tretinoin and Pancreatic-Neoplasms

Pancreatic ductal adenocarcinoma (PDAC) is a gland-forming malignancy arising in the pancreas. It is estimated that in developed countries the incidence of PDAC will continue to rise, and PDAC is now the fourth leading cause of cancer-related deaths in the USA. The mortality of PDAC patients closely parallels the incidence rate, as this malignancy generally remains asymptomatic until it reaches an advanced stage.. The poor prognosis results from the aggressive nature of the tumor, late detection, and resistance to chemotherapy and radiotherapy. Retinoids, vitamin A (retinol) and its metabolites, such as retinoic acid (RA), play critical roles in important biological functions, including cell growth and differentiation, development, metabolism, and immunity. The actions of retinoids in maintaining normal pancreatic functions have generated considerable research interest from investigators interested in understanding and treating PDAC. Altered expression of retinoid receptors and other RA signaling pathway genes in human cancers offers opportunities for target discovery, drug design, and personalized medicine for distinct molecular retinoid subtypes.. The goals of this review are to explore the potential activities of retinoids in the pancreas, to assess the evidence that retinoid functions become dysregulated in PDAC, and to describe the actions of retinoids in new therapies developed to increase patient survival.

Topics: Carcinoma, Pancreatic Ductal; Humans; Pancreatic Neoplasms; Retinoids; Tretinoin; Vitamin A

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Colorectal cancer (CRC) and pancreatic cancer are two very significant contributors to cancer-related deaths. Chronic alcohol consumption is an important risk factor for these cancers. Ethanol is oxidized primarily by alcohol dehydrogenases to acetaldehyde, an agent capable of initiating tumors by forming adducts with proteins and DNA. Acetaldehyde is metabolized by ALDH2, ALDH1B1, and ALDH1A1 to acetate. Retinoic acid (RA) is required for cellular differentiation and is known to arrest tumor development. RA is synthesized from retinaldehyde by the retinaldehyde dehydrogenases, specifically ALDH1A1, ALDH1A2, ALDH1A3, and ALDH8A1. By eliminating acetaldehyde and generating RA, ALDHs can play a crucial regulatory role in the initiation and progression of cancers. ALDH1 catalytic activity has been used as a biomarker to identify and isolate normal and cancer stem cells; its presence in a tumor is associated with poor prognosis in colon and pancreatic cancer. In summary, these ALDHs are not only biomarkers for CRC and pancreatic cancer but also play important mechanistic role in cancer initiation, progression, and eventual prognosis.

Topics: Acetaldehyde; Aldehyde Dehydrogenase; Cell Proliferation; Colorectal Neoplasms; Humans; Pancreatic Neoplasms; Retinaldehyde; Tretinoin

Retinoic acid induces redifferentiation and apoptosis in pancreatic adenocarcinoma cell lines. Redifferentiation includes early reversion into aerobic metabolism as reflected by an increase of mitochondrial activity and mass with normal membrane potential and terminal ductal cell differentiation. Cells in such a state either attempt to correct their DNA abnormalities or commit suicide by apoptosis. In some cell systems, such as pancreatic ductal cells, the stem cells show potential to transdifferentiate into functional normal endocrine cell type. However, since it is impossible to correct a highly corrupted genome, cells eventually succumb to apoptosis. Mitochondrial changes appear to be the enforcing factor for this process. The Transformation--Normalizing-redifferentiation--Apoptosis sequence has been shown by several studies, utilizing various cell types, apoptotic inducers, biomarkers and time frames. Although some studies have shown concomitant apoptosis and redifferentiation, others have reported apoptosis without prior redifferentiation. However, utilizing the appropriate time frame and the markers of earlier mitochondrial changes, one would detect a scenario similar to the retinoid model. This situation can be achieved by delaying apoptosis or reducing the inducer concentration in such systems. The final physiological fate of a normal terminally differentiated cells is apoptosis. Similarly, it is suggested that a degree of normalizing redifferentiation of transformed cells might be expected prior to apoptosis. The former seemed obligatory at least in the retinoid-pancreatic model.

Topics: Animals; Apoptosis; Cell Cycle; Cell Differentiation; Cell Proliferation; Humans; Membrane Potentials; Mitochondria; Pancreatic Neoplasms; Tetrazolium Salts; Thiazoles; Tretinoin

Topics: Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Fatty Acid-Binding Proteins; Humans; Maximum Tolerated Dose; Pancreatic Neoplasms; Receptors, Retinoic Acid; Treatment Outcome; Tretinoin

A key challenge in phase I trials is maintaining rapid escalation in order to avoid exposing too many patients to sub-therapeutic doses, while preserving safety by limiting the frequency of toxic events. Traditional rule-based designs require temporarily stopping recruitment whilst waiting to see whether enrolled patients develop toxicity. This can be both inefficient and introduces logistic challenges to recruitment in the clinic. We describe a novel two-stage dose assignment procedure designed for a phase I clinical trial (STARPAC), where a good estimation of prior was possible.. The STARPAC design uses rule-based design until the first patient has a dose limiting toxicity (DLT) and then switches to a modified CRM, with rules to handle patient recruitment during follow-up of earlier patients. STARPAC design is compared via simulations with the TITE-CRM and 3 + 3 methods in various toxicity estimate (T1-5), rate of recruitment (R1-2), and DLT events timing (DT1-4), scenarios using several metrics: accuracy of maximum tolerated dose (MTD), numbers of DLTs, number of patients enrolled and those missed; duration of trial; and proportion of patients treated at the therapeutic dose or MTD.. The simulations suggest that STARPAC design performed well in MTD estimation and in treating patients at the highest possible therapeutic levels. STARPAC and TITE-CRM were comparable in the number of patients required and DLTs incurred. The 3 + 3 design often had fewer patients and DLTs although this is due to its low escalation rate leading to poor MTD estimation. For the numbers of declined patients and MTD estimation 3 + 3 is uniformly worse, with STARPAC being better in those metrics for high toxicity scenarios and TITE-CRM better with low toxicity. In situations including doses with toxicities both above and below 30%, the STARPAC design outperformed TITE-CRM with respect to every metric.. When considering doses with toxicities both above and below the target of 30% toxicities, the two-stage STARPAC dose escalation design provides a more efficient phase I trial design than either the traditional 3 + 3 or the TITE-CRM design. Trialists should model various designs via simulation to adopt the most efficient design for their clinical scenario.. Clinical Trials NCT03307148 (11 October 2017).

Topics: Albumins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Carcinoma, Pancreatic Ductal; Deoxycytidine; Drug Repositioning; Gemcitabine; Humans; Maximum Tolerated Dose; Paclitaxel; Pancreas; Pancreatic Neoplasms; Patient Selection; Research Design; Response Evaluation Criteria in Solid Tumors; Tretinoin

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; 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Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; 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STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

In pancreatic cancer, excessive desmoplastic stroma severely impedes drug access to tumor cells. By reverting activated pancreatic stellate cells (PSCs) to quiescence, all-trans retinoic acid (ATRA) can attenuate their stromal synthesis and remodel the tumor-promoting microenvironment. However, its modulatory effects have been greatly weakened due to its limited delivery to PSCs. Therefore, we constructed a tripeptide RFC-modified gelatin/oleic acid nanoparticle (RNP@ATRA), which delivered ATRA in an enzyme-triggered popcorn-like manner and effectively resolved the delivery challenges. Specifically, surface RFC was cleaved by aminopeptidase N (APN) on the tumor endothelium to liberate l-arginine, generating nitric oxide (NO) for tumor-specific vasodilation. Then, massive nanoparticles were pushed from the vessels into tumors, showing 5.1- and 4.0-fold higher intratumoral accumulation than free ATRA and APN-inert nanoparticles, respectively. Subsequently, in the interstitium, matrix metalloproteinase-2-induced gelatin degradation caused RNP@ATRA to rapidly release ATRA, promoting its interstitial penetration and PSC delivery. Thus, activated PSCs were efficiently reverted to quiescence, and stroma secretion and vascular compression were reduced, thereby enhancing intratumoral delivery of small-molecule or nanosized chemotherapeutics. Ultimately, RNP@ATRA combined with chemotherapeutics markedly suppressed tumor growth and metastasis without causing additional toxicities. Overall, this work provides a potential nanoplatform for the efficient delivery of PSC-modifying agents in pancreatic cancer and other stroma-rich tumors.

Topics: Cell Line, Tumor; Gelatin; Humans; Matrix Metalloproteinase 2; Nanoparticles; Pancreatic Neoplasms; Tretinoin; Tumor Microenvironment

Activation of pancreatic stellate cells (PSCs) to cancer-associated fibroblasts (CAFs) is responsible for the extensive desmoplastic reaction observed in PDAC stroma: a key driver of pancreatic ductal adenocarcinoma (PDAC) chemoresistance leading to poor prognosis. Specialized pro-resolving mediators (SPMs) are prime modulators of inflammation and its resolution, traditionally thought to be produced by immune cells. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipid mediator profiling PSCs as well as primary human CAFs express enzymes and receptors to produce and respond to SPMs. Human PSC/CAF SPM secretion profile can be modulated by rendering these cells activated [transforming growth factor beta (TGF-β)] or quiescent [all-

Topics: Arachidonate 15-Lipoxygenase; Carcinoma, Pancreatic Ductal; Chromatography, Liquid; Humans; Neoplasm Invasiveness; Pancreatic Neoplasms; Pancreatic Stellate Cells; Tandem Mass Spectrometry; Tretinoin

Topics: Animals; Antineoplastic Agents; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Movement; Cell Proliferation; Deoxycytidine; Down-Regulation; Drug Synergism; Gemcitabine; Humans; Mice; p21-Activated Kinases; Pancreatic Neoplasms; Treatment Outcome; Tretinoin; Xenograft Model Antitumor Assays

The drivers and the specification of CD4

Topics: Adenocarcinoma; Animals; Carcinoma, Pancreatic Ductal; Cell Differentiation; Dendritic Cells; Disease Progression; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Humans; Interleukin-10; Interleukin-17; Lectins, C-Type; Mice, Inbred C57BL; Pancreatic Neoplasms; Phenotype; Signal Transduction; T-Lymphocytes, Regulatory; Th17 Cells; Toll-Like Receptor 2; Tretinoin

Pancreatic ductal adenocarcinoma is characterised by a dense desmoplastic stroma composed of stromal cells and extracellular matrix (ECM). This barrier severely impairs drug delivery and penetration. Activated pancreatic stellate cells (PSCs) play a key role in establishing this unique pathological obstacle, but also offer a potential target for anti-tumour therapy. Here, we construct a tumour microenvironment-responsive nanosystem, based on PEGylated polyethylenimine-coated gold nanoparticles, and utilise it to co-deliver all-trans retinoic acid (ATRA, an inducer of PSC quiescence) and siRNA targeting heat shock protein 47 (HSP47, a collagen-specific molecular chaperone) to re-educate PSCs. The nanosystem simultaneously induces PSC quiescence and inhibits ECM hyperplasia, thereby promoting drug delivery to pancreatic tumours and significantly enhancing the anti-tumour efficacy of chemotherapeutics. Our combination strategy to restore homoeostatic stromal function by targeting activated PSCs represents a promising approach to improving the efficacy of chemotherapy and other therapeutic modalities in a wide range of stroma-rich tumours.

Topics: Animals; Cell Cycle; Endocytosis; Extracellular Matrix; Female; Gene Silencing; Gold; Homeostasis; Humans; Hydrogen-Ion Concentration; Metal Nanoparticles; Mice, Inbred BALB C; Mice, Nude; Pancreatic Neoplasms; Pancreatic Stellate Cells; Polyethylene Glycols; Polyethyleneimine; RNA, Small Interfering; Spheroids, Cellular; Stromal Cells; Tissue Distribution; Tretinoin; Tumor Microenvironment; Xenograft Model Antitumor Assays

We previously showed that gemcitabine resistance in pancreatic cancer chemotherapy correlates with suppressed expression of deoxycytidine kinase (dCK), which catalyzes the rate-limiting step of gemcitabine activation. The purpose of the present study was to find a drug that might be useful to enhance the cytotoxicity of gemcitabine by increasing dCK expression in gemcitabine-resistant human pancreatic cancer cell line AsPC-1. Screening of 40 prescription drugs identified 35 with no intrinsic cytotoxicity towards AsPC-1 cells. When AsPC-1 cells were pre-incubated with these drugs and then incubated with gemcitabine, we found that all-trans retinoic acid (ATRA) significantly decreased the viability by 28% compared with that of non-treated cells. Luciferase assay showed that ATRA transactivated the DCK promoter in AsPC-1 cells by about 2-fold compared with the untreated control, and an increase of dCK protein expression was confirmed by immunoblotting. ATRA decreased the half-maximal inhibitory concentration (IC

Topics: Catalysis; Cell Line, Tumor; Cell Survival; Deoxycytidine; Deoxycytidine Kinase; Drug Resistance, Neoplasm; Drug Synergism; Gemcitabine; Humans; Pancreatic Neoplasms; Tretinoin; Up-Regulation

Topics: Adenocarcinoma; Animals; Carcinoma, Pancreatic Ductal; Gene Expression; Humans; Ligands; Mice; Pancreas; Pancreatic Neoplasms; Receptors, Retinoic Acid; Tretinoin

The hallmark of pancreatic ductal adenocarcinoma (PDAC) is abundant desmoplasia, which is orchestrated by pancreatic stellate cells (PSCs) and accounts for the majority of the stroma surrounding the tumour. Healthy PSCs are quiescent, but upon activation during disease progression, they adopt a myofibroblast-contractile phenotype and secrete and concomitantly reorganise the stiff extracellular matrix (ECM). Transforming growth factor β (TGF-β) is a potent activator of PSCs, and its activation requires spatiotemporal organisation of cellular and extracellular cues to liberate it from an inactive complex with latent TGF-β binding protein (LTBP). Here we study the mechanical activation of TGF-β by PSCs in vitro by investigating LTBP-1 organisation with fibrillar fibronectin and show that all trans-retinoic acid (ATRA), which induces PSC quiescence, down-regulates the ability of PSCs to mechanically organise LTBP-1 and activate TGF-β through a mechanism involving myosin II dependent contractility. Therefore, ATRA inhibits the ability of PSCs to mechanically release active TGF-β, which might otherwise act in an autocrine manner to sustain PSCs in an active state and a tumour-favouring stiff microenvironment.

