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1.
Cancer Med ; 13(11): e7395, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38872370

ABSTRACT

BACKGROUND AND AIMS: Pancreatic cancer is one of the most lethal malignancies, partly due to resistance to conventional chemotherapy. The chemoresistance of malignant tumors is associated with epithelial-mesenchymal transition (EMT) and the stemness of cancer cells. The aim of this study is to investigate the availability and functional mechanisms of trefoil factor family 1 (TFF1), a tumor-suppressive protein in pancreatic carcinogenesis, to treat pancreatic cancer. METHODS: To investigate the role of endogenous TFF1 in human and mice, specimens of human pancreatic cancer and genetically engineered mouse model of pancreatic cancer (KPC/TFF1KO; Pdx1-Cre/LSL-KRASG12D/LSL-p53R172H/TFF1-/-) were analyzed by immunohistochemistry (IHC). To explore the efficacy of extracellular administration of TFF1, recombinant and chemically synthesized TFF1 were administered to pancreatic cancer cell lines, a xenograft mouse model and a transgenic mouse model. RESULTS: The deficiency of TFF1 was associated with increased EMT of cancer cells in mouse models of pancreatic cancer, KPC. The expression of TFF1 in cancer cells was associated with better survival rate of the patients who underwent chemotherapy, and loss of TFF1 deteriorated the benefit of gemcitabine in KPC mice. Extracellular administration of TFF1 inhibited gemcitabine-induced EMT, Wnt pathway activation and cancer stemness, eventually increased apoptosis of pancreatic cancer cells in vitro. In vivo, combined treatment of gemcitabine and subcutaneous administration of TFF1 arrested tumor growth in xenograft mouse model and resulted in the better survival of KPC mice by inhibiting EMT and cancer stemness. CONCLUSION: These results indicate that TFF1 can contribute to establishing a novel strategy to treat pancreatic cancer patients by enhancing chemosensitivity.


Subject(s)
Drug Resistance, Neoplasm , Epithelial-Mesenchymal Transition , Neoplastic Stem Cells , Pancreatic Neoplasms , Trefoil Factor-1 , Animals , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/genetics , Trefoil Factor-1/metabolism , Trefoil Factor-1/genetics , Humans , Mice , Epithelial-Mesenchymal Transition/drug effects , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/drug effects , Cell Line, Tumor , Tumor Suppressor Proteins/metabolism , Tumor Suppressor Proteins/genetics , Xenograft Model Antitumor Assays , Gemcitabine , Mice, Transgenic , Female , Male , Cell Proliferation/drug effects , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Apoptosis/drug effects , Gene Expression Regulation, Neoplastic/drug effects
2.
J Nanobiotechnology ; 22(1): 319, 2024 Jun 08.
Article in English | MEDLINE | ID: mdl-38849938

ABSTRACT

Myeloid-derived suppressor cells (MDSCs) have played a significant role in facilitating tumor immune escape and inducing an immunosuppressive tumor microenvironment. Eliminating MDSCs and tumor cells remains a major challenge in cancer immunotherapy. A novel approach has been developed using gemcitabine-celecoxib twin drug-based nano-assembled carrier-free nanoparticles (GEM-CXB NPs) for dual depletion of MDSCs and tumor cells in breast cancer chemoimmunotherapy. The GEM-CXB NPs exhibit prolonged blood circulation, leading to the preferential accumulation and co-release of GEM and CXB in tumors. This promotes synergistic chemotherapeutic activity by the proliferation inhibition and apoptosis induction against 4T1 tumor cells. In addition, it enhances tumor immunogenicity by immunogenic cell death induction and MDSC-induced immunosuppression alleviation through the depletion of MDSCs. These mechanisms synergistically activate the antitumor immune function of cytotoxic T cells and natural killer cells, inhibit the proliferation of regulatory T cells, and promote the M2 to M1 phenotype repolarization of tumor-associated macrophages, considerably enhancing the overall antitumor and anti-metastasis efficacy in BALB/c mice bearing 4T1 tumors. The simplified engineering of GEM-CXB NPs, with their dual depletion strategy targeting immunosuppressive cells and tumor cells, represents an advanced concept in cancer chemoimmunotherapy.


Subject(s)
Deoxycytidine , Gemcitabine , Immunotherapy , Mice, Inbred BALB C , Myeloid-Derived Suppressor Cells , Nanoparticles , Animals , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Myeloid-Derived Suppressor Cells/drug effects , Mice , Immunotherapy/methods , Female , Nanoparticles/chemistry , Cell Line, Tumor , Tumor Microenvironment/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/immunology , Cell Proliferation/drug effects
3.
Cancer Lett ; 592: 216919, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38704133

ABSTRACT

Efforts to develop targetable molecular bases for drug resistance for pancreatic ductal adenocarcinoma (PDAC) have been equivocally successful. Using RNA-seq and ingenuity pathway analysis we identified that the superpathway of cholesterol biosynthesis is upregulated in gemcitabine resistant (gemR) tumors using a unique PDAC PDX model with resistance to gemcitabine acquired in vivo. Analysis of additional in vitro and in vivo gemR PDAC models showed that HMG-CoA synthase 2 (HMGCS2), an enzyme involved in cholesterol biosynthesis and rate limiting in ketogenesis, is overexpressed in these models. Mechanistic data demonstrate the novel findings that HMGCS2 contributes to gemR and confers metastatic properties in PDAC models, and that HMGCS2 is BRD4 dependent. Further, BET inhibitor JQ1 decreases levels of HMGCS2, sensitizes PDAC cells to gemcitabine, and a combination of gemcitabine and JQ1 induced regressions of gemR tumors in vivo. Our data suggest that decreasing HMGCS2 may reverse gemR, and that HMGCS2 represents a useful therapeutic target for treating gemcitabine resistant PDAC.


