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Phytomedicine : International Journal... Jan 2024Pancreatic cancer is an extremely malignant digestive tumor, however, owing to its high drug resistance of pancreatic cancer, the search for more effective...
BACKGROUND
Pancreatic cancer is an extremely malignant digestive tumor, however, owing to its high drug resistance of pancreatic cancer, the search for more effective anti-pancreatic cancer drugs is urgently needed. Lycorine, an alkaloid of natural plant origin, exerts antitumor effects on a variety of tumors.
PURPOSE
This study aimed to investigate the therapeutic effect of lycorine on pancreatic cancer and elucidate its potential molecular mechanism.
METHODS
Two pancreatic cancer cell lines, PANC-1 and BxPC-3, were used to investigate the therapeutic effects of lycorine on pancreatic cancer in vitro using the CCK8 assay, colony formation assay, 5-Ethynyl-2'- deoxyuridine (EdU) incorporation assay, flow cytometry, and western blotting. Transcriptome sequencing and gene set enrichment analysis (GSEA) were used to analyze the differentially expressed genes and pathways after lycorine treatment. Molecular docking, quantitative real-time PCR (qRT-PCR), oil red O staining, small interfering RNA (siRNA) transfection, and other experiments were performed to further validate the differentially expressed genes and pathways. In vivo experiments were conducted to investigate lycorine's inhibitory effects and toxicity on pancreatic cancer using a tumor-bearing mouse model.
RESULTS
Lycorine inhibited the proliferation of pancreatic cancer cells, caused G2/M phase cycle arrest and induced apoptosis. Transcriptome sequencing and GSEA showed that lycorine inhibition of pancreatic cancer was associated with fatty acid metabolism, and aldehyde dehydrogenase 3A1 (ALDH3A1) was a significantly enriched target in the fatty acid metabolism process. ALDH3A1 expression was significantly upregulated in pancreatic cancer and was closely associated with prognosis. Molecular docking showed that lycorine binds strongly to ALDH3A1. Further studies revealed that lycorine inhibited the fatty acid oxidation (FAO) process in pancreatic cancer cells and induced cell growth inhibition and apoptosis through ALDH3A1. Lycorine also showed significant suppressive effects in tumor-bearing mice. Importantly, it did not result in significant toxicity to liver and kidney of mice, demonstrating its therapeutic potential as a safe antitumor agent.
CONCLUSION
Lycorine inhibited pancreatic cancer cell proliferation, blocked the cell cycle, and induced apoptosis by targeting ALDH3A1. FAO inhibition was identified for the first time as a possible mechanism for the anticancer effects of lycorine. These findings enrich the theory of targeted therapy for pancreatic cancer, expand our understanding of the pharmacological targets of lycorine, and provide a reference for exploring its natural components.
Topics: Animals; Mice; Molecular Docking Simulation; Cell Line, Tumor; Transcriptome; Cell Proliferation; Antineoplastic Agents; Pancreatic Neoplasms; Apoptosis; RNA, Small Interfering; Fatty Acids
PubMed: 37839227
DOI: 10.1016/j.phymed.2023.155128 -
BMJ Case Reports Dec 2023Peripancreatic tuberculosis (PTB) is a very rare variant of tuberculosis and its clinical and radiological findings are similar to those of pancreatic malignancy....
Peripancreatic tuberculosis (PTB) is a very rare variant of tuberculosis and its clinical and radiological findings are similar to those of pancreatic malignancy. Diagnosis of PTB is usually incidental and is made after surgical resection. We are presenting a male patient who had complaints of prolonged fever, significant weight loss and yellowish discolouration of eyes and dark-coloured urine. Investigations revealed that there was a pancreatic mass causing obstructive jaundice. However, the aetiology of the mass, whether tubercular or malignant, was not clear. Hence, the patient was planned for endoscopic ultrasound-guided fine needle aspiration cytology. Cytology and aspirate were sent for a cartridge-based nucleic acid amplification test which revealed the presence of , sensitive to rifampicin. The patient improved completely after treatment with antitubercular therapy.