Topics: Actomyosin; Alternative Splicing; Carcinoma, Pancreatic Ductal; Cytoskeleton; Disease Progression; Fibronectins; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Integrin beta1; Latent TGF-beta Binding Proteins; Myofibroblasts; Myosin Type II; Pancreatic Neoplasms; Pancreatic Stellate Cells; Phenotype; Stress, Mechanical; Transforming Growth Factor beta1; Tretinoin; Tumor Microenvironment

Smoking is an established risk factor for pancreatic cancer (PC), but late diagnosis limits the evaluation of its mechanistic role in the progression of PC. We used a well-established genetically engineered mouse model (LSL-K-ras(G12D)) of PC to elucidate the role of smoking during initiation and development of pancreatic intraepithelial neoplasia (PanIN). The 10-week-old floxed mice (K-ras(G12D); Pdx-1cre) and their control unfloxed (LSL-K-ras(G12D)) littermates were exposed to cigarette smoke (total suspended particles: 150 mg/m(3)) for 20 weeks. Smoke exposure significantly accelerated the development of PanIN lesions in the floxed mice, which correlated with tenfold increase in the expression of cytokeratin19. The systemic accumulation of myeloid-derived suppressor cells (MDSCs) decreased significantly in floxed mice compared with unfloxed controls (P<0.01) after the smoke exposure with the concurrent increase in the macrophage (P<0.05) and dendritic cell (DCs) (P<0.01) population. Further, smoking-induced inflammation (IFN-γ, CXCL2; P<0.05) was accompanied by enhanced activation of pancreatic stellate cells and elevated levels of serum retinoic acid-binding protein 4, indicating increased bioavailability of retinoic acid which contributes to differentiation of MDSCs to tumor-associated macrophages (TAMs) and DCs. TAMs predominantly contribute to the increased expression of heparin-binding epidermal growth factor-like growth factor (EGFR ligand) in pre-neoplastic lesions in smoke-exposed floxed mice that facilitate acinar-to-ductal metaplasia (ADM). Further, smoke exposure also resulted in partial suppression of the immune system early during PC progression. Overall, the present study provides a novel mechanism of smoking-induced increase in ADM in the presence of constitutively active K-ras mutation.

Topics: Acinar Cells; Animals; Carcinoma in Situ; Carcinoma, Pancreatic Ductal; Cell Differentiation; Chemokine CXCL2; Dendritic Cells; Disease Progression; Genes, ras; Heparin-binding EGF-like Growth Factor; Inflammation; Interferon-gamma; Keratin-19; Macrophages; Metaplasia; Mice; Mice, Transgenic; Myeloid Cells; Pancreatic Ducts; Pancreatic Neoplasms; Pancreatic Stellate Cells; Receptors, Retinoic Acid; Signal Transduction; Smoke; Smoking; Tretinoin

Retinoic acid (RA) has important functions during embryonic development being involved in cell growth and differentiation. Although approved for the treatment of acute promyelocytic leukemia, it is still under investigation for different solid tumors including pancreatic cancer. The objective of this study was to analyze how RA affects pancreatic cancer stem cells and how its combination with chemotherapy could impact cell growth.. Using different pancreatic cancer cell lines, we evaluated the effect of RA alone or in combination with chemotherapy regulating cancer stem cells properties and pathways.. Retinoic acid treatment reduces the expression of pancreatic stem cell markers CD24, CD44, CD133, and aldehyde dehydrogenase 1 but not c-Met. Although gemcitabine treatment increases the expression of some of these markers especially CD44 when it is combined with RA, a notable reduction in all of them is observed. Retinoic acid induces a G0/G1 arrest and combined with gemcitabine increases the apoptotic effect produced by chemotherapy probably as a consequence of a regulation of specific stem cell transcription factors.. Retinoic acid regulates self-renewal capacity of cells in pancreatic tumors and should be further investigated in combination with chemotherapy as therapeutic strategy in pancreatic cancer.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Drug Resistance, Neoplasm; Fluorouracil; Gemcitabine; Humans; Neoplastic Stem Cells; Pancreatic Neoplasms; Phenotype; Signal Transduction; Time Factors; Transcription Factors; Tretinoin

Combination chemotherapy for the treatment of pancreatic cancer commonly employs gemcitabine with an EGFR inhibitor such as erlotinib. Here, we show that the retinoic acid derivative, ABPN, exhibits more potent anticancer effects than erlotinib, while exhibiting less toxicity toward noncancerous human control cells. Low micromolar concentrations of ABPN induced apoptosis in BxPC3 and HPAC pancreatic cancer cell lines, concomitant with a reduction in phosphorylated EGFR as well as decreased ErbB3, Met and BRUCE protein levels. The degradation of ErbB3 is a result of proteasomal degradation, possibly due to the ABPN-dependent upregulation of Nrdp1. Administration of ABPN showed significant reductions in tumor size when tested using a mouse xenograft model, with higher potency than erlotinib at the same concentration. Analysis of the tumors demonstrated that ABPN treatment suppressed ErbB3 and Met and induced Nrdp1 in vivo. The data suggest that ABPN may be more suitable in combination chemotherapy with gemcitabine than the more widely used EGFR inhibitor, erlotinib.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Deoxycytidine; Drug Synergism; Erlotinib Hydrochloride; Fluorouracil; Gemcitabine; Humans; Male; Mice, Nude; Pancreatic Neoplasms; Proteasome Endopeptidase Complex; Proteolysis; Proto-Oncogene Proteins c-met; Receptor, ErbB-3; Retinoids; Signal Transduction; Transcriptional Activation; Tretinoin; Tumor Burden; Ubiquitin-Protein Ligases; Xenograft Model Antitumor Assays

Retinoic acid (RA) is a small molecular derivative of vitamin A that is stored in quiescent stellate cells in pancreas stroma. Cancer associated fibroblasts (CAFs) are activated fibroblast cells in pancreatic ductal adenocarcinoma tumor microenvironment. We treated CAFs with RA and found that these cells became static due to the low expression of α-SMA, FAP, and IL-6 and decreased production of extracellular matrix (ECM). Furthermore, we verified that the low secretion of IL-6 from CAFs was related to RA-induced inhibition of migration and epithelial-mesenchymal transition (EMT) of tumor cells. However, RA could not inhibit the migration and EMT of tumor cells directly. Therefore, our study showed that one of the therapeutic effects of RA on tumor cells is through its modulation of CAFs in tumor microenvironment. The tumor microenvironment plays an important role in promoting tumor migration and might be a promising target of biological treatment.

Topics: Carcinoma, Pancreatic Ductal; Cell Communication; Cell Line, Tumor; Cell Movement; Cell Proliferation; Down-Regulation; Epithelial-Mesenchymal Transition; Fibroblasts; Humans; Interleukin-6; Pancreatic Neoplasms; Tretinoin

Accumulating evidence indicates that microRNAs (miRNAs) have great potential as tumor biomarkers and therapeutic agents owing to their functions in tumorigenesis and cancer progression. Aberrant expression of miR-1247 has been found in several cancers and is predicted to play an important role in the pathological processes of pancreatic cancer by miRNA-regulated network analysis. We investigated the expression profile of miR-1247 in pancreatic cancer tissue microarray by in situ hybridization and found that miR-1247 was significantly down-regulated in pancreatic cancer tissues compared to matched benign tissues. High levels of miR-1247 expression were positively correlated with higher overall and recurrence free survival in pancreatic cancer patients, while negatively correlated with tumor grade. Using in vitro and in vivo models, we demonstrated that increased expression of miR-1247 inhibited proliferation, tumorigenicity, colony formation and triggered G0/G1 cell cycle arrest in pancreatic cancer cells. Moreover, we confirmed that neuropilin1 (NRP1) and neuropilin2 (NRP2) are direct targets of miR-1247 by western blot and luciferase reporter assay. Further studies indicated that low dose all trans retinoic acid (ATRA) can induce redifferentiation and restoration of miR-1247 in pancreatic cancer cells. These findings suggest that miR-1247, a novel tumor suppressor, can act as a potential biomarker and therapeutic agent for pancreatic cancer.

Topics: Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Computational Biology; Humans; MicroRNAs; Neuropilin-1; Neuropilin-2; Neuropilins; Pancreatic Neoplasms; Tretinoin

CRABP1 (cellular retinoic acid binding protein 1) belongs to the family of fatty acid binding proteins. Retinoic acid binding is the only known functional activity of this protein. The role of CRABP1 in human carcinogenesis remains poorly understood. Here, for the first time we demonstrated pro-metastatic and pro-tumorigenic activity of CRABP1 in mesenchymal tumors. Further functional analysis revealed that the pro-tumorigenic effect of CRABP1 does not depend on retinoic acid binding activity. These results suggest that CRABP1 could have an alternative intracellular functional activity that contributes to the high malignancy of transformed mesenchymal cells. Microarray analysis detected CRABP1-mediated alterations in the expression of about 100 genes, including those encoding key regulatory proteins. CRABP1 is ubiquitously expressed in monophasic synovial sarcomas, while in biphasic synovial sarcomas it is expressed uniquely by the spindle cells of the aggressive mesenchymal component. High level of CRABP1 expression is associated with lymph node metastasis and poor differentiation/high grade of pancreatic neuroendocrine tumors (pNETs). Presented data suggest CRABP1 as a promising biomarker of pNETs' clinical behavior. Our results give the first evidence of pro-tumorigenic and pro-metastatic activity of CRABP1 in mesenchymal and neuroendocrine tumors.

Topics: Adult; Aged; Cell Line, Transformed; Female; Fibroblasts; Humans; Male; Mesenchymal Stem Cells; Middle Aged; Neoplasm Metastasis; Neuroendocrine Tumors; Pancreatic Neoplasms; Receptors, Retinoic Acid; Sarcoma, Synovial; Tretinoin

Gemcitabine is an anticancer drug used in the treatment of different cancer types, including pancreatic ductal adenocarcinoma. The maximum tolerated dose in humans is restricted by its side effects on healty cells. Furthermore, the fibrotic stroma produced by the pancreatic stellate cells prevents effective delivery of chemotherapeutic agents providing a safe-haven for the cancer cells. This becomes more of a problem considering the short half-life of this drug. Magnetic nanoparticle-based targeted drug delivery systems are a promising alternative to overcome the limitations of classical chemotherapies. The aim of this study is to obtain an effective targeted delivery system for gemcitabine using magnetic nanoparticles (MNPs) and all-trans retinoic acid (ATRA). This dual approach targets the tumor cells and its infrastructure - stellate cells - simultaneously. Gemcitabine and ATRA were loaded onto the PAMAM dendrimer-coated magnetic nanoparticles (DcMNPs), which were synthesized and characterized previously. Drug loading and release characteristics, and stability of the nanoparticles were investigated. Gemcitabine and ATRA loaded MNPs are efficiently taken up by pancreatic cancer and stellate cells successfully targeting and eliminating both cells. Results of this study can provide new insights on pancreatic cancer therapy where tumor is seen as a system with its stroma insead of epithelial cells alone.

Topics: Antineoplastic Agents; Cell Line; Dendrimers; Deoxycytidine; Dose-Response Relationship, Drug; Drug Delivery Systems; Gemcitabine; Humans; Magnetite Nanoparticles; Pancreatic Neoplasms; Pancreatic Stellate Cells; Tretinoin; Tumor Cells, Cultured

Pancreatic cancer and cholangiocarcinoma are aggressive and drug-resistant refractory cancers. Based on N-(4-hydroxyphenyl)retinamide (3), a synthetic amide of all-trans-retinoic acid (RA), p-dodecylaminophenol (1) was developed to be an effective anticancer agent without key side-effects of these agents. Compound 1 suppresses cell growth of pancreatic cancer (MIA Paca2) and cholangiocarcinoma (HuCCT1), potentially by inhibiting ras expression and signaling through ERK pathways in MIA Paca2 cells and both ERK and Akt pathways in HuCCT1 cells. Compound 1 inhibits proliferation of these cells to a greater extent than either RA or 3. Compound 1 may represent a potent and useful anti-cancer drug for use against pancreatic cancer and cholangiocarcinoma that lacks their key side-effects.