Subject(s)
Azepines , Carcinoma, Pancreatic Ductal , Deoxycytidine , Drug Resistance, Neoplasm , Gemcitabine , Hydroxymethylglutaryl-CoA Synthase , Pancreatic Neoplasms , Triazoles , Xenograft Model Antitumor Assays , Animals , Humans , Mice , Antimetabolites, Antineoplastic/pharmacology , Azepines/pharmacology , Bromodomain Containing Proteins , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/genetics , Cell Line, Tumor , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Drug Resistance, Neoplasm/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Hydroxymethylglutaryl-CoA Synthase/metabolism , Hydroxymethylglutaryl-CoA Synthase/genetics , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Transcription Factors/metabolism , Transcription Factors/genetics , Transcription Factors/antagonists & inhibitors , Triazoles/pharmacology , Female , Mice, SCID
4.
J Biochem Mol Toxicol ; 38(6): e23733, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38770938

ABSTRACT

The aim of this investigation was to evaluate the differential expression of the sterol O-acyltransferase 1 (SOAT1) protein in gallbladder cancer tissues and cells, investigate the impact of Avastin on the proliferation, migration, invasion capabilities of gallbladder cancer cells, and its potential to induce cell apoptosis. Immunohistochemical analysis of samples from 145 gallbladder cancer patients was conducted, along with analysis of SOAT1 protein, mRNA expression levels, and cholesterol content in gallbladder cancer cell lines SGC-996, NOZ, and gallbladder cancer (GBC)-SD using Western blot and q-PCR techniques. Furthermore, the effects of Avastin on the proliferation, migration, and invasion capabilities of these gallbladder cancer cell lines were studied, and its ability to induce cell apoptosis was evaluated using flow cytometry, Western blot, and immunohistochemical methods. Additionally, gene expression and pathway analysis were performed, and the synergistic therapeutic effects of Avastin combined with gemcitabine were tested in a gallbladder cancer xenograft model. The study found that SOAT1 expression was significantly upregulated in GBC tissues and positively correlated with lymph node metastasis and TNM staging. In vitro experiments demonstrated that Avastin significantly inhibited the proliferation, migration, and invasion capabilities of SGC-996 and GBC-SD cell lines and induced apoptosis. RNA sequencing analysis revealed multiple differentially expressed genes in cells treated with Avastin, primarily enriched in biological pathways such as signaling transduction, malignant tumors, and the immune system. In vivo, experiments confirmed that Avastin could effectively suppress tumor growth in a gallbladder cancer xenograft model and enhanced the treatment efficacy when used in combination with gemcitabine. Overall, these findings provide new insights and strategies for targeted therapy in gallbladder cancer.


Subject(s)
Gallbladder Neoplasms , Sterol O-Acyltransferase , Gallbladder Neoplasms/pathology , Gallbladder Neoplasms/drug therapy , Gallbladder Neoplasms/metabolism , Gallbladder Neoplasms/genetics , Humans , Female , Male , Cell Line, Tumor , Animals , Middle Aged , Sterol O-Acyltransferase/metabolism , Sterol O-Acyltransferase/genetics , Mice , Gemcitabine , Cell Proliferation/drug effects , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Mice, Nude , Apoptosis/drug effects , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Cell Movement/drug effects , Xenograft Model Antitumor Assays , Aged , Gene Expression Regulation, Neoplastic/drug effects , Mice, Inbred BALB C , Neoplasm Proteins/metabolism , Neoplasm Proteins/genetics
5.
Biochim Biophys Acta Mol Basis Dis ; 1870(6): 167214, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38718846

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC), is characteristic by a heterogeneous tumor microenvironment and gene mutations, conveys a dismal prognosis and low response to chemotherapy and immunotherapy. Here, we found that checkpoint suppressor 1 (CHES1) served as a tumor repressor in PDAC and was associated with patient prognosis. Functional experiments indicated that CHES1 suppressed the proliferation and invasion of PDAC by modulating cellular senescence. To further identify the downstream factor of CHES1 in PDAC, label-free quantitative proteomics analysis was conducted, which showed that the oncogenic Aldo-keto reductase 1B10 (AKR1B10) was transcriptionally repressed by CHES1 in PDAC. And AKR1B10 facilitated the malignant activity and repressed senescent phenotype of PDAC cells. Moreover, pharmaceutical inhibition of AKR1B10 with Oleanolic acid (OA) significantly induced tumor regression and sensitized PDAC cells to gemcitabine, and this combined therapy did not cause obvious side effects. Rescued experiments revealed that CHES1 regulated the tumorigenesis and gemcitabine sensitivity through AKR1B10-mediated senescence in PDAC. In summary, this study revealed that the CHES1/AKR1B10 axis modulated the progression and cellular senescence in PDAC, which might provide revenues for drug-targeting and senescence-inducing therapies for PDAC.


