Search Results (753)

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive type of pancreatic cancer. PDAC is difficult to diagnose due to a lack of symptoms in early stages, resulting in a survival rate of less than 10%. Moreover, often cancerous tissues cannot be surgically resected due to their deep abdomen location. Therefore, early detection is the essential strategy enabling effective PDAC treatment. Over the past few years, the development of nanomaterials for Magnetic Resonance Imaging (MRI) has expanded and improved imaging quality and diagnostic accuracy. Nanomaterials can be currently designed, manufactured and synthesized with other structures to provide improved diagnosis and advanced therapy. Although MRI equipped with the innovative nanomaterials became a powerful tool for the diagnosis and treatment of patients with various cancers, the detection of PDAC remains challenging. Nevertheless, recent advancements in PDAC theranostics provided progress in the detection and treatment of this challenging type of cancer. Present research in this area is focused on suitable carriers, eliminating delivery barriers, and the development of efficient anti-cancer drugs. Herein we discuss the current applications of iron oxide nanoparticles to the MRI diagnosis and treatment of pancreatic cancer. Full article

Carboxypeptidase A4 (CPA4) is an exopeptidase that cleaves peptide bonds at the C-terminal domain within peptides and proteins. It preferentially cleaves peptides with terminal aromatic or branched chain amino acid residues such as phenylalanine, tryptophan, or leucine. CPA4 was first discovered in prostate cancer cells, but it is now known to be expressed in various tissues throughout the body. Its physiologic expression is governed by latexin, a noncompetitive endogenous inhibitor of CPA4. Nevertheless, the overexpression of CPA4 has been associated with the progression and aggressiveness of many malignancies, including prostate, pancreatic, breast and lung cancer, to name a few. CPA4’s role in cancer has been attributed to its disruption of many cellular signaling pathways, e.g., PI3K-AKT-mTOR, STAT3-ERK, AKT-cMyc, GPCR, and estrogen signaling. The dysregulation of these pathways by CPA4 could be responsible for inducing epithelial--mesenchymal transition (EMT), tumor invasion and drug resistance. Although CPA4 has been found to regulate cancer aggressiveness and poor prognosis, no comprehensive review summarizing the role of CPA4 in cancer is available so far. In this review, we provide a brief description of peptidases, their classification, history of CPA4, mechanism of action of CPA4 as a peptidase, its expression in various tissues, including cancers, its role in various tumor types, the associated molecular pathways and cellular processes. We further discuss the limitations of current literature linking CPA4 to cancers and challenges that prevent using CPA4 as a biomarker for cancer aggressiveness and predicting drug response and highlight a number of future strategies that can help to overcome the limitations. Full article

Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), ranks among the most lethal malignancies, with a 5-year survival rate of under 10%. The most prevalent KRAS mutations occur in three hotspot residues: glycine-12 (G12), glycine-13 (G13), and glutamine-61 (Q61), leading to the constant activation of the Ras pathway, making them the primary focus in oncologic drug development. Selective KRAS G12C inhibitors (e.g., sotorasib, adagrasib) have demonstrated moderate efficacy in clinical trials; however, this mutation is infrequent in PDAC. Emerging therapies targeting KRAS G12D and G12V mutations, such as MRTX1133, PROTACs, and active-state inhibitors, show promise in preclinical studies. Pan-RAS inhibitors like ADT-007, RMC-9805, and RMC-6236 compounds provide broader coverage of mutations. Their efficacy and safety are currently being investigated in several clinical trials. A major challenge is the development of resistance mechanisms, including secondary mutations and pathway reactivation. Combination therapies targeting the RAS/MAPK axis, SHP2, mTOR, or SOS1 are under clinical investigation. Immunotherapy alone has demonstrated limited effectiveness, attributed to an immunosuppressive tumor microenvironment, although synergistic effects are noted when paired with KRAS-targeted agents. Furthermore, KRAS mutations reprogram cancer metabolism, enhancing glycolysis, macropinocytosis, and autophagy, which are being explored therapeutically. RNA interference technologies have also shown potential in silencing mutant KRAS and reducing tumorigenicity. Future strategies should emphasize the combination of targeted therapies with metabolic or immunomodulatory agents to overcome resistance and enhance survival in KRAS-mutated PDAC. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers worldwide, characterized by late diagnosis, aggressive progression, and poor response to conventional monotherapies. Combination therapies have emerged as a promising approach to overcome multidrug resistance (MDR), enhance efficacy, and target the complex tumor microenvironment (TME). Nanoparticle-based drug delivery systems (DDSs) have gained significant attention for their ability to co-deliver multiple agents with controlled release profiles. This review comprehensively examines nanoparticle-based platforms developed for PDAC combination therapies, focusing on small-molecule drugs. The systems discussed are drawn from studies published between 2005 and 2025. Full article