Topics: Aminophenols; Antineoplastic Agents; Cell Proliferation; Cholangiocarcinoma; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Pancreatic Neoplasms; Structure-Activity Relationship; Tumor Cells, Cultured

To identify a predictive molecular "signature" for sensitivity to retinoic acid in pancreatic cancer.. Fourteen patient-derived, low-passage pancreatic ductal adenocarcinoma (PDAC) lines with varied expression of fatty acid-binding protein 5 (FABP5) and cellular retinoic acid-binding protein 2 (CRABP2) were used to evaluate the response to all-trans retinoic acid (ATRA). Cell proliferation, apoptosis, and migration/invasion assays were used to measure the in vitro response. Tumor growth was monitored in subcutaneous xenografts in athymic nude mice for 4 weeks.. Response to ATRA was observed to be dependent upon differential expression of FABP5 versus CRABP2. Thus, elevated FABP5 expression was associated with minimal cytotoxicity and tumor growth inhibition and a paradoxical increase in migration and invasion. Conversely, CRABP2 expression in the absence of FABP5 was associated with significant tumor growth inhibition with ATRA, even in gemcitabine-resistant tumors. The ATRA-resistant phenotype of FABP5(high)CRABP2(null) cells could be circumvented by ectopic expression of CRABP2. Alternatively, reexpression of endogenous CRABP2 could be enabled in FABP5(high)CRABP2(null) PDAC lines by exposure to decitabine and trichostatin A, thereby relieving epigenetic silencing of the CRABP2 gene promoter. Immunohistochemical staining for FABP5 in archival human tissue microarrays identifies a subset of cases (13 of 63, ~20%) which are negative for FABP5 expression and might be candidates for ATRA therapy.. The widely used agent ATRA deserves a "second look" in PDAC, but needs to be targeted to patient subsets with biopsy-proven FABP5-negative tumors, or be combined with a chromatin-modifying agent to reexpress endogenous CRABP2.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Blotting, Western; Carcinoma, Pancreatic Ductal; Cell Adhesion; Cell Movement; Cell Proliferation; DNA Methylation; Fatty Acid-Binding Proteins; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Mice; Mice, Nude; Oligonucleotide Array Sequence Analysis; Pancreatic Neoplasms; Promoter Regions, Genetic; Real-Time Polymerase Chain Reaction; Receptors, Retinoic Acid; RNA, Messenger; Tretinoin; Tumor Cells, Cultured

The membrane-bound mucins are thought to play an important biological role in cell-cell and cell-matrix interactions, in cell signaling and in modulating biological properties of cancer cell. MUC4, a transmembrane mucin is overexpressed in pancreatic tumors, while remaining undetectable in the normal pancreas, thus indicating a potential role in pancreatic cancer pathogenesis. The molecular mechanisms involved in the regulation of MUC4 gene are not yet fully understood. Smoking is strongly correlated with pancreatic cancer and in the present study; we elucidate the molecular mechanisms by which nicotine as well as agents like retinoic acid (RA) and interferon-γ (IFN-γ) induce the expression of MUC4 in pancreatic cancer cell lines CD18, CAPAN2, AsPC1 and BxPC3.. Chromatin immunoprecipitation assays and real-time PCR showed that transcription factors E2F1 and STAT1 can positively regulate MUC4 expression at the transcriptional level. IFN-γ and RA could collaborate with nicotine in elevating the expression of MUC4, utilizing E2F1 and STAT1 transcription factors. Depletion of STAT1 or E2F1 abrogated the induction of MUC4; nicotine-mediated induction of MUC4 appeared to require α7-nicotinic acetylcholine receptor subunit. Further, Src and ERK family kinases also mediated the induction of MUC4, since inhibiting these signaling molecules prevented the induction of MUC4. MUC4 was also found to be necessary for the nicotine-mediated invasion of pancreatic cancer cells, suggesting that induction of MUC4 by nicotine and other agents might contribute to the genesis and progression of pancreatic cancer.. Our studies show that agents that can promote the growth and invasion of pancreatic cancer cells induce the MUC4 gene through multiple pathways and this induction requires the transcriptional activity of E2F1 and STAT1. Further, the Src as well as ERK signaling pathways appear to be involved in the induction of this gene. It appears that targeting these signaling pathways might inhibit the expression of MUC4 and prevent the proliferation and invasion of pancreatic cancer cells.

Topics: Cell Line, Tumor; Cell Proliferation; Drug Synergism; E2F1 Transcription Factor; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Neoplastic; Humans; Interferon-gamma; Janus Kinases; Mucin-4; Nicotine; Pancreatic Neoplasms; Promoter Regions, Genetic; Proto-Oncogene Proteins c-akt; Receptors, Nicotinic; Signal Transduction; src-Family Kinases; STAT1 Transcription Factor; Transcriptional Activation; Tretinoin

The bond between the research laboratory and the clinic is especially strong in the field of photomedicine. Much is learned in preclinical animal models, which is translated to the clinic for investigation, and then refinements in theory and technique are explored back in the laboratory. With many cancers becoming resistant to treatment, photodynamic therapy (PDT) offers a mechanistically distinct alternative. Studies have shown that PDT not only mitigates chemoresistance but also synergizes with chemotherapy and molecularly targeted therapies. From the world of biochemistry comes this unique look at 2 approaches to maximize the photodynamic effect through PDT combinations with targeted therapies: 1) using the molecular response after PDT to guide the selection of targeted agents and 2) preconditioning cancer cells to modulate nuclear molecular targets before PDT.

Topics: Aminolevulinic Acid; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cetuximab; Combined Modality Therapy; ErbB Receptors; Female; Humans; Male; Mice; Molecular Targeted Therapy; Ovarian Neoplasms; Pancreatic Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Prostatic Neoplasms; Tretinoin; Vascular Endothelial Growth Factor A; Verteporfin; Vitamin D

Patients with pancreatic ductal adenocarcinoma are deficient in vitamin A, resulting in activation of pancreatic stellate cells (PSCs). We investigated whether restoration of retinol to PSCs restores their quiescence and affects adjacent cancer cells.. PSCs and cancer cell lines (AsPc1 and Capan1) were exposed to doses and isoforms of retinoic acid (RA) in 2-dimensional and 3-dimensional culture conditions (physiomimetic organotypic culture). The effects of all-trans retinoic acid (ATRA) were studied in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre mice, a model of human pancreatic ductal adenocarcinoma.. After incubation with ATRA, PSCs were quiescent and had altered expression of genes that regulate proliferation, morphology, and motility; genes that encode cytoskeletal proteins and cytokines; and genes that control other functions, irrespective of culture conditions or dosage. In the organotypic model, and in mice, ATRA induced quiescence of PSCs and thereby reduced cancer cell proliferation and translocation of β-catenin to the nucleus, increased cancer cell apoptosis, and altered tumor morphology. ATRA reduced the motility of PSCs, so these cells created a "wall" at the junction between the tumor and the matrix that prevented cancer cell invasion. Restoring secreted frizzled-related protein 4 (sFRP4) secretion to quiescent PSCs reduced Wnt-β-catenin signaling in cancer cells and their invasive ability. Human primary and metastatic pancreatic tumor tissues stained strongly for cancer cell nuclear β-catenin but had low levels of sFRP4 (in cancer cells and PSCs).. RA induces quiescence and reduces motility of PSCs, leading to reduced proliferation and increased apoptosis of surrounding pancreatic cancer cells. RA isoforms might be developed as therapeutic reagents for pancreatic cancer.

Topics: Alitretinoin; Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cellular Senescence; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Isotretinoin; Mice; Mice, Mutant Strains; Pancreatic Neoplasms; Pancreatic Stellate Cells; Paracrine Communication; Proto-Oncogene Proteins; RNA Interference; Signal Transduction; Time Factors; Transcription, Genetic; Tretinoin; Wnt Proteins

Pancreatic cancer is one of the leading causes of cancer related deaths in the western world. It is also resistant to most chemotherapeutic modalities. Phosphodiesterase-4 inhibitors (PDE4is) have found applications in the treatment of respiratory diseases. The aim of this study is to investigate the cytotoxic effect of 2 novel PDE4is, the CC-8075 and CC-8062 compounds in pancreatic cancer cells.. Cell proliferation was measured using the sulforhodamine B protein dye. Induction of apoptosis was detected using enzyme-linked immunosorbent assay. Regulation of proteins and posttranslational modifications were determined using immunoblotting.. Treatment of pancreatic cancer cells with CC-8075 and CC-8062 reduces their proliferation and increases apoptosis that is caspase dependent in T3M4 cells. Furthermore, PDE4is increase phosphorylation of p38MAPK, mitogen-activated protein kinase (MAPK) kinase 3/6,MAPKYactivated protein kinase 2, Atf2, and Hsp27. The use of thep38MAPK-specific inhibitors SB202190 and SB203580 results in a modest reduction in PDE4i-induced apoptosis in T3M4 cells. Also, retinoids enhance apoptosis induced by CC-8075 and CC-8062 in GER cells.. These results highlight the antiproliferative effects of the phosphodiesterase inhibitors CC-8075 and CC-8062 in pancreatic cancer cells and suggest that activation of p38MAPK signaling pathway may be associated with this process.

Topics: Alitretinoin; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclic Nucleotide Phosphodiesterases, Type 4; Dose-Response Relationship, Drug; Humans; Imidazoles; p38 Mitogen-Activated Protein Kinases; Pancreatic Neoplasms; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Pyridines; Signal Transduction; Tretinoin

To study the possible actions and mechanisms of peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor, in pancreatic carcinogenesis, especially in angiogenesis.. Expressions of PPARgamma and retinoid acid receptor (RXRalpha) were examined by reverse-transcription polymerase chain reaction (RT-PCR) with immunocytochemical staining. Pancreatic carcinoma cells, PANC-1, were treated either with 9-cis-RA, a ligand of RXRalpha, or with 15-deoxy-Delta(12,14) prostaglandin J(2) (15d-PGJ(2)), a ligand of PPARgamma, or both. Antiproliferative effect was evaluated by cell viability using methyltetrazolium (MTT) assay. A pancreatic carcinoma xenograft tumor model of nude mice was established by inoculating PANC-1 cells subcutaneously. Rosiglitazone, a specific ligand of PPARgamma, was administered via water drinking in experimental group of nude mice. After 75 d, all mice were sacrificed. Expression of proliferating cell nuclear antigen (PCNA) in tumor tissue was examined with immunohistochemical staining. Expression of vascular endothelial growth factor (VEGF) mRNA in PANC-1 cells, which were treated with 15d-PGJ(2) or 9-cis-RA at various concentrations or different duration, was detected by semi-quantitative RT-PCR. Effects of Rosiglitazone on changes of microvascular density (MVD) and VEGF expression were investigated in xenograft tumor tissue. Neovasculature was detected with immunohistochemistry staining labeled with anti-IV collagen antibody, and indicated by MVD.. RT-PCR and immunocytochemical staining showed that PPARgamma and RXRalpha were expressed in PANC-1 cells at both transcription level and translation level. MTT assay demonstrated that 15d-PGJ(2), 9-cis-RA and their combination inhibited the growth of PANC-1 cells in a dose-dependent manner. 9-cis-RA had a combined inhibiting action with 15d-PGJ(2) on the growth of pancreatic carcinoma. In vivo studies revealed that Rosiglitazone significantly suppressed the growth of pancreatic carcinoma as compared to control group (0.48+/-0.23 cm(3) vs 2.488+/-0.59 cm(3), P<0.05), and the growth inhibition rate was 80.7%. Immunohistochemistry study showed that PCNA was down regulated in Rosiglitazone-treated group compared to the control group. 15d-PGJ(2), 9-cis-RA and their combination inhibited the expression of VEGF mRNA in PANC-1 cells in a dose- and time-dependent manner. MVD was decreased more significantly in Rosiglitazone-treated mice (10.67+/-3.07) than in the control group (31.44+/-6.06) (P<0.01). VEGF expression in xenograft tumor tissue was also markedly down-regulated in Rosiglitazone-treated mice.. Activation of PPARgamma inhibits the growth of pancreatic carcinoma both in vitro and in vivo. Suppression of tumor angiogenesis by down-regulating the expression of VEGF may be one of the mechanisms by which PPARgamma activation inhibits the growth of pancreatic carcinoma.

Topics: Animals; Base Sequence; Cell Line, Tumor; Female; Humans; Mice; Mice, Nude; Neovascularization, Pathologic; Pancreatic Neoplasms; PPAR gamma; Prostaglandin D2; Retinoid X Receptor alpha; RNA, Messenger; RNA, Neoplasm; Rosiglitazone; Thiazolidinediones; Transplantation, Heterologous; Tretinoin; Vascular Endothelial Growth Factor A

We recently have shown that Charged multivesicular protein/Chromatin modifying protein1A (Chmp1A) functions as a tumor suppressor in human pancreatic tumor cells. Pancreatic cancer has the worst prognosis of all cancers with a dismal 5-year survival rate. Preclinical studies using ATRA for treating human pancreatic cancer suggest this compound might be useful for treatment of pancreatic cancer patients. However, the molecular mechanism by which ATRA inhibits growth of pancreatic cancer cells is not clear. The objective of our study was to investigate whether Chmp1A is involved in ATRA-mediated growth inhibition of human pancreatic tumor cells.. We performed microarray studies using HEK 293T cells and discovered that Chmp1A positively regulated Cellular retinol-binding protein 1 (CRBP-1). CRBP-1 is a key regulator of All-trans retinoic acid (ATRA) through ATRA metabolism and nuclear localization. Since our microarray data indicates a potential involvement of Chmp1A in ATRA signaling, we tested this hypothesis by treating pancreatic tumor cells with ATRA in vitro. In the ATRA-responsive cell lines, ATRA significantly increased the protein expression of Chmp1A, CRBP-1, P53 and phospho-P53 at serine 15 and 37 position. We found that knockdown of Chmp1A via shRNA abolished the ATRA-mediated growth inhibition of PanC-1 cells. Also, Chmp1A silencing diminished the increase of Chmp1A, P53 and phospho-P53 protein expression induced by ATRA. In the ATRA non-responsive cells, ATRA did not have any effect on the protein level of Chmp1A and P53. Chmp1A over-expression, however, induced growth inhibition of ATRA non-responsive cells, which was accompanied by an increase of Chmp1A, P53 and phospho-P53. Interestingly, in ATRA responsive cells Chmp1A is localized to the nucleus, which became robust upon ATRA treatment. In the ATRA-non-responsive cells, Chmp1A was mainly translocated to the plasma membrane upon ATRA treatment.. Collectively our data provides evidence that Chmp1A mediates the growth inhibitory activity of ATRA in human pancreatic cancer cells via regulation of CRBP-1. Our results also suggest that nuclear localization of Chmp1A is important in mediating ATRA signaling.