Subject(s)
Aldehyde Reductase , Aldo-Keto Reductases , Carcinoma, Pancreatic Ductal , Cellular Senescence , Gemcitabine , Gene Expression Regulation, Neoplastic , Pancreatic Neoplasms , Humans , Cellular Senescence/drug effects , Aldo-Keto Reductases/metabolism , Aldo-Keto Reductases/genetics , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/drug therapy , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/drug therapy , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Aldehyde Reductase/metabolism , Aldehyde Reductase/genetics , Aldehyde Reductase/antagonists & inhibitors , Animals , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Cell Proliferation , Mice , Oleanolic Acid/pharmacology , Oleanolic Acid/analogs & derivatives , Carcinogenesis/metabolism , Carcinogenesis/genetics , Carcinogenesis/pathology , Mice, Nude
6.
Eur J Pharm Biopharm ; 200: 114326, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38759897

ABSTRACT

Glioblastoma (GBM) is a highly deadly brain tumor that does not respond satisfactorily to conventional treatment. The non-alkylating agent gemcitabine (GEM) has been proposed for treating GBM. It can overcome MGMT protein-mediated resistance, a major limitation of conventional therapy with the alkylating agent temozolomide (TMZ). However, GEM's high systemic toxicity and poor permeability across the blood-brain barrier (BBB) pose significant challenges for its delivery to the brain. Thus, mucoadhesive poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) coated with chitosan (CH), suitable for intranasal GEM delivery, were proposed in this work. A central composite design (CCD) was implemented for NPs optimization, and NPs with appropriate characteristics for intranasal administration were obtained. in vitro studies revealed that the NPs possess excellent mucoadhesive properties and the ability to selectively release GEM in the simulated tumor tissue environment. in vitro studies using two human GBM cell lines (U215 and T98G) revealed the NPs' ability to promote GEM's antiproliferative activity to sensitize cells to the effect of TMZ. The findings of this work demonstrate that the developed CH-GEM-NPs are suitable delivery systems for GEM, both as a single therapy and as a chemosensitizer to the GBM gold standard therapy.


Subject(s)
Brain Neoplasms , Chitosan , Deoxycytidine , Drug Repositioning , Gemcitabine , Glioblastoma , Nanoparticles , Polylactic Acid-Polyglycolic Acid Copolymer , Glioblastoma/drug therapy , Glioblastoma/pathology , Deoxycytidine/analogs & derivatives , Deoxycytidine/administration & dosage , Deoxycytidine/pharmacology , Deoxycytidine/chemistry , Humans , Chitosan/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Nanoparticles/chemistry , Cell Line, Tumor , Brain Neoplasms/drug therapy , Brain Neoplasms/metabolism , Drug Repositioning/methods , Temozolomide/administration & dosage , Temozolomide/pharmacology , Temozolomide/pharmacokinetics , Administration, Intranasal , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/pharmacology , Antimetabolites, Antineoplastic/chemistry , Antimetabolites, Antineoplastic/pharmacokinetics , Drug Carriers/chemistry , Blood-Brain Barrier/metabolism , Drug Liberation
7.
Mol Pharm ; 21(6): 2699-2712, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38747900

ABSTRACT

This study aims to encapsulate gemcitabine (GEM) using a phospholipid complex (PLC) in lipid nanoparticles (NPs) to achieve several desirable outcomes, including high drug loading, uniform particle size, improved therapeutic efficacy, and reduced toxicities. The successful preparation of GEM-loaded lipid NPs (GEM-NPs) was accomplished using the emulsification-solidification method, following optimization through Box-Behnken design. The size of the GEM-NP was 138.5 ± 6.7 nm, with a low polydispersity index of 0.282 ± 0.078, as measured by a zetasizer and confirmed by transmission electron and atomic force microscopy. GEM-NPs demonstrated sustained release behavior, surpassing the performance of the free GEM and phospholipid complex. Moreover, GEM-NPs exhibited enhanced cytotoxicity, apoptosis, and cell uptake in Panc-2 and Mia PaCa cells compared to the free GEM. The in vivo pharmacokinetics revealed approximately 4-fold higher bioavailability of GEM-NPs in comparison with free GEM. Additionally, the pharmacodynamic evaluation conducted in a DMBA-induced pancreatic cancer model, involving histological examination, serum IL-6 level estimation, and expression of cleaved caspase-3, showed the potential of GEM-NPs in the management of pancreatic cancer. Consequently, the lipid NP-based approach developed in our investigation demonstrates high stability and uniformity and holds promise for enhancing the therapeutic outcomes of GEM.


Subject(s)
Deoxycytidine , Gemcitabine , Nanoparticles , Pancreatic Neoplasms , Phospholipids , Deoxycytidine/analogs & derivatives , Deoxycytidine/chemistry , Deoxycytidine/pharmacology , Deoxycytidine/pharmacokinetics , Deoxycytidine/administration & dosage , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Nanoparticles/chemistry , Animals , Humans , Cell Line, Tumor , Phospholipids/chemistry , Mice , Particle Size , Apoptosis/drug effects , Drug Carriers/chemistry , Lipids/chemistry , Drug Liberation , Male , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/pharmacokinetics , Antimetabolites, Antineoplastic/chemistry , Antimetabolites, Antineoplastic/pharmacology , Drug Stability , Rats , Liposomes
8.
FASEB J ; 38(10): e23705, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38805171

