scholarly journals SonoVue® vs. Sonazoid™ vs. Optison™: Which Bubble Is Best for Low-Intensity Sonoporation of Pancreatic Ductal Adenocarcinoma?

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 98
Author(s):  
Spiros Kotopoulis ◽  
Mihaela Popa ◽  
Mireia Mayoral Safont ◽  
Elisa Murvold ◽  
Ragnhild Haugse ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Cancer Cell ◽  
Type Equation ◽  
Ultrasound Contrast Agents ◽  
Ductal Adenocarcinoma ◽  
Great Promise ◽  
Tumor Growth Inhibition ◽  
Ultrasound Parameters

The use of ultrasound and microbubbles to enhance therapeutic efficacy (sonoporation) has shown great promise in cancer therapy from in vitro to ongoing clinical studies. The fastest bench-to-bedside translation involves the use of ultrasound contrast agents (microbubbles) and clinical diagnostic scanners. Despite substantial research in this field, it is currently not known which of these microbubbles result in the greatest enhancement of therapy within the applied conditions. Three microbubble formulations—SonoVue®, Sonazoid™, and Optison™—were physiochemically and acoustically characterized. The microbubble response to the ultrasound pulses used in vivo was simulated via a Rayleigh–Plesset type equation. The three formulations were compared in vitro for permeabilization efficacy in three different pancreatic cancer cell lines, and in vivo, using an orthotopic pancreatic cancer (PDAC) murine model. The mice were treated using one of the three formulations exposed to ultrasound from a GE Logiq E9 and C1-5 ultrasound transducer. Characterisation of the microbubbles showed a rapid degradation in concentration, shape, and/or size for both SonoVue® and Optison™ within 30 min of reconstitution/opening. Sonazoid™ showed no degradation after 1 h. Attenuation measurements indicated that SonoVue® was the softest bubble followed by Sonazoid™ then Optison™. Sonazoid™ emitted nonlinear ultrasound at the lowest MIs followed by Optison™, then SonoVue®. Simulations indicated that SonoVue® would be the most effective bubble using the evaluated ultrasound conditions. This was verified in the pre-clinical PDAC model demonstrated by improved survival and largest tumor growth inhibition. In vitro results indicated that the best microbubble formulation depends on the ultrasound parameters and concentration used, with SonoVue® being best at lower intensities and Sonazoid™ at higher intensities.

scholarly journals NR5A2 transcriptional activation by BRD4 promotes pancreatic cancer progression by upregulating GDF15

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Feng Guo ◽  
Yingke Zhou ◽  
Hui Guo ◽  
Dianyun Ren ◽  
Xin Jin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Transcriptional Activation ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Gene Sets ◽  
And Migration

AbstractNR5A2 is a transcription factor regulating the expression of various oncogenes. However, the role of NR5A2 and the specific regulatory mechanism of NR5A2 in pancreatic ductal adenocarcinoma (PDAC) are not thoroughly studied. In our study, Western blotting, real-time PCR, and immunohistochemistry were conducted to assess the expression levels of different molecules. Wound-healing, MTS, colony formation, and transwell assays were employed to evaluate the malignant potential of pancreatic cancer cells. We demonstrated that NR5A2 acted as a negative prognostic biomarker in PDAC. NR5A2 silencing inhibited the proliferation and migration abilities of pancreatic cancer cells in vitro and in vivo. While NR5A2 overexpression markedly promoted both events in vitro. We further identified that NR5A2 was transcriptionally upregulated by BRD4 in pancreatic cancer cells and this was confirmed by Chromatin immunoprecipitation (ChIP) and ChIP-qPCR. Besides, transcriptome RNA sequencing (RNA-Seq) was performed to explore the cancer-promoting effects of NR5A2, we found that GDF15 is a component of multiple down-regulated tumor-promoting gene sets after NR5A2 was silenced. Next, we showed that NR5A2 enhanced the malignancy of pancreatic cancer cells by inducing the transcription of GDF15. Collectively, our findings suggest that NR5A2 expression is induced by BRD4. In turn, NR5A2 activates the transcription of GDF15, promoting pancreatic cancer progression. Therefore, NR5A2 and GDF15 could be promising therapeutic targets in pancreatic cancer.