Topics: Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Endosomal Sorting Complexes Required for Transport; Humans; Nuclear Proteins; Pancreatic Neoplasms; Phosphoproteins; Protein Transport; Retinol-Binding Proteins, Cellular; Tretinoin; Tumor Suppressor Protein p53; Vesicular Transport Proteins

Retinoids are potent growth inhibitory and differentiating agents in a variety of cancer cell types. We have shown that retinoids induce growth arrest in all pancreatic cancer cell lines studied, regardless of their p53 and differentiation status. However, the mechanism of growth inhibition is not known. Since TGF-beta2 is markedly induced by retinoids in other cancers and mediates MUC4 expression in pancreatic cancer cells, we investigated the role of TGF-beta in retinoic acid-mediated growth inhibition in pancreatic cancer cells.. Retinoic acid markedly inhibited proliferation of two cell lines (Capan-2 and Hs766T) in a concentration and time-dependent manner. Retinoic acid increased TGF-beta2 mRNA content and secretion of the active and latent forms of TGF-beta2 (measured by ELISA and bioassay). The concentrations of active and TGF-beta2 secreted in response to 0.1 - 10 muM retinoic acid were between 1-5 pM. TGF-beta2 concentrations within this range also inhibited proliferation. A TGF-beta neutralizing antibody blocked the growth inhibitory effects of retinoic acid in Capan-2 cells and partially inhibitory the effects in Hs766T cells.. These findings indicate that TGF-beta can cause growth inhibition of pancreatic cancer cells, in a p53-independent manner. Furthermore, it demonstrates the fundamental role of TGF-beta in growth inhibition in response to retinoic acid treatment is preserved in vitro.

Topics: Adenocarcinoma; Antibodies; Antibody Specificity; Antineoplastic Agents; Cell Growth Processes; Cell Line, Tumor; Enzyme-Linked Immunosorbent Assay; Humans; Pancreatic Neoplasms; RNA, Messenger; Transforming Growth Factor beta2; Tretinoin

Previous research has shown that the retinoid 9-cis retinoic acid (RA) promotes apoptosis in pancreatic cancer cells. The vitamin D analog EB1089 does not. Furthermore, cotreatment of cells with 9-cis RA and EB1089 abrogates apoptosis. To explain this, we studied the regulation of proteins involved in apoptotic signaling pathways in pancreatic cancer cells.. The pancreatic adenocarcinoma cell line T3M4 was used. Cell proliferation was measured using the SRB protein dye assay. Induction of apoptosis was evaluated using an ELISA assay. Caspase activation was detected using a colorimetric assay based on cleavage of a caspase-associated substrate. Regulation of protein levels and posttranslational events were detected using immunoblotting.. We confirm that EB1089 diminishes apoptosis induced by 9-cis RA in T3M4 cells. We extend the study to show that EB1089 abrogates increases, induced by 9-cis RA, in caspase activation, p27Kip1 protein levels, Bim and Bax protein levels and in Bax/Bcl2 ratio. In addition, the CDKI p21Waf1 and CAII, a differentiation marker for pancreatic cancer cells are also differentially regulated.. These results suggest that the inhibitory effects of EB1089 on 9-cis RA-induced apoptosis lie upstream of caspase activation and could be associated with reduction of p27Kip1 protein levels.

Topics: Adenocarcinoma; Alitretinoin; Antineoplastic Agents; Apoptosis; Calcitriol; Caspases; Cell Division; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p27; Enzyme-Linked Immunosorbent Assay; Humans; Pancreatic Neoplasms; Tretinoin

The pancreatic ductal adenocarcinoma (HPAF) cells have a multipotent stem cell potential. It was hypothesised that all-trans-retinoic acid (atRA) can induce transdifferentiation of these cells into cells with an endocrine phenotype.. To explore this hypothesis, an in vitro system of cells was established. Some cells were treated with atRA at concentrations of 100 nmol/l (non-apoptosis-inducing) and 5 micromol/l (apoptosis-inducing) and harvested. Cells were examined for cell cycle kinetics, apoptosis (terminal deoxynucleotidyl transferase assay and p53 protein expression) and immunomorphological features of redifferentiation (MUC1 and DUPAN-2) and endocrine transdifferentiation (insulin, somatostatin, glucagon, neurone-specific enolase) by using immunoperoxidase staining methods. Levels of insulin, transforming growth factor (TGF) beta2, TGFalpha and epidermal growth factor receptor (EGFR) were measured by enzyme-linked immunosorbent assay (ELISA). The vehicle-treated cells served as a control group.. When compared with untreated cells, cells treated with 100 nmol/l and 5 micromol/l atRA were observed to show (1) decreased proliferative activity (cpm) as indicated by decreased incorporation of thymidine labelled with hydrogen-3; (2) cell cycle arrest; (3) increased apoptotic activity associated with p53 protein overexpression; (4) upregulated expression of the transdifferentiation and redifferentiation markers; (5) morphological changes indicative of transdifferentiation (increased cell size and appearance of dendrites); (6) decreased production of EGFR; (7) upregulation of TGFalpha and TGFbeta2; and (8) increase in basal and glucose-induced insulin secretion.. Functional endocrine transdifferentiation can be induced in HPAF lines by atRA. Further investigations are mandated to explore the underlying mechanisms of this transdifferentiation and to explore its in vivo extrapolation.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Pancreatic Ductal; Cell Cycle; Cell Differentiation; Cell Division; Cell Line, Tumor; Dose-Response Relationship, Drug; ErbB Receptors; Humans; Immunoenzyme Techniques; Insulin; Neoplasm Proteins; Pancreatic Neoplasms; Transforming Growth Factors; Tretinoin; Up-Regulation

Although it is uncommon, pancreatic cancer is known to have a poor prognosis. The aim of the present study was to determine the inhibitory effects of all-trans-retinoic acid (ATRA) on cell growth, cell cycle and alkaline phosphatase (ALP) activity in the human pancreatic cancer cell line PANC-1 in vitro.. Human pancreatic cancer PANC-1 cells were treated by various concentrations of ATRA, and then the cell growth was determined by MTT viability assay. Cell cycle distribution and ALP activity were analyzed by flow cytometry and chemical analyzer, respectively.. ATRA inhibited the growth of PANC-1 cells grown in culture; a dose-dependent inhibitory influence was found. ATRA arrested PANC-1 cells at G2/M phase. The ALP activity of PANC-1 cells was significantly increased by 1-50 micromol/L ATRA.. The antitumor effects of ATRA on human pancreatic cancer cells are associated with G2/M phase arrest and increased ALP activity.

Topics: Alkaline Phosphatase; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma; Cell Cycle; Cell Line, Tumor; DNA Fragmentation; Flow Cytometry; Humans; In Vitro Techniques; Pancreatic Neoplasms; Treatment Outcome; Tretinoin

Pancreatic cancer is one of the tumors with the highest mortality, poorly responding to available chemotherapeutic agents. The objective of this study was to study the anticancer effects of all-trans retinoid acid, a functional form of vitamin A, on pancreatic cancer cells. Human pancreatic cancer MiaPaCa-2 cells were treated with 1, 5, 10, 20, 30, 40 and 50 microM ATRA for 1, 2, 3, 4, 5 or 6 d, respectively. Cell growth was determined by MTT viability assay. The cell cycle distribution and the alkaline phosphatase (ALP) activity were analyzed by flow cytometry and chemical analyzer, respectively. The results show that ATRA significantly inhibited the growth of MiaPaCa-2 cells at 40 and 50 microM. ATRA arrested pancreatic cancer cells at G0/G1 phase. The sub-G1 peak and DNA fragmentation were observed. There were time and dose dependent increases in alkaline phosphatase activity (ALP), an indicator of cell differentiation, upon treatment with ATRA when compared to controls. In conclusion, ATRA has an inhibitory effect on the cell growth of MiaPaCa-2, and its tumor suppressive effect is by means of cell cycle arrest and apoptosis induction.

Topics: Alkaline Phosphatase; Cell Cycle; Cell Line, Tumor; Flow Cytometry; Humans; Pancreatic Neoplasms; Tretinoin

Despite significant progress in understanding the molecular pathology of pancreatic cancer and its precursor lesion: pancreatic intraepithelial neoplasia (PanIN), there remain no molecules with proven clinical utility as prognostic or therapeutic markers. Here, we used oligonucleotide microarrays to interrogate mRNA expression of pancreatic cancer tissue and normal pancreas to identify novel molecular pathways dysregulated in the development and progression of pancreatic cancer.. RNA was hybridized to Affymetrix Genechip HG-U133 oligonucleotide microarrays. A relational database integrating data from publicly available resources was created to identify candidate genes potentially relevant to pancreatic cancer. The protein expression of one candidate, homeobox B2 (HOXB2), in PanIN and pancreatic cancer was assessed using immunohistochemistry.. We identified aberrant expression of several components of the retinoic acid (RA) signaling pathway (RARalpha, MUC4, Id-1, MMP9, uPAR, HB-EGF, HOXB6, and HOXB2), many of which are known to be aberrantly expressed in pancreatic cancer and PanIN. HOXB2, a downstream target of RA, was up-regulated 6.7-fold in pancreatic cancer compared with normal pancreas. Immunohistochemistry revealed ectopic expression of HOXB2 in 15% of early PanIN lesions and 48 of 128 (38%) pancreatic cancer specimens. Expression of HOXB2 was associated with nonresectable tumors and was an independent predictor of poor survival in resected tumors.. We identified aberrant expression of RA signaling components in pancreatic cancer, including HOXB2, which was expressed in a proportion of PanIN lesions. Ectopic expression of HOXB2 was associated with a poor prognosis for all patients with pancreatic cancer and was an independent predictor of survival in patients who underwent resection.

Topics: Adult; Aged; Aged, 80 and over; Cohort Studies; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; Immunohistochemistry; Male; Middle Aged; Multivariate Analysis; Oligonucleotide Array Sequence Analysis; Pancreas; Pancreatic Neoplasms; Signal Transduction; Survival Analysis; Transcription Factors; Tretinoin

All-trans retinoic acid (ATRA) inhibits proliferation of cancer. However, the effects of ATRA on scattering and invasion of pancreatic cancer cells remain unknown. Also, the effects of ATRA on c-Met expression in pancreatic cancer have never been addressed so far. The effects of ATRA on a pancreatic cancer cell line, Capan-1, were determined by proliferation assay, scattering assay and invasion assay. In addition, the expression of c-Met in pancreatic cancer cell lines treated with ATRA was investigated by real-time PCR and western blotting. The growth-inhibitory effect of ATRA was found when the cells were cultured with 5 microM ATRA for 3 days. In cell scattering assay, ATRA-treated pancreatic cancer cells were found to spread out from their colonies. In invasion assay, cells treated with ATRA invaded the matrigel more than vehicle-treated cells. The expression of c-Met was up-regulated both in the mRNA and protein levels after the treatment of ATRA. The highest expression was found at 48 h after the treatment. ATRA induced scattering and invasion of pancreatic cancer cells, although it inhibited proliferation of those cells. In addition, ATRA also increased the protein level of c-Met. These findings may indicate that the use of retinoic acid as an anti-cancer therapeutic drug needs some additional treatments to control cell invasion or scattering.

Topics: Antineoplastic Agents; Cell Proliferation; Humans; Neoplasm Invasiveness; Pancreatic Neoplasms; Proto-Oncogene Proteins c-met; Tretinoin; Tumor Cells, Cultured; Up-Regulation

Our previous investigations showed that retinoids, at specific concentrations, can inhibit cell proliferation. In this investigation, we hypothesize that high concentrations of retinoids can induce phenotypic changes (differentiation) and late apoptosis in pancreatic cancer cells in vitro.. To test our hypothesis, retinoid-induced differentiation was assessed: (1) phenotypically by light and electron microscopy and (2) biochemically by measuring carbonic anhydrase, aerobic metabolic and mucin producing activities. Modulation of transforming growth factor-beta (TGF-beta) and epidermal growth factor (EGF) autocrine pathways were utilized as mechanistic and differentiation markers.. The extensive differentiation-indicative phenotypic changes correlated with several folds increase in the aerobic metabolism (MTT reduction and Mitochondrial mass), carbonic anhydrase activity and mucin production. There was a marked increase in TGF-beta (Bioassay and ELISA) and TGF-beta (RIA) secretion. EGF receptor density (Receptor binding assay) was reduced by 50% within six hours and was reflected on abolishment of EGFR ligand-induced proliferation. Cotreatment with the RAR-alpha antagonist, Ro41-5253 or pan-TGF-beta neutralizing antibody abolished the phenotypic and antiproliferative effects of all-trans retinoic acid. Apoptosis (TUNEL assay) was undetectable after three days of treatment with the maximum concentration used. However, apoptosis was extensively induced after six days of treatment.. High concentrations of retinoids were able to induce phenotypic changes (differentiation) and late apoptosis in pancreatic cancer cells in vitro. The clinical ramifications of these observations await further investigations.