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a notoriously dismal prognosis. As a competitive inhibitor of DNA synthesis, gemcitabine is the cornerstone drug for treating PDAC at all stages. The therapeutic effect of gemcitabine, however, is often hindered by drug resistance, and the underlying mechanisms remain largely unknown. It is unclear whether their response to chemotherapeutics is regulated by endocrine regulators, despite the association between PDAC risk and endocrine deregulation. Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both in vitro and in vivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR-4763-3p and miR-3663-5p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism. We demonstrate that two key enzymes of the pentose phosphate pathway (PPP), G6PD and TKT, are directly targeted by miR-4763-3p and miR-3663-5p. Notably, miR-4763-3p and miR-3663-5p diminish the nucleotide synthesis of the PPP pathway, thereby increasing gemcitabine sensitivity. As a result, PRLR harnesses these two miRNAs to suppress PPP and nucleotide synthesis, subsequently elevating the gemcitabine sensitivity of PDAC cells. Also, PDAC tissues and tumors from LSL-KrasG12D/+, LSL-Trp53R172H/+, and PDX1-cre (KPC) mice exhibit downregulation of PRLR. Bisulfite sequencing of PDAC tissues revealed that PRLR downregulation is due to epigenetic methylation. In this study, we show for the first time that the endocrine receptor PRLR improves the effects of gemcitabine by boosting two new miRNAs that block the PPP pathway and nucleotide synthesis by inhibiting two essential enzymes concurrently. The PRLR-miRNAs-PPP axis may serve as a possible therapeutic target to supplement chemotherapy advantages in PDAC.


Subject(s)
Carcinoma, Pancreatic Ductal , Deoxycytidine , Gemcitabine , Glucosephosphate Dehydrogenase , MicroRNAs , Pancreatic Neoplasms , Receptors, Prolactin , Animals , Female , Humans , Mice , Antimetabolites, Antineoplastic/pharmacology , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Glucosephosphate Dehydrogenase/metabolism , Glucosephosphate Dehydrogenase/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Receptors, Prolactin/metabolism , Receptors, Prolactin/genetics , Mice, Nude
9.
ACS Appl Mater Interfaces ; 16(23): 29686-29698, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38813771

ABSTRACT

Gemcitabine (GEM) is a nucleoside analogue approved as a first line of therapy for pancreatic ductal adenocarcinoma (PDAC). However, rapid metabolism by plasma cytidine deaminase leading to the short half-life, intricate intracellular metabolism, ineffective cell uptake, and swift development of chemoresistance downgrades the clinical efficacy of GEM. ONC201 is a small molecule that inhibits the Akt and ERK pathways and upregulates the TNF-related apoptosis-inducing ligand (TRAIL), which leads to the reversal of both intrinsic and acquired GEM resistance in PDAC treatment. Moreover, the pancreatic cancer cells that were able to bypass apoptosis after treatment of ONC201 get arrested in the G1-phase, which makes them highly sensitive to GEM. To enhance the in vivo stability of GEM, we first synthesized a disulfide bond containing stearate conjugated GEM (lipid-GEM), which makes it sensitive to the redox tumor microenvironment (TME) comprising high glutathione levels. In addition, with the help of colipids 1,2-dioleoyl-glycero-3-phosphocholine (DOPC), cholesterol, and 1,2-distearoyl-glycero-3-phosphoethanolamine-poly(ethylene glycol)-2000 (DSPE-PEG 2000), we were able to synthesize the lipid-GEM conjugate and ONC201 releasing liposomes. A cumulative drug release study confirmed that both ONC201 and GEM showed sustained release from the formulation. Since MUC1 is highly expressed in 70-90% PDAC, we conjugated a MUC1 binding peptide in the liposomes which showed higher cytotoxicity, apoptosis, and cellular internalization by MIA PaCa-2 cells. A biodistribution study further confirmed that the systemic delivery of the liposomes through the tail vein resulted in a higher accumulation of drugs in orthotopic PDAC tumors in NSG mice. The IHC of the excised tumor grafts further confirmed the higher apoptosis and lower metastasis and cell proliferation. Thus, our MUC1 targeting binary drug-releasing liposomal formulation showed higher drug payload, enhanced plasma stability, and accumulation of drugs in the pancreatic orthotopic tumor and thus is a promising therapeutic alternative for the treatment of PDAC.


Subject(s)
Deoxycytidine , Gemcitabine , Pancreatic Neoplasms , Deoxycytidine/analogs & derivatives , Deoxycytidine/chemistry , Deoxycytidine/pharmacology , Animals , Mice , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/metabolism , Humans , Cell Line, Tumor , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrimidines/pharmacokinetics , Apoptosis/drug effects , Liposomes/chemistry , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/pathology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology
10.
Redox Biol ; 73: 103200, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38781729

ABSTRACT

Currently, chemotherapy remains occupying a pivotal place in the treatment of pancreatic ductal adenocarcinoma (PDAC). Nonetheless, the emergence of drug resistance in recent years has limited the clinical efficacy of chemotherapeutic agents, especially gemcitabine (GEM). Through bioinformatics analysis, AT-rich Interactive Domain-containing Protein 3A (ARID3A), one of transcription factors, is discovered to possibly participate in this progress. This study thoroughly investigates the potential role of ARID3A in the malignant progression and GEM chemoresistance of PDAC and explores the underlying mechanisms. The results indicate that ARID3A knockdown suppresses tumor development and enhances the sensitivity of PDAC cells to GEM in vitro and vivo. Mechanically, CUT&Tag profiling sequencing, RNA-sequencing and functional studies demonstrates that decreased ARID3A expression alleviates the transcriptional inhibition of phosphatase and tensin homolog (PTEN), consequently leading to glutathione peroxidase 4 (GPX4) depletion and increased lipid peroxidation levels. Activated ferroptosis induced by the inhibition of GPX4 subsequently restricts tumor progression and reduces GEM resistance in PDAC. This research identifies the ferroptosis regulatory pathway of ARID3A-PTEN-GPX4 axis and reveals its critical role in driving the progression and chemoresistance of pancreatic cancer. Notably, both inhibition of ARID3A and enhancement of ferroptosis can increase chemosensitivity to GEM, which offers a promising opportunity for developing therapeutic strategies to combat acquired chemotherapy resistance in pancreatic cancer.