Topics: Humans; Male; Pancreatic Diseases; Tuberculosis; Pancreatic Neoplasms; Antitubercular Agents; Mycobacterium tuberculosis; Endoscopic Ultrasound-Guided Fine Needle Aspiration
PubMed: 38086575
DOI: 10.1136/bcr-2023-256433 -
Nature Cancer Sep 2023The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing...
The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.
Topics: Humans; Gemcitabine; Protein-Lysine 6-Oxidase; Pancreatic Neoplasms; Pancreatic Diseases
PubMed: 37640930
DOI: 10.1038/s43018-023-00614-y -
Annals of Surgical Oncology Jul 2023Pancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC). Neoadjuvant systemic therapy is recommended as initial treatment. It is... (Meta-Analysis)
Meta-Analysis Review
FOLFIRINOX or Gemcitabine-based Chemotherapy for Borderline Resectable and Locally Advanced Pancreatic Cancer: A Multi-institutional, Patient-Level, Meta-analysis and Systematic Review.
BACKGROUND
Pancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC). Neoadjuvant systemic therapy is recommended as initial treatment. It is currently unclear what chemotherapy should be preferred for patients with BRPC or LAPC.
METHODS
We performed a systematic review and multi-institutional meta-analysis of patient-level data regarding the use of initial systemic therapy for BRPC and LAPC. Outcomes were reported separately for tumor entity and by chemotherapy regimen including FOLFIRINOX (FIO) or gemcitabine-based.
RESULTS
A total of 23 studies comprising 2930 patients were analyzed for overall survival (OS) calculated from the beginning of systemic treatment. OS for patients with BRPC was 22.0 months with FIO, 16.9 months with gemcitabine/nab-paclitaxel (Gem/nab), 21.6 months with gemcitabine/cisplatin or oxaliplatin or docetaxel or capecitabine (GemX), and 10 months with gemcitabine monotherapy (Gem-mono) (p < 0.0001). In patients with LAPC, OS also was higher with FIO (17.1 months) compared with Gem/nab (12.5 months), GemX (12.3 months), and Gem-mono (9.4 months; p < 0.0001). This difference was driven by the patients who did not undergo surgery, where FIO was superior to other regimens. The resection rates for patients with BRPC were 0.55 for gemcitabine-based chemotherapy and 0.53 with FIO. In patients with LAPC, resection rates were 0.19 with Gemcitabine and 0.28 with FIO. In resected patients, OS for patients with BRPC was 32.9 months with FIO and not different compared to Gem/nab, (28.6 months, p = 0.285), GemX (38.8 months, p = 0.1), or Gem-mono (23.1 months, p = 0.083). A similar trend was observed in resected patients converted from LAPC.
CONCLUSIONS
In patients with BRPC or LAPC, primary treatment with FOLFIRINOX compared with Gemcitabine-based chemotherapy appears to provide a survival benefit for patients that are ultimately unresectable. For patients that undergo surgical resection, outcomes are similar between GEM+ and FOLFIRINOX when delivered in the neoadjuvant setting.
Topics: Humans; Gemcitabine; Antineoplastic Combined Chemotherapy Protocols; Oxaliplatin; Pancreatic Neoplasms; Fluorouracil; Leucovorin; Neoadjuvant Therapy; Paclitaxel; Multicenter Studies as Topic
PubMed: 37020094
DOI: 10.1245/s10434-023-13353-2 -
Med (New York, N.Y.) Oct 2023Identifying a metastasis-correlated immune cell composition within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) will help to develop...
BACKGROUND
Identifying a metastasis-correlated immune cell composition within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) will help to develop promising and innovative therapeutic strategies. However, the dynamics of immune cell lineages in the TME of advanced PDAC remains elusive.
METHODS
Twenty-six samples from 11 patients (including 11 primary tumor tissues, 10 blood, and 5 lymph nodes) with different stages were used to develop a multiscale immune profile. High-dimensional single-cell analysis with mass cytometry was performed to search for metastasis-correlated immune changes in the microenvironment. The findings were further validated by published single-cell RNA sequencing (scRNA-seq) data and multiplex fluorescent immunohistochemistry.