Topics: Apoptosis; Carbonic Anhydrases; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Enzyme Induction; ErbB Receptors; Gene Expression Regulation, Neoplastic; Humans; In Vitro Techniques; Microscopy, Electron; Pancreatic Neoplasms; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoids; Time Factors; Transforming Growth Factor beta; Tretinoin

Treatment of cultured PANC-1, MIA PaCa-2, and BxPC-3 human pancreatic adenocarcinoma cells with 0.1 to 1.6 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) for 96 h inhibited the proliferation of these cells in a dose-dependent manner, and PANC-1 and MIA PaCa-2 cells were more sensitive to TPA than BxPC-3 cells. Inhibition of proliferation by TPA in PANC-1 cells was associated with an increase in the level of p21, but this was not observed in MIA PaCa-2 or BxPC-3 cells. The TPA-induced increase of p21 in PANC-1 cells was blocked by bisindolylmaleimide or rottlerin (inhibitors of protein kinase C). Studies in NCr-immunodeficient mice with well established PANC-1 tumor xenografts indicated that daily i.p. injections of TPA strongly inhibited tumor growth, increased the percentage of caspase-3-positive cells, and decreased the ratio of mitotic cells to caspase-3-positive cells in the tumors. Studies with BxPC-3 tumors in NCr mice receiving daily i.p. injections of vehicle, TPA, all-trans retinoic acid (ATRA), or a TPA/ATRA combination showed that TPA had an inhibitory effect on tumor growth, but treatment of the animals with the TPA/ATRA combination had a greater inhibitory effect on tumor growth than TPA alone. Treatment with the TPA/ATRA combination resulted in a substantially decreased ratio of the percentage of mitotic cells to the percentage of caspase-3-positive cells in the tumors compared with tumors from the vehicle-treated control animals. The inhibitory effects of TPA on tumor growth occurred at clinically achievable blood levels.

Topics: Animals; Apoptosis; Body Weight; Cell Cycle; Cell Proliferation; Humans; Immunohistochemistry; Male; Mice; Neoplasm Transplantation; Paclitaxel; Pancreatic Neoplasms; Phosphorylation; Prostatic Neoplasms; Protein Kinase C; Retinoblastoma Protein; Sulindac; Tetradecanoylphorbol Acetate; Transplantation, Heterologous; Tretinoin; Tumor Cells, Cultured

The transmembrane mucin, MUC4, is aberrantly expressed with a high incidence in human pancreatic adenocarcinomas and plays an important role in the pathogenesis of the disease. Our recent studies have shown that interferon-gamma (IFNgamma) and retinoic acid (RA) are important regulators of MUC4 in pancreatic tumour cells. Induction of MUC4 by IFNgamma occurs via a novel pathway involving upregulation of the signal transducer and activator of transcription 1 (STAT-1), whereas its stimulation by RA requires mediation by the transforming growth factor beta-2 (TGFbeta-2). In this study, we have investigated the molecular mechanisms underlying the interaction of IFNgamma and RA in MUC4 regulation in pancreatic tumour cells. We demonstrate that these reagents exert a synergistic induction of MUC4. Interestingly, while the upregulation of STAT-1 by IFNgamma is partially inhibited by RA, IFNgamma is shown to repress RA-driven TGFbeta-2 induction, pointing to the involvement of alternative mechanism(s) in IFNgamma-RA synergism. Moreover, a dose-dependent and cooperative induction of MUC4 promoter activity suggests a regulation at the transcriptional level, most likely by STAT-1 and RAR/RXR (RA receptor/retinoic X receptor) or other IFNgamma/RA-induced secondary intermediate effectors. Our findings provide potential mechanisms that may account for the aberrant expression of MUC4 in pancreatic tumour cells and expose a novel molecular mechanism of gene induction, whereby a reprogramming of signalling pathway through alternative route(s) operates during a synergistic interaction of biological modifiers.

Topics: Cell Line, Tumor; DNA-Binding Proteins; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Interferon-gamma; Mucin-4; Mucins; Pancreatic Neoplasms; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; Signal Transduction; STAT1 Transcription Factor; Trans-Activators; Transcriptional Activation; Tretinoin; Up-Regulation

Cytokines produced by immune cells in pancreatic islets infiltrating are important mediators of beta-cell destruction in insulin-dependent diabetes mellitus. In this study, the effects of retinoic acid (RA) on cytokine-induced beta-cell dysfunction were examined. RA significantly protected interleukin-1 beta (IL-1) and interferon-gamma (IFN-gamma)-mediated cytotoxicity of rat insulinoma cell (RINm5F), and also reduced in IL-1 and IFN-gamma-induced nitric oxide (NO) production, which correlated well with reduced levels of the inducible form of NO synthase (iNOS) mRNA and protein. The molecular mechanism, by which RA inhibited iNOS gene expression, appeared to involve the inhibition of NF-kappa B activation. Our results suggest possible therapeutic value of RA for the prevention of diabetes mellitus progression.

Topics: Animals; Cells, Cultured; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Insulinoma; Interferon-gamma; Interleukin-1; Islets of Langerhans; NF-kappa B; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; Pancreatic Neoplasms; Protective Agents; Rats; Tretinoin

Peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand activated transcription factor, forms a heterodimer with retinoid X receptor alpha (RXRalpha), and its transcriptional activity is thought to be maximal in the presence of both PPARgamma and RXRalpha ligands. Though previous studies suggested that thiazolidinediones (TZDs), known as PPARgamma ligands, inhibit the growth of certain types of cancer cells, little is known about the growth inhibitory effects mediated though activation of PPARgamma/RXRalpha. We examined the effects of troglitazone (one type of TZDs) and 9-cis retinoic acid, a RXRalpha ligand, on activation of PPARgamma/RXRalpha and growth inhibition of human pancreatic cancer cell lines (AsPC1, BxPC3, PSN1, PCI6, Panc1, KMP-4, and KMP-7). Combined treatment of troglitazone and 9-cis retinoic acid showed enhanced transcriptional activity and enhanced antiproliferative effects. In PSN1 cells, G1 cell cycle arrest and apoptosis were induced by troglitazone and these effects were enhanced with additional 9-cis RA. Our findings suggest that activation of PPARgamma/RXRalpha pathway might play an important role in growth inhibition of pancreatic cancer cells via G1 cell cycle arrest and apoptosis. This nuclear receptor might be a suitable molecular target for treatment of pancreatic cancers.

Topics: Alitretinoin; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-2-Associated X Protein; Cell Division; Chromans; Cyclin D1; G1 Phase; Gene Expression Regulation, Neoplastic; Humans; In Situ Nick-End Labeling; Nuclear Proteins; Pancreatic Neoplasms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; Thiazolidinediones; Transcription Factors; Transcription, Genetic; Tretinoin; Troglitazone; Tumor Cells, Cultured

Peroxisome prolixferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor, forms a heterodimer with retinoid X receptor alpha (RXRalpha), and its transcriptional activity is thought to be maximal in the presence of both PPARgamma and RXRalpha ligands. Although previous studies suggested that thiazolidinediones (TZDs), known as PPARgamma ligands, inhibit the growth of several types of tumor cells, the precise mechanism still remains obscure. The present study was designed to examine the effects of PPARgamma/RXRalpha transcriptional activation on cell growth in cancer cells. We compared the effects of six types of TZDs (troglitazone, RS-1303, RS-1330, RS-1387, RS-1455, and RS-1456) and 9-cis RA, an RXRalpha ligand, on the activation of PPARgamma/RXRalpha and the growth inhibition of six types of adenocarcinoma cell lines (MKN45, HT-29, HCT116, HuCCT1, KMP-2, and BxPC3) established from abdominal malignancies. PPARgamma was expressed in all six tumor cell lines and transcriptionally functional in five of the six lines. The stronger PPARgamma activator showed the stronger growth inhibitor in these five cell lines. However, no significant growth inhibitory effect of six types of PPARgamma activators was observed in BxPC3 cells, which showed no significant PPARgamma transactivation by these activators. Simultaneous addition of troglitazone and 9-cis RA enhanced both activation of PPARgamma/RXRalpha and growth inhibition in several types of cancer cells. The degree of PPARgamma/RXRalpha activation correlated with the extent of growth inhibition (r > 0.70, P < 0.05). This growth inhibition was associated with G1 cell cycle arrest and cell differentiation. These findings suggest that activation of the PPARgamma/RXRalpha pathway plays an important role in the growth inhibition of tumor cells and that this nuclear hormone receptor may be a possible novel molecular target for treatment of tumors in humans.

Topics: Adenocarcinoma; Alitretinoin; Antineoplastic Agents; Apoptosis; Biliary Tract Neoplasms; Cell Differentiation; Cell Division; Chromans; Drug Screening Assays, Antitumor; Drug Synergism; Gastrointestinal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Pancreatic Neoplasms; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; Thiazoles; Thiazolidinediones; Transcription Factors; Transcriptional Activation; Tretinoin; Troglitazone; Tumor Cells, Cultured

Analogues of vitamin A have been shown to influence growth of malignant tissue, such as pancreatic cancer.. To study the expression of retinoic acid receptors (RAR) in pancreatic cancer cells and the effect of three different retinoids on the cell number in vitro were studied.. Cell lines were established from 13 patients who underwent surgery for pancreatic adenocarcinoma. The expression of the retinoic acid receptors (RAR) and retinoic X receptor (RXR) subtypes (alpha, beta, and gamma) was studied with western blotting and specific antibodies. The effect of incubation with all-trans-retinoic acid (atRA; tretinoin), 9-cis-retinoic acid (9-cis-RA), and 13-cis-retinoic acid (13-cis-RA; isotretinoin) on the cell number was examined with use of a Roche XTT cell proliferation kit.. The RXR alpha receptor was expressed in all cell lines. RAR alpha,beta and RXR beta were expressed in most of them. RXR gamma was expressed in about half of the cell lines and RAR gamma in only one. Incubation of the cells with retinoids showed a decreased cell number at concentrations of 10(4) M, except for 9-cis-RA, to which only about half of the cell lines responded.. Two or more of the RAR subtypes were expressed in each pancreatic cell line. There was no uniform pattern of receptor expression; however, the cell lines responded with decreased cell number to high concentrations of atRA and 13-cis-RA but not to 9-cis-RA.

Topics: Adenocarcinoma; Alitretinoin; Antineoplastic Agents; Blotting, Western; Cell Division; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Isotretinoin; Pancreatic Neoplasms; Receptors, Retinoic Acid; Retinoid X Receptors; Transcription Factors; Tretinoin; Tumor Cells, Cultured

All-trans-retinoic acid and 9-cis-retinoic acid have been reported to have inhibitory effects on pancreatic adenocarcinoma cells and we have shown that this is partly due to induction of apoptosis. In this study, the mechanisms whereby 9-cis-retinoic acid induces apoptosis in these cells were investigated. An involvement of the Bcl-2 family of proteins was shown, such that 9-cis-retinoic acid causes a decrease in the Bcl-2/Bax ratio. Overexpression of Bcl-2 also resulted in inhibition of apoptosis induced by 9-cis-retinoic acid. Furthermore, two broad-range caspase inhibitors blocked DNA fragmentation induced by 9-cis-retinoic acid, but had no effect on viability defined by mitochondrial activity. Using synthetic retinoids, which bind selectively to specific retinoic acid receptor subtypes, we further established that activation of retinoic acid receptor-gamma is essential for induction of apoptosis. Only pan-retinoic acid receptor and retinoic acid receptor-gamma selective agonists reduced viability and a cell line expressing very low levels of retinoic acid receptor-gamma is resistant to the effects of 9-cis-retinoic acid. A retinoic acid receptor-beta/gamma selective antagonist also suppressed the cytotoxic effects of 9-cis-retinoic acid in a dose-dependent manner. This study provides important insight into the mechanisms involved in suppression of pancreatic tumour cell growth by retinoids. Our results encourage further work evaluating the clinical use of receptor subtype selective retinoids in pancreatic carcinoma.

Topics: Adenocarcinoma; Alitretinoin; Amino Acid Chloromethyl Ketones; Animals; Apoptosis; Aspartic Acid; bcl-2-Associated X Protein; Cysteine Proteinase Inhibitors; DNA Fragmentation; Drug Resistance; Fatty Acids, Unsaturated; Gene Expression Regulation, Neoplastic; Genes, bcl-2; Humans; Mice; Mitochondria; Neoplasm Proteins; Pancreatic Neoplasms; Protein Isoforms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Retinoic Acid Receptor gamma; Retinoid X Receptors; Retinoids; Transcription Factors; Transfection; Tretinoin; Tumor Cells, Cultured

Peroxisome proliferator-activated receptor gamma (PPARgamma) forms a heterodimeric DNA-binding complex with the retinoid X receptor (RXR) and regulates the transcription of its target genes. Activation of PPARgamma has been shown to induce G1 arrest and to inhibit cell growth of human pancreatic carcinoma cell lines. The purpose of the present study was to examine the effect of ligand activation of PPARgamma and RXR on cell growth and on the expression of G1 cyclins in a pancreatic cancer cell line PANC-1, which expresses PPARgamma at high levels. Troglitazone, a specific ligand for PPARgamma, was found to cause a reduction in the growth rate and induced G1 cell cycle arrest and this effect was additive with that of 9-cis retinoic acid (9-cis RA), a ligand for RXR. Of the G1 cyclins tested, troglitazone specifically reduced the expression of cyclin D1 mRNA and the corresponding protein and this effect was also additive with 9-cis RA. These results suggest that the activation of PPARgamma together with RXR may be useful for the suppression of pancreatic cancer cell growth through the reduction in cyclin D1 levels.