Pancreatic cancer is a highly lethal malignant tumor characterized by challenges in early diagnosis and limited therapeutic options, leading to an exceptionally low clinical cure rate. With the advent of novel cancer treatment paradigms, ferroptosis—a form of iron-dependent regulated cell death driven by lipid peroxidation—has emerged as a promising therapeutic strategy, particularly for tumors harboring RAS mutations. However, the poor bioavailability and insufficient tumor-targeting capabilities of conventional drugs constrain the efficacy of ferroptosis-based therapies. Recent advancements in nanotechnology and imaging-guided treatments offer transformative solutions through targeted drug delivery, real-time monitoring of treatment efficacy, and multimodal synergistic strategies. This article aims to elucidate the mechanisms underlying ferroptosis in pancreatic cancer and to summarize the latest identified therapeutic targets for ferroptosis in this context. Furthermore, it reviews the recent progress in nanotechnology-based ferroptosis therapy for pancreatic cancer, encompassing ferroptosis monotherapy, synergistic ferroptosis therapy, and endogenous ferroptosis therapy. Subsequently, the integration of imaging-guided nanotechnology in ferroptosis therapy is summarized. Finally, this paper discusses innovative strategies, such as stroma-targeted ferroptosis therapy, immune-ferroptosis synergy, and AI-driven nanomedicine development, offering new insights and directions for future research in pancreatic cancer treatment. Full article

Background/Objectives: Organ transplantation is a life-saving intervention for patients with terminal organ failure, but long-term success is hindered by graft rejection and dependence on lifelong immunosuppressants. These drugs pose risks such as opportunistic infections and malignancies. Chimeric antigen receptor (CAR) technology, originally developed for cancer immunotherapy, has been adapted to regulatory T cells (Tregs) to enhance their antigen-specific immunosuppressive function. This systematic review evaluates the preclinical development of CAR-Tregs in promoting graft tolerance and suppressing graft-versus-host disease (GvHD). Methods: A systematic review following PROSPERO guidelines (CRD420251073207) was conducted across PubMed, Scopus, and Web of Science for studies published from 2015 to 2024. After screening 105 articles, 17 studies involving CAR-Tregs in preclinical or in vivo transplant or GvHD models were included. Results: CAR-Tregs exhibited superior graft-protective properties compared to unmodified or polyclonal Tregs. HLA-A2-specific CAR-Tregs consistently improved graft survival, reduced inflammatory cytokines, and suppressed immune cell infiltration across skin, heart, and pancreatic islet transplant models. The inclusion of CD28 as a co-stimulatory domain enhanced Treg function and FOXP3 expression. However, challenges such as Treg exhaustion, tonic signaling, and reduced in vivo persistence were noted. Some studies reported synergistic effects when CAR-Tregs were combined with immunosuppressants like rapamycin or tacrolimus. Conclusions: CAR-Tregs offer a promising strategy for inducing targeted immunosuppression in allogeneic transplantation. While preclinical findings are encouraging, further work is needed to optimize CAR design, ensure in vivo stability, and establish clinical-scale manufacturing before translation to human trials. Full article

