scholarly journals Niraparib exhibits a synergistic anti-tumor effect with PD-L1 blockade by inducing an immune response in ovarian cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jinyu Meng ◽  
Jin Peng ◽  
Jie Feng ◽  
Jochen Maurer ◽  
Xiao Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Flow Cytometry ◽  
Immune Response ◽  
T Cells ◽  
Cancer Cells ◽  
Parp Inhibitors ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Sting Pathway

Abstract Background Immune checkpoint blockades (ICBs) therapy showed limited efficacy in ovarian cancer management. Increasing evidence indicated that conventional and targeted therapies could affect tumor-associated immune responses and increase the effectiveness of immunotherapy. However, the effects of Niraparib, one of the poly (ADP) ribose polymerase (PARP) inhibitors, on the immune response remains unclear. Delineating the crosstalk between cytotoxic anticancer agents and cancer-associated immunity may lead to more efficient combinatorial strategies. Methods Programmed death ligand 1 (PD-L1) expression in human ovarian cancer cells after PARP inhibitors treatment was examined by western blotting (WB) and flow cytometry. The expression of poly ADP-ribose polymerase (PARP1), PD-L1, and CD8 in human ovarian cancer tissues was detected by immunohistochemistry(IHC). The effect of Niraparib and PD-L1 blockade in ovarian cancer progression was investigated in vivo. The changes of immune cells and cytokines in vitro and in vivo were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Changes of cGAS/STING signal pathway after Niraparib treatment were determined by WB, ELISA. Results Niraparib upregulated membrane PD-L1 and total PD-L1 expression in ovarian cancer cells and had a synergistic effect with PD-L1 blockade in vivo. In clinical patient samples, Niraparib augmented cytotoxic CD8+T cell proportion and function. In vivo and vitro, Niraparib can also increase the proportion of T cells and combined with PD-L1 blockade could further enhance the effect. Besides, Niraparib activated the cGAS-STING pathway, increasing the levels of cytokines such as CCL5 and CXCL10, which played a vital role in augmenting the infiltration and activation of cytotoxic T cells. Conclusions Niraparib could modulate the immune response via the activation of the cGAS/STING pathway, and combination with PD-L1 blockade could further enhance the effect. These results provide a sound theoretical basis for clinical treatment.

scholarly journals A Combination of Glutaminase Inhibitor 968 and PD-L1 Blockade Boosts the Immune Response against Ovarian Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1749
Author(s):  
Jing-Jing Wang ◽  
Michelle Kwan-Yee Siu ◽  
Yu-Xin Jiang ◽  
Thomas Ho-Yin Leung ◽  
David Wai Chan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
T Cells ◽  
Cancer Cells ◽  
Cd8 T Cells ◽  
Granzyme B ◽  
Combined Treatment ◽  
In Vivo Studies ◽  
Immune Checkpoints ◽  
Ovarian Cancer Cells

Programmed cell death 1 ligand (PD-L1) blockade has been used therapeutically in the treatment of ovarian cancer, and potential combination treatment approaches are under investigation to improve the treatment response rate. The increased dependence on glutamine is widely observed in various type of tumors, including ovarian cancer. Kidney-type glutaminase (GLS), as one of the isotypes of glutaminase, is found to promote tumorigenesis. Here, we have demonstrated that the combined treatment with GLS inhibitor 968 and PD-L1 blockade enhances the immune response against ovarian cancer. Survival analysis using the Kaplan–Meier plotter dataset from ovarian cancer patients revealed that the expression level of GLS predicts poor survival and correlates with the immunosuppressive microenvironment of ovarian cancer. 968 inhibits the proliferation of ovarian cancer cells and enhances granzyme B secretion by CD8+ T cells as detected by XTT assay and flow cytometry, respectively. Furthermore, 968 enhances the apoptosis-inducing ability of CD8+ T cells toward cancer cells and improves the treatment effect of anti-PD-L1 in treating ovarian cancer as assessed by Annexin V apoptosis assay. In vivo studies demonstrated the prolonged overall survival upon combined treatment of 968 with anti-PD-L1 accompanied by increased granzyme B secretion by CD4+ and CD8+ T cells isolated from ovarian tumor xenografts. Additionally, 968 increases the infiltration of CD3+ T cells into tumors, possibly through enhancing the secretion of CXCL10 and CXCL11 by tumor cells. In conclusion, our findings provide a novel insight into ovarian cancer cells influence the immune system in the tumor microenvironment and highlight the potential clinical implication of combination of immune checkpoints with GLS inhibitor 968 in treating ovarian cancer.

scholarly journals Antitumor properties of salinomycin on cisplatin-resistant human ovarian cancer cells in vitro and in vivo: Involvement of p38 MAPK activation

2013 ◽  
Vol 29 (4) ◽  
pp. 1371-1378 ◽  
Author(s):  
BEI ZHANG ◽  
XUEYA WANG ◽  
FENGFENG CAI ◽  
WEIJIE CHEN ◽  
ULI LOESCH ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
P38 Mapk ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Mapk Activation ◽  
Antitumor Properties

Novel organo-osmium(ii) proteosynthesis inhibitors active against human ovarian cancer cells reduce gonad tumor growth in Caenorhabditis elegans

2021 ◽  
Vol 8 (1) ◽  
pp. 141-155
Author(s):  
Enrique Ortega ◽  
Francisco J. Ballester ◽  
Alba Hernández-García ◽  
Samanta Hernández-García ◽  
M. Alejandra Guerrero-Rubio ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Antitumor Activity ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Arene Complexes ◽  
C Elegans

