scholarly journals Downregulation of PD-L1 via FKBP5 by celecoxib augments antitumor effects of PD-1 blockade in a malignant glioma model

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Izumi Yamaguchi ◽  
Kohei Nakajima ◽  
Kenji Shono ◽  
Yoshifumi Mizobuchi ◽  
Toshitaka Fujihara ◽  
...  
Keyword(s):  
Antibody Therapy ◽  
High Expression ◽  
Antibody Treatment ◽  
Antitumor Effects ◽  
Fk506 Binding Protein ◽  
Cox 2 ◽  
Glioma Model ◽  
Human Gbm ◽  
Post Transcriptional Regulation

Abstract Background Antitumor therapies targeting programmed cell death-1 (PD-1) or its ligand-1 (PD-L1) are used in various cancers. However, in glioblastoma (GBM), the expression of PD-L1 varies between patients, and the relationship between this variation and the efficacy of anti-PD-1 antibody therapy remains unclear. High expression levels of PD-L1 affect the proliferation and invasiveness of GBM cells. As COX-2 modulates PD-L1 expression in cancer cells, we tested the hypothesis that the COX-2 inhibitor celecoxib potentiates anti-PD-1 antibody treatment via the downregulation of PD-L1. Methods Six-week-old male C57BL/6 mice injected with murine glioma stem cells (GSCs) were randomly divided into four groups treated with vehicle, celecoxib, anti-PD-1 antibody, or celecoxib plus anti-PD-1 antibody and the antitumor effects of these treatments were assessed. To verify the mechanisms underlying these effects, murine GSCs and human GBM cells were studied in vitro. Results Compared with that with each single treatment, the combination of celecoxib and anti-PD-1 antibody treatment significantly decreased tumor volume and prolonged survival. The high expression of PD-L1 was decreased by celecoxib in the glioma model injected with murine GSCs, cultured murine GSCs, and cultured human GBM cells. This reduction was associated with post-transcriptional regulation of the co-chaperone FK506-binding protein 5 (FKBP5). Conclusions Combination therapy with anti-PD-1 antibody plus celecoxib might be a promising therapeutic strategy to target PD-L1 in glioblastoma. The downregulation of highly-expressed PD-L1 via FKBP5, induced by celecoxib, could play a role in its antitumor effects.

scholarly journals EXTH-06. DOWN-REGULATION OF PD-L1 VIA FKBP5 LOWERED BY A CYCLOOXYGENASE-2 INHIBITOR IN GSCs AND GBM CELLS MAY BE ATTRIBUTABLE TO ENHANCE ANTITUMOR EFFECTS OF IMMUNOTHERAPY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi83-vi83
Author(s):  
Izumi Yamaguchi ◽  
Kohei Nakajima ◽  
Kenji Shono ◽  
Yoshifumi Mizobuchi ◽  
Toshitaka Fujihara ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Antibody Therapy ◽  
High Expression ◽  
Antibody Treatment ◽  
Antitumor Effects ◽  
Down Regulation ◽  
Fk506 Binding Protein ◽  
Cox 2 ◽  
Glioma Model ◽  
Human Gbm

Abstract BACKGROUND Antitumor therapies targeting programmed cell death-1 (PD-1)/its ligand-1 (PD-L1) are influential at present stage. However, in glioblastoma (GBM), the expression of PD-L1 is variable and the role of anti-PD-1 antibody therapy is still unclear. The high expression of PD-L1 affects cell proliferation and invasion in GBM cells. As COX-2 modulates PD-L1 expression in cancer cells, we tested our hypothesis that a COX-2 inhibitor, celecoxib may play a role on anti-PD-1 antibody treatment via down-regulation of PD-L1. METHODS Six weeks old male C57BL/6 mice subjected to intracranial injection of mice glioma stem cells (GSCs) were randomly divided into four treatment groups; vehicle control (VC), celecoxib, anti PD-1 antibody or the combination of celecoxib and anti-PD-1 antibody groups and examined antitumor effects. To verify the mechanisms underlying antitumor effects, mice GSCs and human GBM cells were used. RESULTS Compared to each single treatment in the glioma model, the combination therapy of anti PD-1 antibody and celecoxib significantly decreased the tumor volume and improved the survival period. Importantly, the high expression of PD-L1 in the glioma model, mice GSCs and human GBM cells was decreased by celecoxib. Interestingly, the reduction of PD-L1 was associated with post-transcriptional regulation of co-chaperone FK506-binding protein 5 (FKBP5) by celecoxib. The combination therapy of anti PD-1 antibody with celecoxib could be a promising therapeutic strategy targeting PD-L1 in GSCs and GBM. CONCLUSIONS Down-regulation of PD-L1 via FKBP5 by celecoxib may play a role on the antitumor effects under the overwhelmed expression of PD-L1.