Background: Transcription factor pancreatic and duodenal homeobox 1 (PDX1) plays a central role in pancreatic development and insulin regulation. However, its role in breast cancer remains largely unexplored. Objective: This study investigated the effects of PDX1 knockdown and overexpression on MCF7 breast cancer cell proliferation and responsiveness to paclitaxel and doxorubicin. Methods: PDX1 knockdown and overexpression models were established in MCF7 cells. Cell viability was assessed using the XTT assay following exposure to paclitaxel (5–100 nM) or doxorubicin (125–10 µM). Gene and protein expression levels were analyzed by qRT-PCR and western blotting. Results: PDX1 knockdown in MCF7 cells led to a significant increase in proliferation compared to the scrambled control, with approximately 3.22-fold at 72 h, whereas PDX1 overexpression markedly reduced proliferation by about 2.4-fold at 72 h when compared with the control. Upon treatment with paclitaxel or doxorubicin, knockdown cells showed higher viability, indicating reduced drug sensitivity. In contrast, PDX1-overexpressing cells exhibited a significant decrease in viability after treatment with both drugs, demonstrating enhanced sensitivity. Conclusions: PDX1 exhibits tumor-suppressive properties in MCF7 cells and modulates drug response, suggesting that it may serve as a biomarker or therapeutic target in hormone receptor-positive breast cancer. Full article

Background: Pancreatic cancer is frequently identified as the cancer type with the shortest probable survival time after diagnosis, and efforts to develop successful treatments have had a very limited impact in the clinic. One reason for the limited therapeutic options is the lack of appealing drug targets. The great majority of pancreatic cancers are classified as Pancreatic Ductal Adenocarcinoma (PDAC), in which the genetic landscape is dominated by four genes: KRAS, TP53, CDKN2A, and SMAD4. However, despite extensive knowledge of these genetic drivers, the development of effective therapies has seen only very limited success. Methods: Existing evidence indicates that mutations in the tumour suppressor gene PTEN are uncommon in PDAC (<10% cases). However, the loss of PTEN function through non-genetic mechanisms may be much more common and have a strong impact. We therefore summarise and review a large body of immunohistochemical studies that address the loss of PTEN in PDAC as well as a smaller number of studies addressing other implicated proteins, including KDM6A and ARID1A. Results: These studies show some loss of PTEN protein in more than half of PDAC cases. Furthermore, although genetic changes in genes including KDM6A/UTX and ARID1A are also uncommon, reduced expression of their encoded proteins is observed in many, perhaps most, cases of PDAC. Conclusions: These analyses, which go beyond genetics, highlight the broader set of cellular functions that are dysregulated in many pancreatic cancers and provide broader opportunities for treatment strategies. This review highlights the emerging importance of other drivers in PDAC, which are less well-studied in this context. Full article

Oral microbiota have been implicated in pancreatic ductal adenocarcinoma (PDAC) and may contribute to chemotherapy resistance. While previous studies attributed bacteria-induced resistance to indirect host modulation, recent findings suggest a direct mechanism. Escherichia coli expressing long-form cytidine deaminase (CDD_L) can degrade gemcitabine, a chemotherapeutic agent, into a non-toxic form, leading to resistance. In contrast, bacteria carrying short form (CDD_S) or lacking CDD did not induce resistance. This study investigates whether oral bacteria can cause gemcitabine resistance in PDAC cells through CDD-mediated degradation. Oral microbes associated with PDAC were selected based on CDD isoforms: Aggregatibacter actinomycetemcomitans carrying CDD_L, Enterococcus faecalis, Streptococcus mutans, Porphyromonas gingivalis, all carrying CDD_S, and Fusobacterium nucleatum lacking CDD. The selected microbes, along with wild-type and CDD-deficient E. coli, were co-incubated with gemcitabine to assess its degradation and PDAC cell proliferation. A. actinomycetemcomitans fully degraded gemcitabine and induced resistance. Surprisingly, CDD_S-expressing oral bacteria partially degraded gemcitabine in a strain-dependent manner. Expressing either CDD_L or CDD_S in CDD-deficient E. coli resulted in equivalent gemcitabine degradation and resistance, indicating that CDD function is independent of isoform length. These findings highlight the role of oral bacteria in gemcitabine resistance and the need for strategies to mitigate microbial-driven resistance in PDAC treatment. Full article