Novel Os(ii) arene complexes with a deprotonated ppy or ppy-CHO C^N ligand have been synthesized to selectively act on cancer cells as proteosynthesis inhibitors in vitro and exert antitumor activity in vivo in C. elegans models.

scholarly journals Forkhead Box Protein C2 (FOXC2) Promotes the Resistance of Human Ovarian Cancer Cells to Cisplatin In Vitro and In Vivo

2016 ◽  
Vol 39 (1) ◽  
pp. 242-252 ◽  
Author(s):  
Chanjuan Li ◽  
Hongjuan Ding ◽  
Jing Tian ◽  
Lili Wu ◽  
Yun Wang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Mapk Signaling ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Cancer Tissues ◽  
Mapk Signaling Pathways

Background/Aims: FOXC2 has been reported to play a role in tumor progression, but the correlations of FOXC2 with the cisplatin (CDDP) resistance of ovarian cancer cells are still unclear. The purpose of the present study is to investigate the roles of FOXC2 in the CDDP resistance of ovarian cancer cells and its possible mechanisms. Methods: Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of FOXC2 mRNA in CDDP-resistant or sensitive ovarian cancer tissues and cell lines (SKOV3/CDDP and SKOV3). Gain- and loss-of-function assays were performed to analyze the effects of FOXC2 knockdown or overexpression on the in vitro and in vivo sensitivity of ovarian cancer cells to CDDP and its possible molecular mechanisms. Results: The relative expression level of FOXC2 mRNA in CDDP-resistant ovarian cancer tissues was higher than that in CDDP-sensitive tissues. Also, the expression of FOXC2 mRNA and protein in CDDP-resistant ovarian cancer cell line (SKOV3/CDDP) cell line was higher than that in its parental cell line (SOKV3). Small hairpin RNA (shRNA)-mediated FOXC2 knockdown significantly increased the in vitro and in vive sensitivity of SKOV3/CDDP cells to CDDP by enhancing apoptosis, while upregulation of FOXC2 significantly decreased the in vitro and in vivo sensitivity of SKOV3 cells to CDDP by reducing apoptosis. Furthermore, FOXC2 activates the Akt and MAPK signaling pathways, and then induced the decreased expression of Bcl-2 protein and the increased expression of Bax and cleaved caspase-3 proteins. Conclusions: FOXC2 mediates the CDDP resistance of ovarian cancer cells by activation of the Akt and MAPK signaling pathways, and may be a potential novel therapeutic target for overcoming CDDP resistance in human ovarian cancer.

Adenovirus 5 E1a-mediated gene therapy for human ovarian cancer cells in vitro and in vivo

2001 ◽  
Vol 11 (1) ◽  
pp. 18-23 ◽  
Author(s):  
R.-Y. Zang ◽  
D.-R. Shi ◽  
H.-J. Lu ◽  
S.-M. Cai ◽  
D.-R. Lu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Gene Therapy ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Adenovirus 5

scholarly journals RETRACTED ARTICLE: Long noncoding RNA MLK7-AS1 promotes ovarian cancer cells progression by modulating miR-375/YAP1 axis

2018 ◽  
Vol 37 (1) ◽  
Author(s):  
Huan Yan ◽  
Hong Li ◽  
Pengyun Li ◽  
Xia Li ◽  
Jianjian Lin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Wound Healing ◽  
Cancer Cells ◽  
Cell Lines ◽  
Colony Formation ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Cancer Tissues

Abstract Background Long noncoding RNAs (LncRNAs) have been reported to be abnormally expressed in human ovarian cancer and associated with the proliferation and metastasis of cancer cells. The objective of this study was to investigate the role and the underlying mechanisms of LncRNA MAP3K20 antisense RNA 1 (MLK7-AS1) in ovarian cancer. Methods The expression level of MLK7-AS1 was investigated in human ovarian cancer tissues and cell lines. The effects of MLK7-AS1 knockdown on ovarian cancer cell proliferation, migration, invasion and apoptosis were evaluated in vitro using MTT, colony formation assays, wound healing assays, transwell assays and flow cytometry. Furthermore, the in vivo effects were determined using the immunodeficient NSG female mice. Luciferase reporter assays were employed to identify interactions among MLK7-AS1 and its target genes. Results In the current study, MLK7-AS1 was specifically upregulated in ovarian cancer tissues and cell lines. Knockdown of MLK7-AS1 inhibited the ability of cell migration, invasion, proliferation, colony formation and wound healing, whereas promoted cell apoptosis in vitro. By using online tools and mechanistic analysis, we demonstrated that MLK7-AS1 could directly bind to miR-375 and downregulate its expression. Besides, MLK7-AS1 reversed the inhibitory effect of miR-375 on the growth of ovarian cancer cells, which might be involved in the upregulation of Yes-associated protein 1 (YAP1) expression. Moreover, knockdown MLK7-AS1 expression inhibited primary tumor growth in ovary and metastatic tumors in multiple peritoneal organs including liver and spleen in vivo, which were partly abolished by miR-375 inhibition. Mechanically, we found that MLK7-AS1 modulated the epithelial-mesenchymal transition (EMT) process by interacting with miR-375/YAP1 both in vivo and vitro, which promoted the expression of Slug. Conclusions Taken together, our study showed for the first time that MLK7-AS1 interacted with miR-375 to promote proliferation, metastasis, and EMT process in ovarian cancer cells through upregulating YAP1.

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