scholarly journals TB-4 Antitumor effects of a novel curcumin derivative curcumin monoglucuronide on glioblastoma cells in vitro and in vivo

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi6-vi6
Author(s):  
Takashi Fujii ◽  
Shun Yamamuro ◽  
Masamichi Takahashi ◽  
Akihide Kondo ◽  
Yoshitaka Narita ◽  
...  
Keyword(s):  
Cell Death ◽  
Water Soluble ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Multiple Cell ◽  
Human Gbm ◽  
Dose Dependent ◽  
Novel Therapeutic

Abstract The therapeutic outcome of glioblastomas (GBMs) is still very poor. Therefore, invention of novel therapeutic methods against GBM cases is considered urgent. The antitumor effects of naturally-derived compounds are attracting attention recently, and therapeutic efficacy of curcumin, a plant-derived compound previously used for multiple purpose, has been indicated in many cancer systems; however, clinical application of curcumin is considered difficult because of its poor bioavailability (under 1 %). Curcumin monoglucuronide (CMG), a water-soluble prodrug of curcumin recently developed for overcoming this weakness, has been demonstrated excellent antitumor effects for several malignancies in vitro and in vivo; therefore, we investigated the effects of CMG against GBM cells. CMG induced cell death of human GBM cells lines (T98G, U251MG, and U87MG) by dose dependent manner by triggering multiple forms of cell death such as apoptosis and perthanatos. Immunoblotting of CMG-treated GBM cell lysates demonstrated activation of multiple cell death signaling. Furthermore, immunodeficiency mice harboring intracerebral U87MG cell xenografts systemically treated by CMG showed significantly prolonged survival compared with control mice. These results suggest CMG would be a novel therapeutic agent against GBM cases.

Antitumor effects of vaccination with dendritic cells transfected with modified receptor for hyaluronan-mediated motility mRNA in a mouse glioma model

2007 ◽  
Vol 106 (4) ◽  
pp. 638-645 ◽  
Author(s):  
Takayuki Amano ◽  
Koji Kajiwara ◽  
Koichi Yoshikawa ◽  
Jun Morioka ◽  
Sadahiro Nomura ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Therapeutic Potential ◽  
Immunohistochemical Analysis ◽  
Antitumor Effects ◽  
Serological Screening ◽  
Lysosomal Sorting ◽  
Glioma Model ◽  
Vaccination Therapy ◽  
Mouse Glioma

Object The receptor for hyaluronan-mediated motility (RHAMM) is frequently overexpressed in brain tumors and was recently identified as an immunogenic antigen by using serological screening of cDNA expression libraries. In this study, which was conducted using a mouse glioma model, the authors tested the hypothesis that vaccination with dendritic cells transfected with RHAMM mRNA induces strong immunological antitumor effects. Methods The authors constructed a plasmid for transduction of the mRNAs transcribed in vitro into dendritic cells, which were then used to transport the intracellular protein RHAMM efficiently into major histocompatibility complex class II compartments by adding a late endosomal–lysosomal sorting signal to the RHAMM gene. The dendritic cells transfected with this RHAMM mRNA were injected intraperitoneally into the mouse glioma model 3 and 10 days after tumor cell implantation. The antitumor effects of the vaccine were estimated by the survival rate, histological analysis, and immunohistochemical findings for immune cells. Mice in the group treated by vaccination therapy with dendritic cells transfected with RHAMM mRNA survived significantly longer than those in the control groups. Immunohistochemical analysis revealed that greater numbers of T lymphocytes containing T cells activated by CD4+, CD8+, and CD25+ were found in the group vaccinated with dendritic cells transfected with RHAMM mRNA. Conclusions These results demonstrate the therapeutic potential of vaccination with dendritic cells transfected with RHAMM mRNA for the treatment of malignant glioma.