Pancreatic cancer is one of the most lethal malignancies, in part due to its profound metabolic adaptability, which underlies drug resistance and therapeutic failure. This study explores the metabolic rewiring associated with resistance to treatment using a systems metabolomics approach. Exposure to the redox-disrupting agent erastin revealed key metabolic vulnerabilities but failed to produce lasting growth suppression. Combinatorial treatments with methotrexate or alpelisib significantly impaired proliferation and triggered marked metabolic shifts. Systems-level analyses identified serine metabolism as a central adaptive pathway in resilient cells. Metabolic tracing and gene expression profiling showed increased de novo serine biosynthesis and uptake, supporting redox homeostasis, biosynthetic activity, and epigenetic regulation. Notably, cells that resumed growth after drug withdrawal exhibited transcriptional reprogramming involving serine-driven pathways, along with elevated expression of genes linked to survival, proliferation, and migration. These findings establish serine metabolism as a functional biomarker of metabolic plasticity and adaptive resilience in pancreatic cancer, suggesting that targeting this adaptive axis may enhance therapeutic efficacy. Full article

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types due to its late diagnosis, low survival rates, and high frequency of metastasis. Considering the molecular mechanism of PDAC development has not been fully elucidated, this study aimed to shed more light on the molecular regulatory signatures of circular RNAs (circRNAs) in PDAC progression and provide a different perspective to identify potential biomarkers as well as discover candidate repositioned drug molecules for the prevention or treatment of PDAC with network-based integrative analysis. The mRNA, miRNA, and circRNA expression profiles of PDAC were obtained from nine microarray datasets. Differentially expressed genes (DEGs), microRNAs (DEmiRNAs), and circular RNAs (DEcircRNAs) were identified. The competing endogenous RNA (ceRNA; DEG–DEmiRNA–DEcircRNA) regulatory network was constructed, which included 12 DEcircRNAs, 64 DEGs, and 6 miRNAs specific to PDAC. The ADAM12, MET, QKI, SEC23A, and ZEB2 were identified as hub genes and demonstrated significant survival probability for PDAC. In addition to providing novel biomarkers for diagnosis that can be detected non-invasively, the secretion levels of hub genes-associated proteins were found in plasma, serum, and oral epithelium. The drug repositioning analysis revealed vorinostat, meclocycline sulfosalicylate, and trichostatin A, which exhibited significant binding affinities to the hub genes compared to their inhibitors via molecular docking analysis. Full article

Mesenchymal stem cells (MSCs) have recently shown great promise as potential anticancer drug delivery carriers. MSCs exhibit tropism to inflammatory sites, such as tumor beds, and resistance to chemotherapeutics. The aim of this study was to examine the efficacy of gemcitabine (GEM) conjugated with flurbiprofen (FLU) as a potential agent enhancing the GEM cytotoxic effect. Pancreatic cancer cell lines (PCCs), including PANC-1, AsPC-1, and BxPC-3, were studied meticulously. Moreover, the usefulness of bone-marrow-derived mesenchymal stem cells (BM-MSCs) treated with GEM and FLU, and the conditioned media from above these cells (CM) as elements supporting the in vitro action of GEM, inducing apoptosis, necrosis, and inhibiting the cell cycle, was tested. The results showed that CM-GEM exhibited higher cytotoxicity towards the selected PCCs compared to GEM alone. Furthermore, the obtained data revealed lower sensitivity of these cells to treatment, which promotes the utilization of BM-MSCs as potential drug carriers. Based on the presented findings, it seems that applying FLU in the antiproliferative effect of GEM might be regarded as an effective strategy in the therapy of pancreatic cancer, especially in the inhibition of proliferation and induction of cancer cell death. Full article

Background/Objectives: Chronic inflammation is a key driver of cancer. Interleukin 33 (IL-33) has emerged as a crucial factor involved in the pathogenesis of cancer-prone chronic inflammation. IL-33 functions as a cytokine and a nuclear protein to initiate chronic inflammation and cancer. However, small molecules capable of suppressing IL-33 expression to block its cytokine and nuclear functions are underexplored. Methods: The impact of tropisetron on IL-33 expression and its role in suppressing pancreatitis and pancreatitis-mediated pancreatic cancer were examined. Results: We demonstrate that tropisetron suppresses IL-33 expression, with high potential to serve as a novel therapeutic strategy for preventing chronic inflammation and its cancer sequela. Through screening 1018 Food and Drug Administration (FDA)-approved drugs, we discovered that tropisetron, a 5-hydroxytryptamine type 3 (5-HT3) antagonist commonly used to prevent and treat nausea and vomiting, effectively blocked IL-33 expression by suppressing IRF3 activation. Tropisetron inhibited pancreatitis and its progression to pancreatic cancer in mice. Conclusions: Tropisetron is an IL-33 inhibitor and can provide a novel therapeutic strategy to prevent and treat chronic pancreatitis and its associated cancer. Full article