Topics: Alitretinoin; Animals; Antineoplastic Agents; Blotting, Northern; Blotting, Western; Carcinoma; Cell Division; Chromans; Cyclin D1; Dose-Response Relationship, Drug; Drug Synergism; G1 Phase; Humans; Pancreatic Neoplasms; Rats; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Thiazoles; Thiazolidinediones; Transcription Factors; Transfection; Tretinoin; Troglitazone; Tumor Cells, Cultured

Retinoids, which are derivatives of vitamin A, are important factors involved in the control of biologic functions such as cell growth and differentiation, development, and carcinogenesis. We have shown previously that the naturally occurring retinoids all-trans-retinoic acid (ATRA) and 9-cisretinoic acid (9cRA) induce growth inhibition followed by apoptosis in pancreatic adenocarcinoma cells in vitro.. To evaluate the efficacy of retinoids in combination with the chemotherapeutic drugs gemcitabine and cisplatin.. In vitro growth inhibition and induction of apoptosis by different combinations of retinoids and cytotoxic drugs were studied by using the T3M-4 and BxPc-3 cell lines. For in vivo studies, T3M-4 cells were injected subcutaneously in nude mice.. Pre-treatment of pancreatic adenocarcinoma cells with ATRA or 9cRA before the addition of the drugs resulted in significant reduction in cell number compared with treatment with the drugs alone. Pre-treatment with 9cRA followed by gemcitabine or cisplatin alone also resulted in a strong increase in the percentage of cells undergoing programmed cell death, or apoptosis. Furthermore, there was an indication that the combination of ATRA and gemcitabine caused increased apoptosis in vivo.. Our results clearly suggest the need for additional studies exploring the potential role of the combination of retinoids and gemcitabine in the management of pancreatic cancer.

Topics: Adenocarcinoma; Alitretinoin; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cisplatin; Deoxycytidine; Drug Synergism; Female; Gemcitabine; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Tretinoin; Tumor Cells, Cultured

The clearance of apoptotic cells is crucial to avoid chronic inflammation and autoimmunity. Little is known about the factors that regulate it in vivo. We show that granulocyte-macrophage colony-stimulating factor (GM-CSF) administration to carcinoma patients confers to their leukocytes a significantly higher ability to phagocytose apoptotic cells than before (P < 0.005). GM-CSF increased the concentration of monocytes and polymorphonuclear leukocytes in the peripheral blood and activated circulating polymorphonuclear leukocytes. Both effects abated early after treatment, whereas phagocytosis of apoptotic cells was still significantly higher after 18 days compared with basal values (P < 0.005 and P < 0.025 for monocytes and polymorphonuclear leukocytes, respectively). On in vitro phagocytosis of apoptotic cells monocytes, but not polymorphonuclear leukocytes, up-regulated MHC class II membrane expression. These findings are consistent with the possibility that GM-CSF endows both scavenger and antigen-presenting leukocytes with the ability to internalize apoptotic tumor cells.

Topics: Adult; Aged; Antineoplastic Agents; Apoptosis; Carcinoma; Carcinoma, Renal Cell; Colonic Neoplasms; Combined Modality Therapy; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunologic Factors; Interferon-alpha; Jurkat Cells; Kidney Neoplasms; Leukocyte Count; Male; Middle Aged; Monocytes; Neutrophils; Pancreatic Neoplasms; Phagocytosis; Tretinoin

Retinoids and vitamin D are known to exert important anti-tumour effects in a variety of cell types. In this study the effects of 9-cis-retinoic acid (9cRA) the vitamin D analogues EB1089 and CB1093 on three pancreatic adenocarcinoma cell lines were investigated. All compounds caused inhibition of in vitro growth but the vitamin D analogues were generally the more potent growth inhibitors. They were also more effective on their own than in combination with 9cRA. Growth arrest correlated with an increased proportion of cells in the G0/G1 phase. Apoptosis was induced in the three cell lines by 9cRA, whereas neither EB1089 nor CB1093 had this effect. Furthermore, addition of EB1089 or CB1093 together with 9cRA resulted in significantly reduced apoptosis. Our results show that retinoic acids as well as vitamin D analogues have inhibitory effects on pancreatic tumour cells but different and antagonistic mechanisms seem to be employed.

Topics: Alitretinoin; Antineoplastic Agents; Apoptosis; Calcitriol; Cell Division; Drug Screening Assays, Antitumor; Humans; Pancreatic Neoplasms; Tretinoin; Tumor Cells, Cultured; Vitamin D

The MUC4 mucin is considered as the homologue of rat sialomucin complex (SMC, rat Muc4) due to its similar structural organization. Like SMC, MUC4 may also exist as two subunits: a mucin type unit known as MUC4alpha and a growth factor-like transmembrane subunit, MUC4beta. The expression of MUC4 in normal human pancreas is not detectable, but it is highly expressed in pancreatic tumor cells. In the present study, we investigated the regulation of MUC4 expression in human pancreatic tumor cells CD18/HPAF, exhibiting a high level of MUC4 transcripts and protein. When these cells were adapted to grow in the serum-free medium (CD18/HPAF-SF), the MUC4 expression was undetectable. Among several serum constituents, all-trans-retinoic acid (RA) induced the expression of MUC4 transcripts in a concentration- and time-dependent manner. The RA-mediated increase in the level of the MUC4 transcript coincided with an increased expression of transforming growth factor-beta2 (TGF-beta2) transcript. The antagonist of the retinoic acid receptor (RAR)-alpha (Ro41-5253) abrogated the expression of MUC4 and TGF-beta2 induced by RA. The exogenous addition of TGF-beta2 also increased the MUC4 expression. The TGF-beta-neutralizing antibody blocked the RA-induced as well as TGF-beta2-mediated MUC4 expression. In conclusion, induction of MUC4 expression in pancreatic carcinoma by RA is mediated through the RAR-alpha signaling pathway, and TGF-beta2 may serve as an interim mediator of this regulated expression.

Topics: Humans; Mucin-4; Mucins; Pancreatic Neoplasms; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; RNA, Messenger; Transforming Growth Factor beta; Tretinoin; Tumor Cells, Cultured

The expression of midkine (MK) was investigated in pancreatic ductal hyperplasias, atypical hyperplasias and adenocarcinomas induced by N-nitrosobis(2-oxopropyl)amine (BOP) in hamsters, and in hamster ductal adenocarcinoma cell lines (HPD-1NR, -2NR and -3NR). MK mRNA was clearly overexpressed in invasive pancreatic duct adenocarcinomas (PCs) and the three cell lines as assessed by northern blot analysis, and MK protein expression increased from ductal hyperplasia through atypical hyperplasias, intraductal carcinomas and invasive PCs by immunohistochemistry. The extent of overexpression of MK mRNA in PCs was almost the same as in hamster whole embryonic tissue. MK is reported to be a retinoid-responsive gene, but MK mRNA expression was not affected by treatment with all-trans retinoic acid (tRA) or N-(4-hydroxyphenyl)retinamide (4-HPR) in HPD-1NR cells. The results thus suggest that MK expression is involved in the development and progression of pancreatic ductal adenocarcinomas induced by BOP in hamsters, with loss of upregulation by retinoic acid.

Topics: Animals; Antineoplastic Agents; Blotting, Northern; Carcinoma, Pancreatic Ductal; Carrier Proteins; Cell Division; Cells, Cultured; Cricetinae; Cytokines; Disease Models, Animal; Female; Fenretinide; Gene Expression; Immunohistochemistry; Mesocricetus; Midkine; Nitrosamines; Pancreatic Neoplasms; RNA, Messenger; Tretinoin

In this study, we investigated the effect of a novel retinobenzoic acid, 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101), on the growth of 4 human pancreatic-cancer cell lines; BxPC-3, MIAPaCa-2, CFPAC-1 and AsPC-1. TAC-101 significantly inhibited the proliferation of BxPC-3 and MIAPaCa-2 cells in a time- and concentration-dependent manner, but not the proliferation of AsPC-1 cells. Furthermore, the anti-proliferative effects of TAC-101 on BxPC-3 and MIAPaCa-2 cells were stronger than those of all-trans retinoic acid. Flow-cytometric analyses indicated that treatment of BxPC-3 with TAC-101 strongly induces cell-cycle arrest at the G1 phase. The cell-cycle arrest induced by TAC-101 was accompanied by reduction of retinoblastoma-gene product (RB) phosphorylation and an increase of 2 cyclin-dependent kinase (CDK) inhibitors, p21(WAF1/Cip1) (p21) and p27Kip1 (p27). TAC-101 also caused a decrease in cyclin A and thymidylate synthase, which are E2F-regulated gene products. No changes were observed in the expression of cyclin D1, cyclin E on CDK2. In addition, Hoechst staining, gel electrophoresis and flow-cytometric analysis indicated that a marked reduction in the number of BxPC-3 cells with TAC-101 was related to the induction of apoptosis. Our results suggest that TAC-101 inhibits the growth of certain pancreatic-cancer cells by means of G1-phase cell-cycle arrest resulting from the reduction of RB phosphorylation and the up-regulation of p21 and p27 as well as the induction of apoptosis. TAC-101 may therefore be a useful agent for new therapeutic strategies focusing on inhibition of pancreatic-cancer-cell proliferation.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Benzoates; Cell Cycle; Cell Division; Cell Nucleus; DNA Fragmentation; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Kinetics; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Receptors, Retinoic Acid; Retinoblastoma Protein; Retinoic Acid Receptor alpha; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Tretinoin; Trimethylsilyl Compounds; Tumor Cells, Cultured

In this study we used differential display reverse transcription-polymerase chain reaction to search for differentially expressed all-trans-retinoic acid (ATRA)-responsive genes in pancreatic carcinoma cells. We identified the kinesin-related protein HsEg5, which plays an essential role in spindle assembly and spindle function during mitosis, as a novel molecule involved in ATRA-mediated growth inhibition. Using Northern and Western blot analysis we demonstrated that ATRA significantly inhibits HsEg5 expression in various pancreatic carcinoma cell lines as well as in HaCat keratinocytes. Inhibition of HsEg5 expression by ATRA occurs at the posttranscriptional level. As a consequence, tumor cells synchronized in S-phase revealed a retarded progression through G2/M phase of the cell cycle indicating that HsEg5 inhibition results in a delayed progression through mitosis. Furthermore, a significant decrease of HsEg5 protein expression achieved by antisense transfection revealed a significant growth inhibition compared with control cells. Therefore, HsEg5 represents a novel molecule involved in ATRA-mediated growth inhibition, suggesting that vitamin A derivatives can interact with the bipolar spindle apparatus during mitosis.

Topics: Cell Cycle; Cell Division; Gene Expression Regulation; HL-60 Cells; Humans; Keratinocytes; Kinesins; Mitosis; Oligonucleotides, Antisense; Pancreatic Neoplasms; Polymerase Chain Reaction; Protein Processing, Post-Translational; Transfection; Tretinoin; Tumor Cells, Cultured; Xenopus Proteins

Pancreatic carcinoma is an invasive and metastasizing type of malignancy. We established six pancreatic cancer cell lines from human pancreatic carcinomas, three highly metastatic lines (KP-1NL, KP-4, and SUIT-2) and three minimally metastatic lines (KP-2, KP-3, and BxPC-3). The three highly metastatic cell lines grew in a fibroblastoid pattern on collagen gels, whereas the three minimally metastatic cell lines grew in an epithelioid pattern under similar conditions. Western blot and Northern blot analyses indicated much higher levels of E-cadherin in the three minimally metastatic cell lines relative to the three highly metastatic cell lines. When the effect of all-trans-retinoic acid on the growth patterns of the three highly metastatic lines was examined, we observed a dramatic change from fibroblastoid to epithelioid growth in SUIT-2 cells. Although all six cell lines had comparable levels of retinoic acid receptor-gamma, retinoic acid receptor-beta was expressed only in SUIT-2 cells. Treating SUIT-2 cells with retinoic acid also induced the upregulation of E-cadherin expression. When SUIT-2 cells were treated with retinoic acid receptor-specific agonists, 13-cis-retinoic acid and Am555S, a morphological change from fibroblastoid to epithelioid growth was induced. Retinoic acid receptor-specific antagonists, LE135 and LE540, inhibited retinoic acid-induced change of the growth patterns. The effect of retinoic acid and its derivatives on the growth pattern was discussed in a possible association with their antimetastatic activities of pancreatic cancer.

Topics: beta Catenin; Cadherins; Cell Differentiation; Cell Division; Cell Line; Collagen; Cytoskeletal Proteins; DNA Probes; Humans; Neoplasm Metastasis; Pancreatic Neoplasms; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; Trans-Activators; Tretinoin; Tumor Cells, Cultured

Retinoids inhibit growth and induce differentiation in a variety of pancreatic carcinoma cells. The goal of this study was to examine the molecular mechanisms responsible for retinoid sensitivity.. Anchorage-independent growth was examined in AR42J, DSL-6A/C1, and Capan-2 cells using a human tumor clonogenic assay. Retinoid receptors were characterized by a reverse-transcription polymerase chain reaction. Retinoic acid receptor gamma1 (RARgamma1) was stably transfected into AR42J cells using lipofectamin and into DSL-6A/C1 using ballistomagnetic gene transfer. Receptor expression was verified using Southern and Northern blotting as well as electrophoretic mobility shift assays.. Retinoid treatment resulted in a dose-dependent growth inhibition of Capan-2 cells, whereas growth was not affected in AR42J and DSL-6A/C1 cells. A selective loss of RARgamma1 expression was observed in both retinoid-resistant cell lines, whereas all other retinoid receptor subtypes showed an identical expression pattern. Retinoid treatment of three independent RARgamma1-expressing cell clones of AR42J and DSL-6A/C1 cells resulted in pronounced growth inhibition compared with wild-type control cells.. RARgamma1 expression determines sensitivity of pancreatic carcinoma cells to retinoid-mediated growth inhibition and might therefore serve as a valuable predictive marker for retinoid treatment of pancreatic cancer.