Hyperglycemia Promotes Pancreatic Cancer Initiation and Progression by Activating the Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 21 ◽  
Author(s):  
Huiming Chen ◽  
Junfeng Zhao ◽  
Ningning Jiang ◽  
Zheng Wang ◽  
Chang Liu
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Precancerous Lesions ◽  
Clinical Specimen ◽  
Ductal Adenocarcinoma ◽  
Dependent Manner ◽  
Pancreatic Cancer Cells ◽  
Cancer Initiation

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, with a 5-year survival rate of less than 10% because of the limited knowledge of tumor-promoting factors and their underlying mechanism. Diabetes mellitus (DM) and hyperglycemia are risk factors for many cancers, including PDAC, that modulate multiple downstream signaling pathways, such as the wingless/integrated (Wnt)/β-catenin signaling pathway. However, whether hyperglycemia promotes PDAC initiation and progression by activating the Wnt/β-catenin signaling pathway remains unclear. Methods: In this study, we used bioinformatics analysis and clinical specimen analysis to evaluate the activation states of the Wnt/βcatenin signaling pathway. In addition, colony formation assays, Transwell assays and wound-healing assays were used to evaluate the malignant biological behaviors of pancreatic cancer cells (PCs) under hyperglycemic conditions. To describe the effects of hyperglycemia and the Wnt/β-catenin signaling pathway on the initiation of PDAC, we used pancreatitis-driven pancreatic cancer initiation models in vivo and pancreatic acinar cell 3-dimensional culture in vitro. Results: Wnt/β-catenin signaling pathway-related molecules were overexpressed in PDAC tissues/cells and correlated with poor prognosis in PDAC patients. In addition, hyperglycemia exacerbated the abnormal activation of β-catenin in PDAC and enhanced the malignant biological behaviors of PCs in a Wnt/β-catenin signaling pathway-dependent manner. Indeed, hyperglycemia accelerated the formation of pancreatic precancerous lesions by activating the Wnt/β-catenin signaling pathway in vivo and in vitro. Conclusion: Hyperglycemia promotes pancreatic cancer initiation and progression by activating the Wnt/β-catenin signaling pathway.

scholarly journals Deferasirox, an oral iron chelator, with gemcitabine synergistically inhibits pancreatic cancer cell growth in vitro and in vivo

Oncotarget ◽  
2018 ◽  
Vol 9 (47) ◽  
pp. 28434-28444 ◽  
Author(s):  
Shuhei Shinoda ◽  
Seiji Kaino ◽  
Shogo Amano ◽  
Hirofumi Harima ◽  
Toshihiko Matsumoto ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Growth ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Iron Chelator ◽  
Oral Iron ◽  
Cancer Cell Growth ◽  
Oral Iron Chelator

scholarly journals KIF4A Regulates the Progression of Pancreatic Ductal Adenocarcinoma through Proliferation and Invasion

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Jing Chen ◽  
Cui-Cui Zhao ◽  
Fei-Ran Chen ◽  
Guo-Wei Feng ◽  
Fei Luo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Disease Free Survival ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion

Background. Pancreatic cancer is a malignant tumor of the digestive tract, which is difficult to diagnose and treat due to bad early diagnosis. We aimed to explore the role of kinesin superfamily 4A (KIF4A) in pancreatic ductal adenocarcinoma (PDAC). Methods. We first used the bioinformatic website to screen the data of pancreatic cancer in TCGA, and KIF4A protein was detected among the 86 specimens of patients in our hospital combined with clinic-pathological characteristics and survival analysis. KIF4A loss-expression cell lines were established by RNA interference (RNAi). In addition, we performed in vitro cell assays to detect the changes in cell proliferation, migration, and invasion. The proteins involved in the proliferation and metastasis of cancer cells were also detected by western blot. The above results could be proved in vivo. Further, the correlation between KIF4A and CDC5L was analyzed by TCGA and IHC data. Results. We first found a high expression of KIF4A in pancreatic cancer, suggesting a role of KIF4A in the development of pancreatic cancer. KIF4A was found to be differentially expressed ( P < 0.05 ) among the 86 specimens of patients in our hospital and was significantly associated with PDAC TNM stages and tumor size. High KIF4A expression also significantly worsened overall survival (OS) and disease-free survival rate (DFS) ( P < 0.05 , respectively). In addition, cell proliferation, migration, and invasion were inhibited by the KIF4A-shRNA group compared with the control ( P < 0.05 , respectively). In the end, knockdown of KIF4A could inhibit tumor development and metastasis in vivo. Further, the positive correlation between KIF4A and CDC5L existed, and KIF4A might promote pancreatic cancer proliferation by affecting CDC5L expression. Conclusion. In conclusion, the high expression level of KIF4A in PDAC was closely related to poor clinical and pathological status, lymphatic metastasis, and vascular invasion. KIF4A might be involved in promoting the development of PDAC in vitro and in vivo, which might be a new therapeutic target of PDAC.