Background/Objectives: PARP inhibitors (PARPis) currently play frontline roles in the management of prostate, pancreatic, ovarian and breast cancers, but their roles in colorectal cancer (CRC) management have yet to be clarified. Importantly, the specific predictive biomarkers for PARPis in CRC are still matters of investigations. The aim of this study is to identify the potential predictive biomarkers of PARP inhibition in CRC. Methods: Gene set enrichment analyses (GSEAs) and drug ontology enrichment analyses (DOEAs) of PARPi response gene sets were applied as the surrogates of PARPi response to two CRC cohorts in order to compare the predictive capacities of TP53 mutation status, MSI status, as well as PARP1 and PARP2 expression for PARP inhibition to those of a homologous repair deficiency surrogate, and large-scale state transition (LST). Differential enrichment score (ES) and ontology enrichment (OE) analyses were used to interrogate the differential correlation of the predictive biomarkers with PARPi response, relative to LST. Results: The results demonstrated that LST-low, rather than LST-high, CRC subsets exhibited an enrichment of the PARPi response, in contrast to what has been established for other cancers. Furthermore, CRC subsets with wild-type TP53, positive MSI, as well as high PARP1 and PARP2 expression exhibited an enrichment of the PARPi response gene sets. Moreover, there was no differential enrichment of the PARPi response between LST and each of the MSI statuses, PARP1 expression and PARP2 expression. Furthermore, the preliminary differential enrichment observed between the LST-based and TP53 mutation status-based PARPi responses could not be validated with further testing. Conclusions: MSI status, TP53 mutation status as well as PARP1 and PARP2 expression may be substitutes for low LST as predictive biomarkers of PARPi response in CRC. Full article

Background/Objectives: Pomegranate (Punica granatum) peel, often discarded as waste, contains abundant bioactive compounds such as polyphenols, vitamins, flavonoids, tannins, anthocyanins, and many more. This contributes to remarkable bioactivities, including anticancer, anti-inflammatory, antioxidant, antibacterial, and antifungal properties. Pancreatic cancer is a deadly cancer with a 9% survival rate. Its aggressiveness, invasiveness, quick metastasis, and poor prognosis significantly decrease the survival rate. Thus, we aim to explore pomegranate peel as a possible alternative medication for treating pancreatic cancer through virtual methods. Methods: Firstly, bioactive compounds were collected from multiple databases and screened for oral bioavailability (OB) ≥ 0.3 and drug likeness (DL) ≥ 0.18 scores. Simultaneously, network pharmacology was employed to extract the most probable targets for pancreatic cancer. Further computational analyses were performed, including molecular docking, molecular dynamics simulation, and in silico pharmacokinetics evaluation. Results: Consequently, the top 10 key targets from network analysis were AKT1, IL6, TNF, SRC, STAT3, EGFR, BCL2, HSP90AA1, HIF1A, and PTGS2. However, only AKT1, EGFR, BCL2, HSP90AA1, and PTGS2 exhibited strong binding affinities with pomegranate compounds, which are significantly declared in affected cells to enhance cancer progression. Outcomes from molecular dynamics simulations, particularly RMSD, RMSF, hydrogen bonding, and radius of gyration (Rg), confirmed stable interactions between 1-O-Galloyl-beta-D-glucose, epicatechin, phloridzin, and epicatechin gallate with respective target proteins. Conclusions: This suggests that pomegranate peels hold anticancer bioactive compounds for treating pancreatic cancer. Surprisingly, most compounds adhere to Lipinski’s and Pfizer’s rules and display no toxicity. However, as this study relies entirely on computational methods, experimental validation is necessary to confirm these findings and assess real-world efficacy and potential side effects. Full article