Subject(s)
DNA-Binding Proteins , Drug Resistance, Neoplasm , Ferroptosis , Gene Expression Regulation, Neoplastic , PTEN Phosphohydrolase , Pancreatic Neoplasms , Transcription Factors , Ferroptosis/drug effects , Ferroptosis/genetics , Humans , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , Drug Resistance, Neoplasm/genetics , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Mice , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Animals , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Gemcitabine , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Cell Proliferation/drug effects , Xenograft Model Antitumor Assays , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics
11.
Phytomedicine ; 129: 155656, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38723529

ABSTRACT

BACKGROUND: Gemcitabine is the first-line chemotherapy drug that can easily cause chemotherapy resistance. Huaier is a traditional Chinese medicine and shows an antitumor effect in pancreatic cancer, but whether it can enhance the gemcitabine chemotherapeutic response and the potential mechanism remain unknown. PURPOSE: This study was performed to explore the effect of Huaier in promoting the tumor-killing effect of gemcitabine and elucidate the possible mechanism in pancreatic cancer. METHODS: Cell Counting Kit-8 assays and colony formation assays were used to detect proliferation after different treatments. Protein coimmunoprecipitation was applied to demonstrate protein interactions. Nuclear protein extraction and immunofluorescence were used to confirm the intracellular localization of the proteins. Western blotting was performed to detect cell proliferation-related protein expression or cancer stem cell-associated protein expression. Sphere formation assays and flow cytometry were used to assess the stemness of pancreatic cancer cells. The in vivo xenograft model was used to confirm the inhibitory effect under physiological conditions, and immunohistochemistry was used to detect protein expression. RESULTS: Huaier suppressed the proliferation and stem cell-like properties of pancreatic cancer cells. We found that Huaier suppressed the expression of forkhead box protein M1 (FoxM1). In addition, Huaier inhibited FoxM1 function by blocking its nuclear translocation. Treatment with Huaier reversed the stemness induced by gemcitabine in a FoxM1-dependent manner. Furthermore, we verified the above results by an in vivo study, which reached the same conclusion as those in vitro. CONCLUSION: Overall, this study illustrates that Huaier augments the tumor-killing effect of gemcitabine through suppressing the stemness induced by gemcitabine in a FoxM1-dependent way. These results indicate that Huaier can be applied to overcome gemcitabine resistance.


Subject(s)
Cell Proliferation , Deoxycytidine , Forkhead Box Protein M1 , Gemcitabine , Mice, Nude , Neoplastic Stem Cells , Pancreatic Neoplasms , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Forkhead Box Protein M1/metabolism , Humans , Animals , Pancreatic Neoplasms/drug therapy , Neoplastic Stem Cells/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Mice , Mice, Inbred BALB C , Xenograft Model Antitumor Assays , Drugs, Chinese Herbal/pharmacology , Complex Mixtures , Trametes
12.
Neoplasia ; 53: 101002, 2024 07.
Article in English | MEDLINE | ID: mdl-38744194

ABSTRACT

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) poorly responds to antineoplastic agents. Discrepancies between preclinical success and clinical failure of compounds has been a continuous challenge and major obstacle in PDAC research. AIM: To investigate the association of the tumor microenvironment (TME) composition and gemcitabine metabolizing enzyme (GME) expression in vitro and several in vivo models. METHODS: mRNA expression and protein levels of GME (cytosolic 5'-nucleotidase 1 A; NT5C1A, cytidine deaminase; CDA, deoxycytidine kinase; DCK), gemcitabine transporters (ENT1, ENT2, RRM1, RRM2) and stromal components (hyaluroninc acid, podoplanin, masson trichrome, picrosirius) were assessed by qRT-PCR and immunohistochemistry in murine LSL-KrasG12D/+;LSL-Trp53R172 H/+; Pdx-1-Cre (KPC), orthotopically transplanted mice (OTM), human primary resected PDAC tissue (hPRT), corresponding patient-derived xenograft (PDX) mice, and KPC-SPARC-/- mice. mRNA expression of GME was analyzed in PDAC cell lines (Panc-1, MIA PaCa, BXPC3 and L3.6) upon incubation on collagen or pancreatic stellate cell (PSC) conditioned media by qRT-PCR. RESULTS: Endogenous KPC tumors exhibited significantly higher levels of GME compared to OTM. However, GME levels did not differ between hPRT and corresponding PDX mice. Using Kendalls Tau correlation coefficient we did not show a significant correlation of GME and components of the TME except for NT5C1A and hyaluronic acid in PDX mice (p=0.029). GME were not significantly altered upon SPARC depletion in vivo, and upon treatment with PSC-conditioned media or incubation on collagen plated dishes in vitro. CONCLUSIONS: Our findings suggest that the expression of GME is independent from the deposition of stromal components. KPC mice are most appropriate to study stromal composition whereas PDX mice maintain GME expression of the corresponding hPRT and could be best suited for pharmacokinetic studies.


