells show potent cytotoxicity against various types of cancer cells in a major histocompatibility complex unrestricted manner. Phosphoantigens and nitrogen-containing bisphosphonates (N-bis) stimulate γδ T cells via interaction between the γδ T cell receptor (TCR) and butyrophilin subfamily 3 member A1 (BTN3A1) expressed on target cells. γδ T cell immunotherapy is classified as either in vivo or ex vivo according to the method of activation. Immunotherapy with activated γδ T cells is well tolerated; however, the clinical benefits are unsatisfactory. Therefore, the antitumor effects need to be increased. Administration of γδ T cells into local cavities might improve antitumor effects by increasing the effector-to-target cell ratio. Some anticancer and molecularly targeted agents increase the cytotoxicity of γδ T cells via mechanisms involving natural killer group 2 member D (NKG2D)-mediated recognition of target cells. Both the tumor microenvironment and cancer stem cells exert immunosuppressive effects via mechanisms that include inhibitory immune checkpoint molecules. Therefore, co-immunotherapy with γδ T cells plus immune checkpoint inhibitors is a strategy that may improve cytotoxicity. The use of a bispecific antibody and chimeric antigen receptor might be effective to overcome current therapeutic limitations. Such strategies should be tested in a clinical research setting.

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Hesperidin Induces Mitochondria Mediated Intrinsic Apoptosis in HPV-positive Cervical Cancer Cells via Regulation of E6/p53 Expression

10.21203/rs.3.rs-105340/v1 ◽

2020 ◽

Author(s):

Fang Ren ◽

Gong Zhang ◽

Caiyu Li ◽

Gailing Li ◽

Yuan Cao ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Protein Level ◽

Potential Candidate ◽

Dependent Manner ◽

Antitumor Effects ◽

P53 Expression ◽

Cervical Cancer Cells ◽

Apoptotic Proteins

Abstract Background: Hesperetin, an active compound found in citrus fruits, possesses antiproliferative effects toward several types of cancer cell lines, including cervical cancer. In this study, we explore the antitumor effects of Hesperetin on the human cervical cancer human papilloma virus (HPV)-positive (CaSki and HeLa) and HPV-negative (C-33A) cell lines and further elucidated the underlying mechanisms of this action. Methods: Cell viability and proliferation was measured by the MTT assay and 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay, respectively. dUTP-fluorescein nick end-labeling (TUNEL) staining, Annexin V‑fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining and flow cytometry was used to assess the degree of apoptosis. JC-1 staining assay was used to evaluate the change of mitochondrial membrane potential (ΔΨm) and Western blot assays were used to determine apoptosis-related factors at protein level. Results: Hesperetin (100, 200 and 400 μM) exhibited a significant exclusive inhibitory effect against the growth of HPV-infected CaSki and HeLa cancer cells via induction of apoptosis in a concentration-dependent manner, while it was almost not active in HPV-negative C-33A cancer cells and normal cervix epithelial H8 cells. Moreover, this antitumor effect executed by Hesperetin was associated with disruption of ΔΨm, the release of cytochrome c from mitochondria, activation of pro-apoptotic proteins (Bax, cleaved caspase-3 and caspase-9) and inhibition of anti-apoptotic proteins (Bcl-2). During this process, cleaved caspase-8 remained unchanged. In addition, Hesperetin led to a downregulation of E6 oncoprotein expression and upregulation of tumor suppressor protein p53 level. Conclusions: Collectively, these results implicated that Hesperetin can induce apoptosis of HPV‑positive cervical cancer cells via a mitochondria-mediated intrinsic signaling pathway, together with the repression of E6 and enhancement of p53 protein level, indicating Hesperetin may be considered as a potential candidate for the development of innovative anti-HPV cervical cancer agents.

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Buformin increases radiosensitivity in cervical cancer cells via cell-cycle arrest and delayed DNA-damage repair

Experimental Biology and Medicine ◽

10.1177/1535370218813320 ◽

2018 ◽

Vol 243 (14) ◽

pp. 1133-1140

Author(s):

Ling Chen ◽

Ting Zhang ◽

Qiuli Liu ◽

Mei Tang ◽

Yu’e Yang ◽

...

Keyword(s):

Cell Cycle ◽

Cervical Cancer ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Clinical Treatment ◽

Phase Cell ◽

Antitumor Effects ◽

Cycle Arrest ◽

Cervical Cancer Cells ◽

Old Drugs

Buformin is a commonly used hypoglycemic agent, and numerous studies have shown that buformin has potent antitumor effects in several malignancies. In this study, we aimed to assess the cytotoxic effect of buformin combined with ionizing radiation (IR) on two human cervical cancer cell lines (Hela and Siha). Cytotoxicity was detected by colony formation assays; impacts on the cell cycle and apoptosis were detected by flow cytometric analyses. Changes in histone H2AX (γ-H2AX) phosphorylation and impacts on the AMPK/S6 pathway were also explored. Our data show that the combination of buformin and IR had a much stronger antiproliferative effect and resulted in more apoptosis than did buformin or IR alone. Combination treatment with a low dose of buformin (10 µM) and IR (4 Gy) caused G2/M-phase cell cycle arrest. Consistent with these findings, Western blotting showed that the combination of buformin and IR activated AMPK and suppressed S6. In addition, delayed disappearance of γ-H2AX was detected by immunofluorescence in cervical cancer cells treated with buformin plus IR. Taken together, the data indicate that the combination of a low concentration of buformin and IR increases the radiosensitivity of cervical cancer cells via cell cycle arrest and inhibition of DNA repair. Based on these results, we strongly support the use of buformin as an effective agent for improving IR treatment efficiency in the context of cervical cancer. Impact statement Our idea originated in the thought of discovering new effects of old drugs. Although this study is a basic research, it is very close to clinical treatment. Flow cytometry and immunofluorescence were used to verify that buformin increases radiosensitivity. We aimed to address one of the thorniest problems in treatment process. Based on discovering new effects of old drugs, it is feasible to use buformin as an anticancer drug in clinical application. This will provide new ideas for clinical treatment.

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