Topics: Animals; Antineoplastic Agents; Carcinoma; Cell Division; Cell Line; Dose-Response Relationship, Drug; Drug Resistance; Humans; Pancreas; Pancreatic Neoplasms; Rats; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; Transfection; Tretinoin

Matrix metalloproteinases play an important role in the control of local tumour growth and metastasis of human pancreatic cancer.. To examine expression of recently discovered stromelysin 3 (STR-3) in human pancreatic cancer and pancreatic carcinoma cell lines and to investigate their regulation by retinoids.. STR-3 expression was examined by immunohistochemistry in 21 human pancreatic carcinomas. Expression of STR-3 and regulation by retinoids was assessed in five human pancreatic carcinoma cell lines using western and northern blotting as well as nuclear run on assays.. There was pronounced overexpression of STR-3 in 17 of 21 (80.9%) pancreatic carcinoma specimens. STR-3 expression was predominantly located in peritumourous stromal cells. Six of 21 (28.5%) carcinomas also revealed STR-3 expression in epithelial tumour cells whereas no STR-3 expression was observed in non-transformed pancreas. All five pancreatic carcinoma cell lines expressed STR-3 mRNA and protein. Furthermore, retinoid treatment results in a time and dose dependent inhibition of STR-3 protein expression. This inhibition seems to be post-transcriptional as neither STR-3 gene transcription nor mRNA steady state concentrations were affected by retinoids.. STR-3 overexpression in stromal as well as epithelial elements during pancreatic carcinogenesis might contribute to the aggressive local growth and metastasis of pancreatic cancer and can be therapeutically targeted by retinoids.

Topics: Blotting, Western; Humans; Immunohistochemistry; Matrix Metalloproteinase 11; Metalloendopeptidases; Neoplasm Proteins; Pancreatic Neoplasms; RNA, Neoplasm; Tretinoin; Tumor Cells, Cultured

The initial step in tumor invasion and metastasis is determined by adhesion of tumor cells to basement membranes. To evaluate their potential therapeutic use in controlling local growth and metastasis, the effects of retinoids on the adhesive properties in the human pancreatic carcinoma cell line DAN-G were examined.. The effects of retinoids on cellular adhesion were assessed by adhesion assays in vitro. The expression of laminin-binding proteins was characterized by Northern blotting, radioimmunoprecipitation, and flow-cytometric analysis.. Treatment with retinoids results in a time- and dose-dependent inhibition of DAN-G cell adhesion to fibronection and laminin but not to collagens I, IV, and VI. The adhesion of DAN-G cells to laminin could be blocked completely by anti-alpha 6 and anti-beta 1 antibodies but not by the synthetic peptide YIGSR. Flow-cytometric analysis of DAN-G cells showed no quantitative difference for alpha 6-integrin expression in retinoid-treated and -untreated DAN-G cells. Furthermore, radioimmunoprecipitation showed no difference in the appearance of alpha 6 beta 1-integrin expression after retinoid incubation.. Retinoids decrease pancreatic carcinoma cell adhesion to laminin via an as yet unidentified mechanism involving alteration of the alpha 6 beta 1-integrin receptor function and thereby open interesting perspectives for the modulation of infiltrative growth and metastasis in pancreatic cancer.

Topics: Animals; Carcinoma; Cell Adhesion; Integrin alpha6beta1; Integrins; Laminin; Pancreatic Neoplasms; Rats; Retinoids; Stereoisomerism; Tretinoin; Tumor Cells, Cultured

Effective chemotherapy for pancreatic cancer is urgently needed. The anti-proliferative activity of a new retinoid, mofarotene (RO40-8757), was compared with that of other retinoids, such as all trans-retinoic acid, 13-cis retinoic acid and 9-cis retinoic acid, on 9 pancreatic cancer cell lines in relation to the effects on various cell cycle-regulating factors. After treatment with each retinoid, anti-proliferative effect was determined by the MTT method and expression of cell cycle-regulating factors, such as cyclins (D1, E and A), cyclin-dependent kinases (2 and 4), cyclin-dependent kinase inhibitors (p21 and p27) and retinoblastoma protein, was analyzed by Western blotting. Mofarotene showed half-maximal inhibition of cell proliferation at concentrations between 0.14 x 10(-6) and 3.8 x 10(-6) mol/l with little cytotoxicity. In contrast, the other retinoids did not inhibit the growth of all cell lines by over 50% compared to controls. A marked increase in the fraction of cells in G1 phase of the cell cycle was observed after mofarotene treatment; this was associated with marked up-regulation of p21/p27 and a shift of retinoblastoma protein into the hypophosphorylated form. In conclusion, mofarotene inhibits the growth of pancreatic cancer cells by inducing G1-phase cell cycle-inhibitory factors (p21, p27 and hypophosphorylated form of Rb protein) and is considered to be a useful agent for pancreatic cancer treatment.

Topics: Alitretinoin; Antineoplastic Agents; Blotting, Western; CDC2-CDC28 Kinases; Cell Cycle; Cell Cycle Proteins; Cell Division; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases; Cyclins; Dose-Response Relationship, Drug; Humans; Isotretinoin; Microtubule-Associated Proteins; Morpholines; Pancreatic Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Retinoblastoma Protein; Retinoids; Time Factors; Tretinoin; Tumor Cells, Cultured; Tumor Suppressor Proteins; Up-Regulation

We detected the antiproliferative effect with MTT test and investigated the changes in biological properties, cytomorphology and ultrastructure through cytopathology and electronic microscopy. Cell growth of JF-305 was inhibited by all-trans retinoic acid (ATRA). The maximal inhibitory rate was 34.7%. The number of proliferative cells reduced (P < 0.01). Cell metabolism slowed down, secretory functions recovered, and malignant degree decreased. ATRA can inhibit the proliferation and induce the differentiation of human pancreatic adenocarcinoma JF-305 cells.

Topics: Adenocarcinoma; Antineoplastic Agents; Cell Division; Cell Transformation, Neoplastic; Humans; Pancreatic Neoplasms; Tretinoin; Tumor Cells, Cultured

Retinoids and vitamin D are important factors that regulate cellular growth and differentiation. An additive growth-inhibitory effect of retinoids and vitamin D analogues has been demonstrated for human myeloma, leukaemic and breast cancer cells. We set out to study the effects of the vitamin D analogue EB1089 and the retinoids all-trans- and 9-cis-retinoic acid on the human pancreatic adenocarcinoma cell lines Capan 1 and Capan 2 and the undifferentiated pancreatic carcinoma cell line Hs766T. The cell lines investigated expressed vitamin D receptor, retinoic acid receptor (RAR)-alpha and gamma as determined by polymerase chain reaction after reverse transcription. RAR-beta was expressed only in Hs766T cells. Addition of all-trans-retinoic acid increased the amount of RAR-alpha mRNA in the three cell lines and induced RAR-beta mRNA in Capan 1 and Capan 2 cells. All-trans-retinoic acid at a concentration of 10 nM inhibited the growth of Capan 1 and Capan 2 cells by 40% relative to controls. 9-cis-Retinoic acid was less effective. Neither all-trans-retinoic acid nor 9-cis-retinoic acid affected the growth of Hs766T cells. EB1089, if added alone to the cells, did not significantly inhibit growth. However, the combination of 1 nM EB1089 with 10 nM all-trans-retinoic acid exerted a growth-inhibitory effect of 90% in Capan 1 cells and of 70% in Capan 2 cells. Our data suggest that vitamin D analogues together with retinoids inhibit the growth of human pancreatic cancer cells. However, in vivo studies are necessary to examine the potential use of retinoids and vitamin D analogues on pancreatic cancer.

Topics: Animals; Antineoplastic Agents; Base Sequence; beta 2-Microglobulin; Calcitriol; Cell Division; Cell Line; DNA Primers; Kidney; Molecular Sequence Data; Pancreatic Neoplasms; Polymerase Chain Reaction; Rats; Receptors, Calcitriol; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Transcription, Genetic; Tretinoin; Tumor Cells, Cultured

Retinoids are a class of molecules structurally related to vitamin A that have potent antiproliferative and differentiating effects on a variety of normal and neoplastic tissues. All-trans-retinoic acid (ATRA) has become a first-line chemotherapeutic agent in the treatment of certain leukemias; however, the effect of ATRA on pancreatic tumors is unknown. The purpose of this study was to determine the effect of ATRA on the growth characteristics of both exocrine and endocrine human pancreatic cancer cell lines. The in vitro growth of four cell lines was examined after treatment with a wide dose range of ATRA. The growth of all tumor cell lines was inhibited by ATRA in a dose-dependent fashion beginning at 0.1 microgram M. The in vivo growth of functioning human pancreatic carcinoid (BON) xenografts in Balb/c athymic mice was determined by treatment with several doses of ATRA over 1 month. The growth of BON tumors was inhibited in a dose-dependent fashion. These results suggest that ATRA exerts direct antiproliferative effects on both exocrine and endocrine human pancreatic cancers and may be useful in the chemotherapy of these tumors.

Topics: Animals; Cell Division; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Pancreatic Neoplasms; Tretinoin; Tumor Cells, Cultured

We have investigated the role of protein kinase C (PKC) isoenzymes in the differential growth regulation of human pancreatic carcinoma cell lines by all-trans retinoic acid (RA). RA treatment results in dose-dependent stimulation of anchorage-independent growth in AsPc1 cells and growth inhibition in Capan 2 cells. Both cell lines express an identical pattern of nuclear RA and retinoid X receptors as determined by RT-PCR. Western blotting using monospecific antibodies revealed that both cell lines express PKC isoenzymes alpha and zeta, whereas beta, gamma, delta, and epsilon were not detected. Incubation with RA in the growth-stimulated AsPc1 cell line resulted in induction of PKC alpha expression, whereas PKC alpha expression was decreased by RA in the growth-inhibited Capan 2 cell line. In contrast, PKC zeta expression was not affected by RA in either cell line. Incubation of AsPc1 cells with the phorbol ester 12-O-tetradecanoyl phorbol 13-acetate resulted in a time- and dose-dependent selective down-regulation of PKC alpha but not zeta. The dose-dependent decrease of intracellular PKC alpha concentration correlated well with the anchorage-independent growth rate of AsPc1 cells. Furthermore, selective down-regulation of PKC alpha blocks subsequent growth stimulation by RA in AsPc1 cells. When PKC alpha concentration was decreased by stably transfecting AsPc1 cells with a PKC alpha complementary DNA antisense construct, RA-stimulated growth could also be partially blocked. These data, therefore, suggest that differential regulation of PKC alpha expression plays a central role in determining the bidirectional effects of RA on growth in pancreatic carcinoma cells.

Topics: Base Sequence; Carcinoma; Cell Division; Humans; Isoenzymes; Molecular Probes; Molecular Sequence Data; Pancreatic Neoplasms; Protein Kinase C; Protein Kinase C-alpha; Receptors, Retinoic Acid; Retinoid X Receptors; Transcription Factors; Tretinoin; Tumor Cells, Cultured

The antiproliferative and differentiation-inducing effects of all-trans retinoic acid (RA) and sodium butyrate (SB) were investigated in four pancreatic ductal adenocarcinoma cell lines, two poorly differentiated ones (PT45 and PaTu-II), one moderately to poorly differentiated one (Panc-1) and one highly differentiated one (A818-1). Treatment with 20 microM RA resulted in moderate inhibition of cell growth in all cell lines, but clear evidence of cytodifferentiation (including elongated cell processes, increased rough endoplasmic reticulum, intensified immunostaining for the mucin marker (M1) was found only in PT45 and Panc-1. These phenotypic changes were paralleled by upregulation of RAR (retinoic acid receptor)-alpha and -gamma mRNA. SB (1 and 2 mM) treatment inhibited the cell growth of all cell lines much more prominently than RA. Cytodifferentiation was also largely restricted to PT45 and Panc-1. A noticeable phenomenon was enhancement of the expression of the neuroendocrine markers synaptophysin and Lcu7 in Panc-1 cells. In conclusion, it is evident that the original differentiation status of cells and their responsiveness to the agents are not clearly associated, and that RA responsiveness correlates with upregulation of RAR-alpha and -gamma mRNA.

Topics: Blotting, Northern; Blotting, Western; Butyrates; Butyric Acid; Carcinoma, Ductal, Breast; CD57 Antigens; Cell Division; Endoplasmic Reticulum, Rough; Humans; Immunohistochemistry; Microscopy, Phase-Contrast; Mucins; Pancreatic Neoplasms; Phenotype; Receptors, Retinoic Acid; RNA, Messenger; Synaptophysin; Tretinoin; Tumor Cells, Cultured

Carbonic anhydrase II (CA II) generates bicarbonate in human pancreatic duct cells. We have developed the human pancreatic duct cell line DANG as a model to study the effects of all-trans-retinoic acid (ATRA) on CA II gene expression. ATRA treatment resulted in a time- and dose-dependent inhibition of CA II mRNA concentrations in DANG cells. These inhibitory effects were paralleled by a time-dependent decrease of CA II protein concentrations. Nuclear run on analysis revealed that the decrease of CA II mRNA concentrations was due to a decreased rate of CA II gene transcription. These data show that ATRA transcriptionally modulates CA II gene expression in human pancreatic carcinoma cells.