Subject(s)
Deoxycytidine , Disease Models, Animal , Gemcitabine , Pancreatic Neoplasms , Stromal Cells , Tumor Microenvironment , Animals , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Mice , Humans , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Cell Line, Tumor , Stromal Cells/metabolism , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , Xenograft Model Antitumor Assays , Antimetabolites, Antineoplastic/pharmacology , Gene Expression Regulation, Neoplastic/drug effects
13.
Cell Rep ; 43(5): 114176, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38691454

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis due to therapeutic resistance. We show that PDAC cells undergo global epigenetic reprogramming to acquire chemoresistance, a process that is driven at least in part by protein arginine methyltransferase 1 (PRMT1). Genetic or pharmacological PRMT1 inhibition impairs adaptive epigenetic reprogramming and delays acquired resistance to gemcitabine and other common chemo drugs. Mechanistically, gemcitabine treatment induces translocation of PRMT1 into the nucleus, where its enzymatic activity limits the assembly of chromatin-bound MAFF/BACH1 transcriptional complexes. Cut&Tag chromatin profiling of H3K27Ac, MAFF, and BACH1 suggests a pivotal role for MAFF/BACH1 in global epigenetic response to gemcitabine, which is confirmed by genetically silencing MAFF. PRMT1 and MAFF/BACH1 signature genes identified by Cut&Tag analysis distinguish gemcitabine-resistant from gemcitabine-sensitive patient-derived xenografts of PDAC, supporting the PRMT1-MAFF/BACH1 epigenetic regulatory axis as a potential therapeutic avenue for improving the efficacy and durability of chemotherapies in patients of PDAC.


Subject(s)
Deoxycytidine , Drug Resistance, Neoplasm , Epigenesis, Genetic , Gemcitabine , Pancreatic Neoplasms , Protein-Arginine N-Methyltransferases , Repressor Proteins , Protein-Arginine N-Methyltransferases/metabolism , Protein-Arginine N-Methyltransferases/genetics , Humans , Drug Resistance, Neoplasm/genetics , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Repressor Proteins/metabolism , Repressor Proteins/genetics , Cell Line, Tumor , Animals , Mice , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/pathology , Gene Expression Regulation, Neoplastic/drug effects , Cellular Reprogramming/drug effects , Cellular Reprogramming/genetics
14.
Biochem Pharmacol ; 225: 116253, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38701869

ABSTRACT

Infection with Helicobacter pylori (H. pylori or Hp) is associated with an increased susceptibility to gastric diseases, notably gastric cancer (GC). This study investigates the impact of Hp infection on chemoresistance and immune activity in GC cells. Hp infection in AGS and MKN-74 cells promoted proliferation, migration and invasion, apoptosis resistance, and tumorigenic activity of cells under cisplatin (DDP) plus gemcitabine (GEM) treatment. Additionally, it dampened activity of the co-cultured CD8+ T cells. Hp infection increased POU class 5 homeobox 1 (POU5F1) level, which further activated secreted phosphoprotein 1 (SPP1) transcription to increase its expression. Silencing of either SPP1 or POU5F1 enhanced the GEM sensitivity in GC cells, and it increased the populations of CD8+ T cells and the secretion of immune-active cytokines both in vitro and in xenograft tumors in immunocompetent mice. However, the effects of POU5F1 silencing were counteracted by SPP1 overexpression. Furthermore, the POU5F1/SPP1 axis activated the PI3K/AKT signaling pathway. This study demonstrates that Hp infection induces POU5F1 upregulation and SPP1 activation, leading to increased DDP/GEM resistance and T cell inactivation in GC cells.


Subject(s)
Drug Resistance, Neoplasm , Helicobacter Infections , Helicobacter pylori , Octamer Transcription Factor-3 , Osteopontin , Stomach Neoplasms , Up-Regulation , Stomach Neoplasms/metabolism , Humans , Animals , Up-Regulation/drug effects , Mice , Helicobacter Infections/metabolism , Helicobacter Infections/microbiology , Helicobacter Infections/immunology , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/physiology , Octamer Transcription Factor-3/metabolism , Octamer Transcription Factor-3/genetics , Helicobacter pylori/drug effects , Helicobacter pylori/physiology , Osteopontin/metabolism , Osteopontin/genetics , Cisplatin/pharmacology , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , T-Lymphocytes/immunology , Male , Mice, Nude
15.
Cancer Lett ; 595: 216997, 2024 Jul 28.
Article in English | MEDLINE | ID: mdl-38801887