FINDINGS
High-dimensional single-cell profiling revealed that the three immune-relevant sites formed a distinct immune atlas. Interestingly, the PDAC microenvironment with the potential for metastatic spread to the liver was characterized by a decreased proportion of CD103PD-1CD39 T cells with cytotoxic and exhausted functional status and an increased proportion of CD73 macrophages. Analysis of scRNA-seq data of PDAC further confirmed the identified subsets and revealed strong potential interactions via various ligand-receptor pairs between the identified T subsets and the macrophages. Moreover, stratified patients with different immune compositions correlated with clinical outcomes of PDAC.
CONCLUSIONS
Our study uncovered metastasis-correlated immune changes, suggesting that ecosystem-based patient classification in PDAC will facilitate the identification of candidates likely to benefit from immunotherapy.
FUNDING
This work was supported by the National Key Research and Development Program of China, the Shanghai International Science and Technology Collaboration Program, the Shanghai Sailing Program, and the Key Laboratory of diagnosis and treatment of severe hepato-pancreatic diseases of Zhejiang Province.
Topics: Humans; Ecosystem; China; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Liver Neoplasms; Tumor Microenvironment
PubMed: 37633269
DOI: 10.1016/j.medj.2023.07.010 -
Revista Espanola de Enfermedades... Jul 2023This year, 2023, marks the fiftieth anniversary of the introduction of therapeutic endoscopic retrograde cholangiopancreatography (ERCP), which completely changed the...
This year, 2023, marks the fiftieth anniversary of the introduction of therapeutic endoscopic retrograde cholangiopancreatography (ERCP), which completely changed the management of biliary and pancreatic diseases. As in other invasive procedures, two intrinsically related concepts soon appeared: drainage success and complications. It was observed that ERCP is the most dangerous procedure regularly performed by gastrointestinal endoscopists, with a morbidity and mortality of 5-10 % and 0.1-1 %, respectively. ERCP is by far one of the best examples of a complex endoscopic technique.
Topics: Humans; Cholangiopancreatography, Endoscopic Retrograde; Pancreatic Diseases; Drainage; Retrospective Studies
PubMed: 36809925
DOI: 10.17235/reed.2023.9507/2022 -
Gastrointestinal Endoscopy Clinics of... Oct 2023In the last half century, endotherapy for pancreatic diseases has changed considerably. Although endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic... (Review)
Review
In the last half century, endotherapy for pancreatic diseases has changed considerably. Although endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) were introduced initially as diagnostic tools, they quickly evolved into therapeutic tools for preventing and managing complications of pancreatitis. More recently, therapeutic endoscopy has shown potential in palliation and cure of pancreatic neoplasms. This article discusses the changing landscape of pancreatic endotherapy as therapeutic ERCP and EUS were introduced and because they have evolved to treat different diseases.
Topics: Humans; Pancreas; Cholangiopancreatography, Endoscopic Retrograde; Endosonography; Pancreatitis; Pancreatic Diseases
PubMed: 37709404
DOI: 10.1016/j.giec.2023.03.012 -
Gastroenterology May 2024Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplastic stroma surrounding most tumors. Activated stromal fibroblasts, namely cancer-associated...
BACKGROUND & AIMS
Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplastic stroma surrounding most tumors. Activated stromal fibroblasts, namely cancer-associated fibroblasts (CAFs), play a major role in PDAC progression. We analyzed whether CAFs influence acinar cells and impact PDAC initiation, that is, acinar-to-ductal metaplasia (ADM). ADM connection with PDAC pathophysiology is indicated, but not yet established. We hypothesized that CAF secretome might play a significant role in ADM in PDAC initiation.
METHODS
Mouse and human acinar cell organoids, acinar cells cocultured with CAFs and exposed to CAF-conditioned media, acinar cell explants, and CAF cocultures were examined by means of quantitative reverse transcription polymerase chain reaction, RNA sequencing, immunoblotting, and confocal microscopy. Data from liquid chromatography with tandem mass spectrometry analysis of CAF-conditioned medium and RNA sequencing data of acinar cells post-conditioned medium exposure were integrated using bioinformatics tools to identify the molecular mechanism for CAF-induced ADM. Using confocal microscopy, immunoblotting, and quantitative reverse transcription polymerase chain reaction analysis, we validated the depletion of a key signaling axis in the cell line, acinar explant coculture, and mouse cancer-associated fibroblasts (mCAFs).