Topics: Carbonic Anhydrases; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Pancreas; Pancreatic Neoplasms; Transcription, Genetic; Tretinoin; Tumor Cells, Cultured

All-trans retinoic acid, a metabolite of retinol, is a possible morphogen in vertebrate development. Two classes of cellular proteins, which specifically bind all-trans retinoic acid, are thought to mediate its action: the nuclear retinoic acid receptors (RAR alpha, beta, gamma), and the cytoplasmic binding proteins known as cellular retinoic acid-binding proteins I and II (CRABP I and II). The function of the retinoic acid receptors is to regulate gene transcription by binding to DNA in conjunction with the nuclear retinoid X receptors (RXR alpha, beta, gamma), which in turn have 9-cis retinoic acid as a ligand. Several lines of evidence suggest that the role of the cellular retinoic acid-binding proteins is to control the concentration of free retinoic acid reaching the nucleus in a given cell. Here, we have addressed the role of the cellular retinoic acid-binding protein I in development by ectopically expressing it in the mouse lens, under the control of the alpha A-crystallin promoter. We show that this ectopic expression interferes with the development of the lens and with the differentiation of the secondary lens fiber cells, causing cataract formation. These results suggest that correct regulation of intracellular retinoic acid concentration is required for normal eye development. In addition, the generated transgenic mice also present expression of the transgene in the pancreas and develop pancreatic carcinomas, suggesting that overexpression of the cellular retinoic acid-binding protein is the cause of the tumors. These results taken together provide evidence for a role of the cellular retinoic acid-binding protein in development and cell differentiation. The relevance of these findings to the possible role of the cellular retinoic acid-binding proteins in the transduction of the retinoic acid signal is discussed.

Topics: Animals; Blotting, Northern; Cataract; Cell Differentiation; Gene Expression; In Situ Hybridization; Lens, Crystalline; Mice; Mice, Transgenic; Morphogenesis; Pancreatic Neoplasms; Receptors, Retinoic Acid; Tretinoin

Tiazofurin (TR), an inhibitor of IMP dehydrogenase, causes remissions and induced differentiation in human leukemia through lowering the concentrations of GTP and dGTP. A deoxycytidine analog, difluorodeoxycytidine (DFDC), is an anti-tumor agent phosphorylated by deoxycytidine kinase, resulting in decreased concentration of dCTP, leading to inhibition of DNA synthesis. In HL-60 cells DFDC induced differentiation and inhibited proliferation in a dose-dependent manner (IC50 = 4 nM); TR provided synergism with DFDC. DFDC inhibited proliferation in OVCAR-5 human ovarian carcinoma cells (IC50 = 25 nM) and colony formation in PANC-1 human pancreatic carcinoma cells (IC50 = 2 nM) and rat hepatoma 3924A cells (IC50 = 22 nM). TR and DFDC are synergistically cytotoxic in hepatoma cells and additive in PANC-1 cells. The two drugs together should be helpful in treating leukemias and solid tumors in humans.

Topics: Animals; Antimetabolites, Antineoplastic; Cell Differentiation; Cell Line; Cell Survival; Deoxycytidine; Dose-Response Relationship, Drug; Drug Synergism; Female; Gemcitabine; Humans; IMP Dehydrogenase; Kinetics; Leukemia, Promyelocytic, Acute; Liver Neoplasms, Experimental; Models, Biological; Ovarian Neoplasms; Pancreatic Neoplasms; Rats; Ribavirin; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Stem Cell Assay

Current evidence suggests that carbonic anhydrase II (CA II) is produced by pancreatic duct cells but not by pancreatic acinar or islet cells. The aim of this study was to determine whether CA II homologous RNA and CA II immunoreactive protein are produced by cell lines established from human pancreatic adenocarcinomas. A 1.7-Kb CA II homologous RNA was detected in poly(A+) RNA isolated from normal human pancreas, normal human liver, and to varying degrees in the cell lines examined. The CA II immunoreactivity corresponding to approximately 30 kD (consistent with the established molecular mass of CA II) was also detected by immunoblotting in normal human pancreas, normal human liver, and some of the cell lines. We also found that the levels of CA II homologous RNA increase in the pancreatic adenocarcinoma cell lines following treatment with the differentiating agent, retinoic acid.

Topics: Adenocarcinoma; Carbonic Anhydrases; Cytosol; Gene Expression; Humans; Immunoblotting; Liver; Molecular Weight; Nucleic Acid Hybridization; Pancreas; Pancreatic Neoplasms; Poly A; RNA; RNA, Messenger; Tretinoin; Tumor Cells, Cultured

Vitamin A (retinol) is required for insulin secretion, and retinoic acid substitutes for retinol in this function. To determine if retinol acts at the beta-cell level, we assayed beta-cells of the rat insulinoma (RINm5F) line for cytosolic retinol- and retinoic acid-binding proteins (CRBP and CRABP) by radioimmunoassay (RIA) and [3H]retinol and [3H]retinoic acid binding to cytosol extracts. Furthermore, we tested whether insulin release from cells was affected by addition of retinol or retinoic acid to culture medium. RINm5F cells were grown to near confluence before assay of CRBP and CRABP. Scatchard analysis showed the Kd for retinol to be approximately 6 nM at a level of 4.5 pmol/mg protein or 300,000 sites/cell. Sucrose density-gradient assay showed single discrete peaks migrating at 2S for both retinol and retinoic acid. RIA of whole-cell extracts showed CRBP and CRABP levels of 5.27 +/- 0.41 and 2.95 +/- 0.75 pmol/mg protein, respectively. Retinol (1.75 microM) and retinoic acid (0.175 and 1.75 microM) increased KCl-induced insulin release. Considered together, the presence of CRBP and CRABP in a beta-cell line and the increase in KCl-induced insulin release by retinol and retinoic acid are consistent with the idea that retinol has a functional role in insulin secretion and suggest a potential mechanism of action at the beta-cell level similar to that observed in other retinoid-responsive cells.

Topics: Animals; Carrier Proteins; Cell Line; Insulin; Insulin Secretion; Insulinoma; Kinetics; Neoplasm Proteins; Pancreatic Neoplasms; Potassium Chloride; Rats; Receptors, Retinoic Acid; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Tretinoin; Tumor Cells, Cultured; Vitamin A

Cytosolic retinoic acid receptor in carcinoma, chronic pancreatitis, and normal pancreatic tissue were examined using sucrose density gradient centrifugation, isoelectric focussing on agarose gel and saturation analysis. Thirteen patients were studied. Cytosolic retinoic acid binding protein (cRABP) was detected in all the samples with chronic pancreatitis and pancreatic carcinoma, but not in the normal tissue. Using sucrose gradient centrifugation, the highest concentrations of cRABP were found in pancreatic carcinoma tissues, ranging from 5.5-23.9 pmol/mg protein. These concentrations were markedly different than in chronic pancreatitis tissue (0.7-2.7 pmol/mg protein). Saturation analysis of cRABP showed a mean dissociation constant of 21.5 nM and maximum binding sites of 5.2 pmol/mg protein. Cytosolic retinoic acid binding protein was separated at an isoelectric point of 4.5 on agarose gel. The presence of cRABP suggest that retinoic acid may have a role to play in the function of the pancreas.

Topics: Adult; Aged; Aged, 80 and over; Carrier Proteins; Chronic Disease; Cytosol; Humans; Middle Aged; Neoplasm Proteins; Pancreas; Pancreatic Neoplasms; Pancreatitis; Receptors, Retinoic Acid; Tretinoin

A panel of human cell lines was screened for production of colony-stimulating factor-1 (CSF-1) using a specific radioreceptor assay and criterion of macrophage colony growth in mouse bone marrow culture. The pancreatic carcinoma lines MIA PaCa and PANC were found to secrete high levels of CSF-1. In a bone marrow proliferation assay, the activities from these two lines were blocked by a CSF-1 specific neutralizing antiserum, confirming the predominant content of this macrophage growth factor. MIA PaCA cells stopped secreting CSF-1 when transferred to various serum-free media. Serum-free production could be reinitiated by phorbol myristic acetate (PMA). Purified CSF-1 from serum-free MIA PaCa cells stimulated the formation of 14-day colonies from total and nonadherent mononuclear human bone marrow cells. Most of the colonies consisted exclusively of large, dispersed macrophages that were intensely stained for nonspecific esterase. Although similar numbers of human 14-day colonies were stimulated by CSF-1 and other CSFs, more CSF-1 was required for the proliferation of human as compared with murine bone marrow progenitors. Northern analysis of mRNA from induced-MIA PaCa cells, using a human CSF-1 oligonucleotide probe, revealed multiple species of CSF-1 mRNA ranging from 1.5 to 4.5 kilobases (kb). Uninduced, serum-free cultures showed only the largest mRNA species, suggesting that serum removal interfered with CSF-1 mRNA processing related to synthesis and/or secretion of the protein. Regulation of the production of CSF-1 may be an important physiological process in hematopoiesis and macrophage functioning.

Topics: Animals; Bone Marrow Cells; Carcinoma; Cell Line; Colony-Stimulating Factors; Gene Expression Regulation; Humans; Macrophages; Mice; Pancreatic Neoplasms; RNA, Messenger; Tetradecanoylphorbol Acetate; Tretinoin

The usefulness of a short-term azaserine [CAS: 115-02-6; diazoacetate serine (ester)]-rat model for the screening of retinoids (known chemopreventive agents) and the effect of two retinoids on the growth of azaserine-induced, presumptive preneoplastic foci of acinar cells were examined. At 14 days of age, male Lewis rats were each given injections of a single dose of 30 mg azaserine/kg body weight. These rats were weaned to test diets to which retinoids were added. At 4 months post initiation, pancreata were examined by quantitative stereologic methods to determine number and mean size of foci. Two phenotypically different populations of foci were observed and characterized as acidophilic or basophilic. Retinylidene dimedone and N-2-hydroxyethylretinamide decreased the number and size of the acidophilic foci but not the basophilic foci. The inhibition of growth of the acidophilic foci correlates well with the known effects of these retinoids in long-term carcinogenicity studies.

Topics: Animals; Azaserine; Dose-Response Relationship, Drug; Male; Pancreatic Neoplasms; Rats; Rats, Inbred Lew; Retinoids; Tretinoin

Syrian hamsters were treated with either a low (10 mg/kg body weight) or high (40 mg/kg body weight) single dose of bis(2-oxopropyl)nitrosamine (BOP) and beginning 1 week later fed either low (0.2 mmol/kg diet) or high (0.4-1.0 mmol/kg diet) levels of one of four retinoids [13 cis retinoic acid (13-cis-RA), N-ethylretinamide (ERA), N-(2-hydroxyethyl)retinamide (OHERA) or N-(phenyl)retinamide (PRA)] for periods of 40 or 50 weeks. The high retinoid levels (0.4-1.0 mmol/kg diet) fed following the highest BOP treatment enhanced pancreatic carcinoma yields (average number/effective animal) in males fed all four retinoids, and in females fed ERA and 13-cis-RA. Enhanced adenoma yields were also seen in all groups when high retinoid levels were fed following 40 mg BOP/kg body weight. However, these retinoid levels caused an increased adenoma yield in male hamsters only and did not modify carcinoma yields when fed following 10 mg BOP/kg body weight. Similarly, tumor yields at extra-pancreatic sites were elevated in retinoid-fed hamsters of both sexes after 40 mg BOP/kg body weight and in males fed ERA and 13-cis-RA after 10 mg BOP/kg body weight when retinoids were given at the high levels (0.4-1.0 mmol/kg diet). Increased incidences of bile duct and liver tumors in particular were found in hamsters given 40 mg BOP/kg body weight. Consumption of retinoid levels of 0.4 mmol/kg diet and above was also associated with a high incidence of liver cell necrosis, ovarian cysts and ovarian hemorrhage. Retinoids (ERA, OHERA, and PRA) fed at the low level (0.2 mmol/kg diet) following the low BOP dose did not enhance carcinogenesis in the pancreas or at other sites and did not cause alterations in morphologic observations.

Topics: Animals; Body Weight; Cricetinae; Dose-Response Relationship, Drug; Female; Isomerism; Isotretinoin; Male; Mesocricetus; Neoplasms; Nitrosamines; Pancreatic Neoplasms; Sex Factors; Tretinoin

Syrian hamsters were given in a single dose of N-nitrosobis(2-oxopropyl)-amine (BOP) (40 mg/kg, s.c.) and 1 week later were fed 1 of 4 retinoid types (13-cis-retinoic acid (13-cis-RA), N-ethylretinamide (ERA), 2-hydroxyethylretinamide (OH-ERA), or 4-hydroxyphenylretinamide (PRA)) each at 3 levels (0.05, 0.1, 0.2 mM/kg diet). The pancreatic carcinoma incidence was not influenced significantly by feeding retinoids. The pancreatic adenoma incidence, however, was reduced by feeding each of the retinoids to female hamsters, with the reduction varying with the retinoid fed (13-cis-RA greater than ERA and OH-ERA greater than PRA). In male hamsters increased numbers of pancreatic adenomas were observed after feeding OH-ERA and PRA. Tumors induced in other tissues were reduced by retinoids in females, but not in males. Females fed 13-cis-RA and ERA had a lower incidence of gall bladder polyps, and feeding OH-ERA reduced the liver tumor incidence. Food consumption and serum alkaline phosphatase ans aspartate amino transferase activities were not influenced by BOP or retinoid type or level. Body and pancreas weight were influenced by retinoid level, but the effects were not consistently dose-related.

Topics: Animals; Carcinoma; Cricetinae; Female; Fenretinide; Male; Mesocricetus; Neoplasms, Experimental; Nitrosamines; Pancreatic Neoplasms; Sex Factors; Tretinoin