Cordycepin inhibits pancreatic cancer cell growth in vitro and in vivo via targeting FGFR2 and blocking ERK signaling

2020 ◽  
Vol 18 (5) ◽  
pp. 345-355
Author(s):  
Xue-Ying LI ◽  
Homng TAO ◽  
Can JIN ◽  
Zhen-Yun DU ◽  
Wen-Feng LIAO ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Growth ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Erk Signaling ◽  
Cancer Cell Growth

scholarly journals IFN-γ down-regulates the PD-1 expression and assist nivolumab in PD-1-blockade effect on CD8+ T-lymphocytes in pancreatic cancer

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Guoping Ding ◽  
Tao Shen ◽  
Chen Yan ◽  
Mingjie Zhang ◽  
Zhengrong Wu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Lymphocytes ◽  
Ductal Adenocarcinoma ◽  
Cytotoxic Activities ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Cd8 T Lymphocytes ◽  
Ifn Γ

Abstract Background Pancreatic cancer is characterized by a highly immunosuppressive tumor microenvironment and evasion of immune surveillance. Although programmed cell death 1 receptor (PD-1) blockade has achieved certain success in immunogenic cancers, the responses to the PD-1 antibody are not effective or sustained in patients with pancreatic cancer. Methods Firstly, PD-1 expressions on peripheral CD8+ T-lymphocytes of patients with pancreatic cancer and healthy donors were measured. In in vitro study, peripheral T-lymphocytes were isolated and treated with nivolumab and/or interferon-γ, and next, PD-1-blockade effects, proliferations, cytokine secretions and cytotoxic activities were tested after different treatments. In in vivo study, mice bearing subcutaneous pancreatic cancer cell lines were treated with induced T-lymphocytes and tumor sizes were measured. Results PD-1 protein expression is increased on peripheral CD8+ T cells in patients with pancreatic ductal adenocarcinoma compared with that in health donor. PD-1 expression on CD8+ T-lymphocytes was decreased by nivolumab in a concentration-dependent manner in vitro. IFN-γ could directly down-regulate expression of PD-1 in vitro. Furthermore, the combination therapy of nivolumab and IFN-γ resulted in greatest effect of PD-1-blockde (1.73 ± 0.78), compared with IFN-γ along (18.63 ± 0.82) and nivolumab along (13.65 ± 1.22). Moreover, the effects of nivolumab plus IFN-γ largest promoted the T-lymphocytes function of proliferations, cytokine secretions and cytotoxic activities. Most importantly, T-lymphocytes induced by nivolumab plus IFN-γ presented the best repression of tumor growth. Conclusions IFN-γ plus a PD-1-blockading agent could enhance the immunologic function and might play a crucial role in effective adoptive transfer treatments of pancreatic cancer.

Effect of NVP-BEZ235, a dual PI3K/mTOR inhibitor, on chemotherapy and antiangiogenic response in pancreatic cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 243-243 ◽  
Author(s):  
Katherine T. Ostapoff ◽  
Niranjan Awasthi ◽  
Peter L. Yen ◽  
Changhua Zhang ◽  
Margaret A. Schwarz ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Combination Therapy ◽  
Mtor Inhibitor ◽  
Mammalian Target Of Rapamycin ◽  
Animal Experiments ◽  
Ductal Adenocarcinoma ◽  
Clinical Benefits ◽  
Induced Apoptosis

243 Background: The phosphatidylinositol-3-kinase (PI3K)/AKT and mammalian target of rapamycin (mTOR) signaling pathway dysregulation is a prominent feature of pancreatic ductal adenocarcinoma (PDAC). Gemcitabine (GEM), a standard systemic treatment for PDAC, has limited clinical benefits. The present study investigated the effects of NVP-BEZ235 (BEZ235), a novel dual PI3K/mTOR inhibitor, in combination with gemcitabine and endothelial monocyte activating polypeptide II (EMAP) in experimental PDAC. Methods: Protein expression and cell proliferation were analyzed by Western blotting and WST-1 assay. Animal experiments were performed in murine xenografts. Results: BEZ235 inhibited phospho-AKT (Ser473) and phospho-mTOR (Ser2448) expression in PDAC (AsPC-1), endothelial (HUVECs) and fibroblast (WI-38) cells. NVP-BEZ235 also caused a significant dephosphorylation of downstream mTORC1 target proteins phospho-p70 S6K (Thr389) and phospho-4E-BP1 (Thr37/46). In vitro 72-hour proliferation of four PDAC cell lines was significantly inhibited by BEZ235. Additive effects on proliferation inhibition were observed in the BEZ235 and GEM combination in PDAC cells and in combination of BEZ235 or EMAP with gemcitabine in HUVECs and WI-38 cells. BEZ235, alone or in combination with GEM and EMAP, induced apoptosis in AsPC-1, HUVECs and WI-38 cells as observed by increased expression of cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and caspase-3 proteins. PDAC in vivo therapy demonstrated that compared to controls (median survival: 16 days), animal survival increased after BEZ235 and EMAP therapy alone (both 21 days) and GEM monotherapy (28 days). Further increases in survival occurred in combination therapy groups BEZ235+GEM (30 days, p=0.007), BEZ235+EMAP (27 days, p=0.02), GEM+EMAP (31 days, p=0.001) and BEZ235+GEM +EMAP (33 days, p=0.004). Conclusions: BEZ235 has experimental PDAC antitumor activity in vitro and in vivo that can be enhanced in combination with cytotoxic (GEM) and antiendothelial (EMAP) agents. These findings demonstrate advantages of combination therapy strategies targeting multiple pathways in pancreatic cancer treatment.

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