Vaccine therapy with dendritic cells transfected with Il13ra2 mRNA for glioma in mice

2010 ◽  
Vol 113 (2) ◽  
pp. 270-279 ◽  
Author(s):  
Makoto Saka ◽  
Takayuki Amano ◽  
Koji Kajiwara ◽  
Koichi Yoshikawa ◽  
Makoto Ideguchi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Therapeutic Potential ◽  
Immunohistochemical Analysis ◽  
Antitumor Effects ◽  
Histocompatibility Complex ◽  
Lysosomal Sorting ◽  
Glioma Model ◽  
Vaccination Therapy ◽  
Mouse Glioma

Object The Il13ra2 gene is often overexpressed in brain tumors, making Il13ra2 one of the vaccine targets for immunotherapy of glioma. In this study, using a mouse glioma model, the authors tested the hypothesis that vaccination using dendritic cells transfected with Il13ra2 mRNA induces strong immunological antitumor effects. Methods A plasmid was constructed for transduction of the mRNAs transcribed in vitro into dendritic cells. This was done to transport the intracellular protein efficiently into major histocompatibility complex class II compartments by adding a late endosomal/lysosomal sorting signal to the Il13ra2 gene. The dendritic cells transfected with this Il13ra2 mRNA were injected intraperitoneally into the mouse glioma model at 3 and 10 days after tumor cell implantation. The antitumor effects were estimated based on the survival rate, results of histological analysis, and immunohistochemical findings for immune cells. Results The group treated by vaccination therapy with dendritic cells transfected with Il13ra2 mRNA survived significantly longer than did the control groups. Immunohistochemical analysis revealed that greater numbers of T lymphocytes containing CD4+ and CD8+ T cells were found in the group vaccinated with dendritic cells transfected with Il13ra2 mRNA. Conclusions These results demonstrate the therapeutic potential of vaccination with dendritic cells transfected with Il13ra2 mRNA for the treatment of malignant glioma.

Enhanced 5-fluorouracil cytotoxicity in high COX-2 expressing hepatocellular carcinoma cells by wogonin via the PI3K/Akt pathway

2013 ◽  
Vol 91 (4) ◽  
pp. 221-229 ◽  
Author(s):  
Li Zhao ◽  
Yun-Ying Sha ◽  
Qing Zhao ◽  
Jing Yao ◽  
Bin-Bin Zhu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Human Tumor ◽  
Inhibitory Effect ◽  
Chemotherapeutic Agents ◽  
Carcinoma Cells ◽  
Antitumor Effects ◽  
Synergistic Inhibitory Effect ◽  
Cox 2

Combination therapies may increase the antitumor effects and reduce the adverse effects for the treatment of hepatocellular carcinoma. In this study, we determined the effects of 5-fluorouracil alone or in combination with wogonin in vitro and in vivo, and we investigated the possible mechanisms. The combination of these 2 drugs led to a decrease in survival and a significant synergistic inhibitory effect on high COX-2 expression in SMMC-7721 hepatocellular carcinoma (HCC) cells. Furthermore, the results show that this combination inhibits COX-2 expression and increases sensitivity to chemotherapeutic agents partly through regulating the PI3K/Akt signaling pathway. Moreover, the combination treatment caused a significant growth inhibition of human tumor xenografts in vivo. In conclusion, wogonin may increase the cytotoxicity of some antineoplastic agents and it can be used in combination with these agents as a novel therapeutic regimen for HCC treatment.

scholarly journals Defucosylated Mouse–Dog Chimeric Anti-EGFR Antibody Exerts Antitumor Activities in Mouse Xenograft Models of Canine Tumors

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3599
Author(s):  
Guanjie Li ◽  
Tomokazu Ohishi ◽  
Mika K. Kaneko ◽  
Junko Takei ◽  
Takuya Mizuno ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Line ◽  
Growth Factor Receptor ◽  
High Sensitivity ◽  
Osteosarcoma Cell ◽  
Antibody Treatment ◽  
Antitumor Effects ◽  
Vitro Analysis