RESULTS
A close association of acino-ductal markers (Ulex europaeus agglutinin 1, amylase, cytokeratin-19) and mCAFs (α-smooth muscle actin) in LSL-Kras; LSL-Trp53; Pdx1 (KPC) and LSL-Kras; Pdx1 (KC) autochthonous progression tumor tissue was observed. Caerulein treatment-induced mCAFs increased cytokeratin-19 and decreased amylase in wild-type and KC pancreas. Likewise, acinar-mCAF cocultures revealed the induction of ductal transdifferentiation in cell line, acinar-organoid, and explant coculture formats in WT and KC mice pancreas. Proteomic and transcriptomic data integration revealed a novel laminin α5/integrinα4/stat3 axis responsible for CAF-mediated acinar-to-ductal cell transdifferentiation.
CONCLUSIONS
Results collectively suggest the first evidence for CAF-influenced acino-ductal phenotypic switchover, thus highlighting the tumor microenvironment role in pancreatic carcinogenesis inception.
Topics: Animals; Humans; Mice; Acinar Cells; Cancer-Associated Fibroblasts; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Transdifferentiation; Coculture Techniques; Culture Media, Conditioned; Laminin; Metaplasia; Organoids; Pancreatic Neoplasms; Signal Transduction; Tumor Microenvironment
PubMed: 38154529
DOI: 10.1053/j.gastro.2023.12.018 -
Clinical Nutrition (Edinburgh, Scotland) Feb 2024Both acute and chronic pancreatitis are frequent diseases of the pancreas, which, despite being of benign nature, are related to a significant risk of malnutrition and...
Both acute and chronic pancreatitis are frequent diseases of the pancreas, which, despite being of benign nature, are related to a significant risk of malnutrition and may require nutritional support. Acute necrotizing pancreatitis is encountered in 20 % of patients with acute pancreatitis, is associated with increased morbidity and mortality, and may require artificial nutrition by enteral or parenteral route, as well as additional endoscopic, radiological or surgical interventions. Chronic pancreatitis represents a chronic inflammation of the pancreatic gland with development of fibrosis. Abdominal pain leading to decreased oral intake, as well as exocrine and endocrine failure are frequent complications of the disease. All of the above represent risk factors related to malnutrition. Therefore, patients with chronic pancreatitis should be considered at risk, screened and supplemented accordingly. Moreover, osteoporosis and increased facture risk should be acknowledged in patients with chronic pancreatitis, and preventive measures should be considered.
Topics: Humans; Acute Disease; Enteral Nutrition; Pancreatitis, Chronic; Malnutrition
PubMed: 38169174
DOI: 10.1016/j.clnu.2023.12.019 -
Nature Communications Jul 2023The response rate of pancreatic cancer to chemotherapy or immunotherapy pancreatic cancer is low. Although minimally invasive irreversible electroporation (IRE) ablation...
The response rate of pancreatic cancer to chemotherapy or immunotherapy pancreatic cancer is low. Although minimally invasive irreversible electroporation (IRE) ablation is a promising option for irresectable pancreatic cancers, the immunosuppressive tumour microenvironment that characterizes this tumour type enables tumour recurrence. Thus, strengthening endogenous adaptive antitumour immunity is critical for improving the outcome of ablation therapy and post-ablation immune therapy. Here we present a hydrogel microsphere vaccine that amplifies post-ablation anti-cancer immune response via releasing its cargo of FLT3L and CD40L at the relatively lower pH of the tumour bed. The vaccine facilitates migration of the tumour-resident type 1 conventional dendritic cells (cDC1) to the tumour-draining lymph nodes (TdLN), thus initiating the cDC1-mediated antigen cross-presentation cascade, resulting in enhanced endogenous CD8 T cell response. We show in an orthotopic pancreatic cancer model in male mice that the hydrogel microsphere vaccine transforms the immunologically cold tumour microenvironment into hot in a safe and efficient manner, thus significantly increasing survival and inhibiting the growth of distant metastases.
Topics: Hydrogels; Microspheres; Pancreatic Neoplasms; Male; Animals; Mice; Cell Line, Tumor; Mice, Inbred C57BL; Cancer Vaccines; Electroporation; CD8-Positive T-Lymphocytes
PubMed: 37433774
DOI: 10.1038/s41467-023-39759-w