ABSTRACT

Anti-FGFR treatment for cholangiocarcinoma (CCA) with fibroblast growth factor receptor (FGFR) alteration is a promising treatment option. Since the antitumor mechanisms of anti-FGFR inhibitors and conventional cytotoxic drugs differ, synergistic effects can be possible. This study aimed to evaluate the efficacy of the combined administration of gemcitabine (GEM) and pemigatinib in CCA cells with FGFR2 alterations. To simulate the treatment for patients with 3 kinds of CCA, chemonaïve CCA with activation of the FGF pathway, chemo-resistant CCA with activation of the FGF pathway, and CCA without FGF pathway activation (as controls), we evaluated 3 different CCA cell lines, CCLP-1 (with a FGFR2 fusion mutation), CCLP-GR (GEM-resistant cells established from CCLP-1), and HuCCT1 (without FGFR mutations). There was no significant difference between CCLP-1 and HuCCT1 in GEM suspensibility (IC50 = 19.3, 22.6 mg/dl, p = 0.1187), and the drug sensitivity to pemigatinib did not differ between CCLP-1 and CCLP-GR (IC50 = 7.18,7.60 nM, p = 0.3089). Interestingly, only CCLP-1 showed a synergistic effect with combination therapy consisting of GEM plus pemigatinib in vitro and in vivo. In a comparison of the reaction to GEM exposure, only CCLP-1 cells showed an increase in the activation of downstream proteins in the FGF pathway, especially FRS2 and ERK. In association with this reaction, cell cycle and mitosis were increased with GEM exposure in CCLP-1, but HuCCT1/CCLP-GR did not show this reaction. Our results suggested that combination therapy with GEM plus pemigatinib is a promising treatment for chemonaïve patients with CCA with activation of the FGF pathway.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Bile Duct Neoplasms , Cholangiocarcinoma , Deoxycytidine , Drug Synergism , Gemcitabine , Pyrimidines , Receptor, Fibroblast Growth Factor, Type 2 , Xenograft Model Antitumor Assays , Humans , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/pathology , Cholangiocarcinoma/genetics , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/administration & dosage , Animals , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/pathology , Bile Duct Neoplasms/genetics , Cell Line, Tumor , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Pyrimidines/pharmacology , Pyrimidines/administration & dosage , Receptor, Fibroblast Growth Factor, Type 2/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Receptor, Fibroblast Growth Factor, Type 2/genetics , Mice , Cell Proliferation/drug effects , Mice, Nude , Signal Transduction/drug effects , Fibroblast Growth Factors/metabolism , Fibroblast Growth Factors/genetics , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Receptors, Fibroblast Growth Factor/metabolism , Drug Resistance, Neoplasm/drug effects , Protein Kinase Inhibitors/pharmacology , Mutation , Apoptosis/drug effects , Morpholines , Pyrroles
16.
Int J Biol Macromol ; 270(Pt 1): 131949, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38749890

ABSTRACT

Granular ß-1,3-glucan extracted from the wall of Ganoderma lucidum spores, named GPG, is a bioregulator. In this study, we investigated the structural, thermal, and other physical properties of GPG. We determined whether GPG ameliorated immunosuppression caused by Gemcitabine (GEM) chemotherapy. Triple-negative breast cancer mice with GPG combined with GEM treatment had reduced tumor burdens. In addition, GEM treatment alone altered the tumor microenvironment(TME), including a reduction in antitumor T cells and a rise in myeloid-derived suppressor cells (MDSC) and regulatory T cells (Tregs). However, combined GPG treatment reversed the tumor immunosuppressive microenvironment induced by GEM. GPG inhibited bone marrow (BM)-derived MDSC differentiation and reversed MDSC expansion induced by conditioned medium (CM) in GEM-treated E0771 cells through a Dectin-1 pathway. In addition, GPG downgraded PD-L1 and IDO1 expression on MDSC while boosting MHC-II, CD86, TNF-α, and IL-6 expression. In conclusion, this study demonstrated that GPG could alleviate the adverse effects induced by GEM chemotherapy by regulating TME.


Subject(s)
Myeloid-Derived Suppressor Cells , Reishi , Spores, Fungal , Triple Negative Breast Neoplasms , Tumor Microenvironment , beta-Glucans , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Animals , Myeloid-Derived Suppressor Cells/drug effects , Myeloid-Derived Suppressor Cells/metabolism , Myeloid-Derived Suppressor Cells/immunology , Mice , beta-Glucans/pharmacology , beta-Glucans/chemistry , Reishi/chemistry , Female , Tumor Microenvironment/drug effects , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Lectins, C-Type
17.
Int J Biol Macromol ; 269(Pt 2): 132019, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38729498

ABSTRACT

The clinical use of chemotherapy for refractory osteosarcoma (OS) is limited due to its multiorgan toxicity. To overcome this challenge, new dosage forms and combination treatments, such as phototherapy, are being explored to improve targeted delivery and cytocompatibility of chemotherapeutic agents. In addition, inducing ferroptosis in iron-rich tumors could be a promising strategy to enhance OS therapy. In this study, a novel formulation was developed using natural biological H-ferritin (HFn) encapsulating the photosensitizer IR-780 and the chemotherapy drug gemcitabine (Gem) for OS-specific targeted therapy (HFn@Gem/IR-780 NPs). HFn@Gem/IR-780 NPs were designed to specifically bind and internalize into OS cells by interacting with transferrin receptor 1 (TfR1) which is overexpressed on the surface of OS cell membranes. The Gem and IR-780 were then released responsively under mildly acidic conditions in tumors. HFn@Gem/IR-780 NPs achieved cascaded antitumor therapeutic efficacy through the combination of chemotherapy and phototherapy under near-infrared irradiation in vitro and in vivo. Importantly, HFn@Gem/IR-780 NPs demonstrated excellent safety profile with significantly decreased drug exposure to normal organs, indicating its potential for reducing systemic toxicity. Thus, utilizing HFn as a vehicle to encapsulate highly effective antitumor drugs provides a promising approach for the treatment of OS metastasis and relapse.


Subject(s)
Deoxycytidine , Ferroptosis , Gemcitabine , Nanoparticles , Osteosarcoma , Osteosarcoma/drug therapy , Osteosarcoma/pathology , Osteosarcoma/metabolism , Ferroptosis/drug effects , Animals , Humans , Cell Line, Tumor , Mice , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Nanoparticles/chemistry , Bone Neoplasms/drug therapy , Bone Neoplasms/metabolism , Bone Neoplasms/pathology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Neoplasm Metastasis , Xenograft Model Antitumor Assays , Indoles
18.
J Biochem Mol Toxicol ; 38(6): e23737, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38798245