The epidermal growth factor receptor (EGFR) contributes to tumor malignancy via gene amplification and protein overexpression. Previously, we developed an anti-human EGFR (hEGFR) monoclonal antibody, namely EMab-134, which detects hEGFR and dog EGFR (dEGFR) with high sensitivity and specificity. In this study, we produced a defucosylated mouse–dog chimeric anti-EGFR monoclonal antibody, namely E134Bf. In vitro analysis revealed that E134Bf highly exerted antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against a canine osteosarcoma cell line (D-17) and a canine fibroblastic cell line (A-72), both of which express endogenous dEGFR. Moreover, in vivo administration of E134Bf significantly suppressed the development of D-17 and A-72 compared with the control dog IgG in mouse xenografts. These results indicate that E134Bf exerts antitumor effects against dEGFR-expressing canine cancers and could be valuable as part of an antibody treatment regimen for dogs.

Decreased Expression of α2,8 Sialyltransferase and Increased Expression of β1,4 N-Acetylgalactosaminyltransferase in Gastrointestinal Cancers

2002 ◽  
Vol 227 (3) ◽  
pp. 196-200 ◽  
Author(s):  
Yasuhiro Koh ◽  
Takuya Tsunoda ◽  
Makoto Iwahashi ◽  
Hiroki Yamaue ◽  
Kiwao Ishimoto ◽  
...  
Keyword(s):  
Antibody Therapy ◽  
Expression Level ◽  
Gastrointestinal Cancers ◽  
Antibody Treatment ◽  
Antitumor Effects ◽  
Gm2 Ganglioside ◽  
Normal Tissues ◽  
Cancer Group ◽  
Colorectal Cancer Patients

Gangliosides such as GD3, GM2, and GD2 are abundantly expressed on the cell surfaces of various malignant cells, suggesting the potential for anti-ganglioside antibody therapy for tumors. Anti-ganglioside GD2 antibody treatment is currently undergoing clinical trials for melanoma and neuroblastoma. We previously reported high in vivo antitumor effects of anti-GM2 ganglioside antibody against lung cancer. To determine whether anti-GM2 antibody may be clinically indicated for gastrointestinal cancers, we evaluated the mRNA expression of α2,8 sialyltransferase, a GD3 synthase, and β1,4 N-acetylgalactosaminyltransferase (β1,4 GalNAc-T), a GM2/GD2 synthase, in gastrointestinal cancers. We performed modified semi-quantitative RT-PCR, which reduces complexity incidental to radiolabeling on samples taken from small surgically removed clinical specimens. Stomach (19/22) and colorectal (21/30) cancers showed decreased expression of α2,8 sialyltransferase as compared with respective normal tissues (P < 0.05). In contrast, increased expression of β1,4 GalNAc-T was detected in both types of tumors. Clinicopathological analysis revealed significantly higher expression level of α2,8 sialyltransferase in the poorly differentiated than in the well-differentiated stomach cancer group (P < 0.05). Furthermore, the expression level of α2,8 sialyltransferase was significantly decreased in male as compared with female colorectal cancer patients (P < 0.05). These results suggest that expression level of GM2 ganglioside is elevated in gastrointestinal cancer, and that anti-GM2 antibody may be applicable to its treatment.

High Dose Celecoxib and Metronomic ‘Low-Dose’ Cyclophosphamide Is Effective Therapy in Patients with Relapsed and Refractory Aggressive Histology NHL.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4622-4622
Author(s):  
Rena Buckstein ◽  
M. Crump ◽  
Y. Shaked ◽  
D. Spaner ◽  
E. Piliotis ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Median Time ◽  
Low Dose ◽  
Circulating Endothelial Cells ◽  
High Dose ◽  
Antitumor Effects ◽  
Aggressive Histology ◽  
Cox 2 ◽  
Grade 3