ABSTRACT

Recently, olsalazine a DNA hypomethylating agent was found to inhibit the growth of breast cancer cells. The present study was carried out to evaluate the effects of olsalazine pretreatment in the potentiation of chemosensitivity of gemcitabine for the treatment of hepatocellular carcinoma (HCC). In silico molecular docking was performed to analyze the interaction of olsalazine and gemcitabine with DNMT1 and DNA, respectively, using the AutoDock tools 1.5.6. Cytotoxicity of olsalazine, gemcitabine, and combination were measured on human HePG2 cells using MTT assay. Antiproliferative effects were assessed using animal model of N-nitrosodiethylamine and carbon tetrachloride-induced HCC. Treatment was initiated from 8th week of induction to 11th week and change in body weight, liver weight, and survival rate were measured. Following treatment, blood samples were collected for estimation serum biochemistry. Blood serum was used for the estimation of inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), C-reactive protein [CRP], lactate dehydrogenase (LDH), and P53 levels. Oxidative stress markers were measured in liver tissue homogenates. Histopathology and immunohistochemistry (IHC) were performed on liver sections to detect the morphological changes and P53 expression. Docking analysis revealed the interactions between olsalazine and DNMT1 with a binding energy score of -5.34 and gemcitabine and DNA with a binding energy score of -5.93. Olsalazine pretreatment potentiated the antiproliferative effect of gemcitabine in cell line study. In the group receiving olsalazine pretreatment showed significant reductions in relative liver weight and improved survival rate of gemcitabine treatment group. Serum biochemical markers: serum glutamate pyruvate transaminase, serum glutamic oxaloacetic transaminase, alkaline phosphatase, and bilirubin revealed improved liver functions. Olsalazine pretreatment also reduced the levels of inflammatory markers like CRP, LDH, TNF-α, and IL-6 and oxidative stress markers dose dependently. Histopathology and IHC showed improved liver morphology with potentiated the induction of P53 upon olsalazine pretreatment in combination with gemcitabine. In conclusion, sequential combination of olsalazine and gemcitabine improved the treatment outcomes during the progression of HCC.


Subject(s)
Carcinoma, Hepatocellular , Deoxycytidine , Gemcitabine , Liver Neoplasms , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/metabolism , Animals , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Hep G2 Cells , Molecular Docking Simulation , Male , Drug Synergism , Rats , DNA (Cytosine-5-)-Methyltransferase 1/metabolism
19.
Cells ; 13(9)2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38727266

ABSTRACT

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with high mortality due to early metastatic dissemination and high chemoresistance. All these factors are favored by its extracellular matrix (ECM)-rich microenvironment, which is also highly hypoxic and acidic. Gemcitabine (GEM) is still the first-line therapy in PDAC. However, it is quickly deaminated to its inactive metabolite. Several GEM prodrugs have emerged to improve its cytotoxicity. Here, we analyzed how the acidic/hypoxic tumor microenvironment (TME) affects the response of PDAC cell death and invadopodia-mediated ECM proteolysis to both GEM and its C18 prodrug. METHODS: For this, two PDAC cell lines, PANC-1 and Mia PaCa-2 were adapted to pHe 6.6 or not for 1 month, grown as 3D organotypic cultures and exposed to either GEM or C18 in the presence and absence of acidosis and the hypoxia inducer, deferoxamine. RESULTS: We found that C18 has higher cytotoxic and anti-invadopodia activity than GEM in all culture conditions and especially in acid and hypoxic environments. CONCLUSIONS: We propose C18 as a more effective approach to conventional GEM in developing new therapeutic strategies overcoming PDAC chemoresistance.


Subject(s)
Deoxycytidine , Gemcitabine , Pancreatic Neoplasms , Tumor Microenvironment , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Humans , Tumor Microenvironment/drug effects , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/metabolism , Cell Line, Tumor , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/metabolism , Podosomes/metabolism , Podosomes/drug effects , Drug Resistance, Neoplasm/drug effects , Prodrugs/pharmacology
20.
Int J Mol Sci ; 25(9)2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38732087

ABSTRACT

Non-muscle invasive bladder cancer is a common tumour in men and women. In case of resistance to the standard therapeutic agents, gemcitabine can be used as off-label instillation therapy into the bladder. To reduce potential side effects, continuous efforts are made to optimise the therapeutic potential of drugs, thereby reducing the effective dose and consequently the pharmacological burden of the medication. We recently demonstrated that it is possible to significantly increase the therapeutic efficacy of mitomycin C against a bladder carcinoma cell line by exposure to non-toxic doses of blue light (453 nm). In the present study, we investigated whether the therapeutically supportive effect of blue light can be further enhanced by the additional use of the wavelength-specific photosensitiser riboflavin. We found that the gemcitabine-induced cytotoxicity of bladder cancer cell lines (BFTC-905, SW-1710, RT-112) was significantly enhanced by non-toxic doses of blue light in the presence of riboflavin. Enhanced cytotoxicity correlated with decreased levels of mitochondrial ATP synthesis and increased lipid peroxidation was most likely the result of increased oxidative stress. Due to these properties, blue light in combination with riboflavin could represent an effective therapy option with few side effects and increase the success of local treatment of bladder cancer, whereby the dose of the chemotherapeutic agent used and thus the chemical load could be significantly reduced with similar or improved therapeutic success.


Subject(s)
Deoxycytidine , Gemcitabine , Light , Riboflavin , Urinary Bladder Neoplasms , Humans , Riboflavin/pharmacology , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/metabolism , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Cell Line, Tumor , Photosensitizing Agents/pharmacology , Oxidative Stress/drug effects , Cell Survival/drug effects , Cell Survival/radiation effects , Lipid Peroxidation/drug effects , Adenosine Triphosphate/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondria/radiation effects , Blue Light
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