Abstract Background: Relapsed aggressive histology non-Hodgkin’s lymphoma (NHL) has a poor prognosis, and new treatments are needed. Angiogenesis is increased in aggressive NHL and may be a target in these diseases. Low-dose chronic chemotherapy (metronomic chemotherapy, MC) inhibits angiogenesis in vitro and in vivo. Since COX-2 may promote neoplasia and tumor angiogenesis, selective COX-2 inhibitors may have antitumor effects in NHL. We assessed response and toxicity to MC and COX-2 inhibition in patients (pts.) with relapsed aggressive NHL following anthracycline-based chemotherapy. Methods: Pts. with measurable disease and normal renal function received cyclophosphamide 50 mg po qd + celecoxib 400 mg po bid. Pts. were assessed clinically and radiologically in serial fashion. We measured serial plasma VEGF and TSP-1 levels and pharmacokinetics (PK) were performed in selected pts. Serial circulating endothelial cells (CEC) and their precursors (CEP) were measured by flow cytometry as of October 2003. Results: To date, 29 of a planned 32 pts. have been enrolled; 3 are ineligible and 25 are evaluable for response. Median age: 62 y (range 22–83). Histology: 17 DLBCL, 1 MCL, 3 transformed (CLL+FL), 2 T cell, 3 anaplastic large cell. Median 2.7 yrs from diagnosis (range 0.5–9.5); Median # of previous chemotherapy regimens: 3 (range 1–6); 31% were chemoresistant to preceding regimen; 8 had undergone prior ASCT. Median time to death or last follow-up: 4 mos (range 0.9–22). Response:10/25 pts. responded (2 CR/CRu, 8 PR, ORR 40%) at a median time of 4.6 mos, and at last f/up, 6/10 remained in PR at 22, 21, 16, 11, 8 and 7 mos. respectively. Three pts. achieved stable disease (SD) but 2 later progressed at a median time of 6 mos (range 4–14 mos) and 12/25 progressed primarily (PD) at a median time of 1.9 mos (range &lt;1–9); 10 have died of NHL (median time 4 mos). 2 partial responders discontinued treatment in PR at 21 and 16 mos for cumulative cyclophosphamide exposure exceeding 40,000 mg. Both progressed within 2–3 months of drug disontinuation. Median OS and PFS are 8.5 and 3.9 mos, respectively. Adverse events (# pts): grade 3–4 ANC (2), grade 3 plt (3), grade 3 hypertension (1), grade 3 atrial arrhythmia(1) and grade 3 drug rash (1). Plasma VEGF and TSP-1 levels do not appear to correlate with response but the number of circulating endothelial cells (CEC) and their precursors (CEP) decline in responders. Celecoxib and cyclophosphamide pharmacokinetics will be presented. This regimen has been well tolerated with minimal GI toxicity. 90% of responders had normal LDH compared with 25% with PD. No patient with preceding chemoresistance responded. Conclusions: MC with high-dose celecoxib and low-dose cyclophosphamide is well tolerated and active in 40% of heavily pre-treated patients with relapsed aggressive NHL. The anti-angiogenic activity of this regimen is still being determined.

Multitarget inhibition of drug-resistant multiple myeloma cell lines by dimethyl-celecoxib (DMC), a non–COX-2 inhibitory analog of celecoxib

Blood ◽  
2005 ◽  
Vol 106 (13) ◽  
pp. 4330-4338 ◽  
Author(s):  
Adel Kardosh ◽  
Nathaniel Soriano ◽  
Yen-Ting Liu ◽  
Jasim Uddin ◽  
Nicos A. Petasis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Myeloma Cell ◽  
Drug Resistant ◽  
Antitumor Effects ◽  
Inhibition Of Proliferation ◽  
Multiple Myeloma Cell ◽  
Cox 2

2,5-dimethyl-celecoxib (DMC) is a close structural analog of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib that lacks COX-2 inhibitory function. We and others have demonstrated that DMC, despite its inability to block COX-2, is able to potently mimic the antitumor effects of celecoxib in vitro and in vivo. In this current study, we investigated whether DMC would also be able to inhibit the growth of highly drug-resistant tumor cell variants. We focused on human multiple myeloma (MM) cells, as patients with MM frequently develop drug-resistant disease and ultimately succumb to death. Here we show that DMC (and celecoxib) inhibits the proliferation of various multiple myeloma cell lines, including several (multi) drug-resistant variants. Growth inhibition in drug-sensitive and drug-resistant cells is mediated via multiple effects, which include diminished signal transducer and activator of transcription 3 (STAT-3) and mitogen-activated protein (MAP) kinase kinase (MEK) activity, reduced expression of survivin and various cyclins, and is followed by apoptotic cell death. Thus, our study demonstrates that inhibition of proliferation and induction of apoptosis by DMC (and celecoxib) can be accomplished even in highly drug-resistant multiple myeloma cells, and that this effect is achieved via the blockage of multiple targets that are critical for multiple myeloma cell growth and survival.

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