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Mebendazole augments sensitivity to sorafenib by targeting MAPK and BCL-2 signalling in n-nitrosodiethylamine-induced murine hepatocellular carcinoma.

Sorafenib (SO) is a multi-kinase inhibitor that targets upstream signals in the MAPK pathway. Drug resistance and transient survival benefits are the main obstacles associated with SO treatment in Hepatocellular carcinoma (HCC) patients. Mebendazole (MBZ), an anthelmintic agent, has demonstrated activity against various cancer types. Therefore, we aimed to investigate the possible mechanisms of MBZ other than its anti-tubulin activity. MBZ (100 mg/kg/day, P.O.) was administered to N-nitrosodiethylamine-induced HCC mice as a monotherapeutic agent or in combination with SO. Our results revealed

Mechanisms of nitrosamine-mediated neurodegeneration: potential relevance to sporadic Alzheimer's disease.

Streptozotocin (STZ) is a nitrosamine-related compound that causes Alzheimer's disease (AD)-type neurodegeneration with cognitive impairment, brain insulin resistance, and brain insulin deficiency. Nitrosamines and STZ mediate their adverse effects by causing DNA damage, oxidative stress, lipid peroxidation, pro-inflammatory cytokine activation, and cell death, all of which occur in AD. We tested the hypothesis that exposure to N-nitrosodiethylamine (NDEA), which is widely present in processed/preserved foods, causes AD-type molecular and biochemical abnormalities in central nervous system (CN

The ménage à trois of autophagy, lipid droplets and liver disease.

Autophagic pathways cross with lipid homeostasis and thus provide energy and essential building blocks that are indispensable for liver func … emokine receptor 3; DAGs: diacylglycerols; DAMPs: danger/damage-associated molecular patterns; DEN: diethylnitrosamine; DGAT: diacylglycerol O-acyltransferase; DNL: de novo lipogenesis; EHBP1/NACSIN (EH domain binding protein 1); EHD2/PAST2: EH domain containing 2; CoA: coenzyme A; CCL/chemokines: chemokine ligands; CCl4: carbon tetrachloride; ER: endoplasmic reticu …

The role of the innate immune system in the development and treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Most patients present with advanced or metastatic HCC at diagnosis and face a dismal prognosis. Tyrosine kinases are the gold standard treatment for this disease but yield limited survival benefits. Immune checkpoint inhibitors that augment adaptive immunity have been tested in HCC. Complex interactions between tumor cells, lymphocytes and the tumor environment determine the efficacy of such immunotherapies. Innate immune mechanisms - known drivers of liver disease progression in pre-HCC conditions such as fibrosis or cirr

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… Just recently, our group demonstrated that CXCR6-deficient mice had a significantly higher tumor burden than wild-type mice in a model of diethylnitrosamine-induced liver cancer in mice. … Schneider C , Teufel A , Yevsa T Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer . Gut 61 ( 12 ), 1733 – 1743 ( 2012 ). 22267597 10.1136/gutjnl-2011-301116 PMC4533880 51. …

Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition.

Obesity can result in insulin resistance, hepatosteatosis, and nonalcoholic steatohepatitis (NASH) and increases liver cancer risk. Obesity-induced insulin resistance depends, in part, on chronic activation of mammalian target of rapamycin complex 1 (mTORC1), which also occurs in human and mouse hepatocellular carcinoma (HCC), a frequently fatal liver cancer. Correspondingly, mTORC1 inhibitors have been considered as potential NASH and HCC treatments. Using a mouse model in which high-fat diet enhances HCC induction by the hepatic carcinogen DEN, we examined whether mTORC1 inhibition attenuate

Menin promotes hepatocellular carcinogenesis and epigenetically up-regulates Yap1 transcription.

Menin is a scaffold protein encoded by the multiple endocrine neoplasia type 1 (MEN1) gene in humans, and it interacts with a variety of transcriptional proteins to control active or repressive cellular processes. Here, we show that heterozygous ablation of Men1 in female mice reduces chemical carcinogen-induced liver carcinogenesis and represses the activation of the inflammation pathway. Using ChIP-on-chip screens and ChIP assays, we find that menin occupancy frequently coincides with H3K4me3 at the promoter of many liver cancer-related genes, such as Yes-associated protein (Yap1). Increased

MiR-30e-3p Influences Tumor Phenotype through MDM2/TP53 Axis and Predicts Sorafenib Resistance in Hepatocellular Carcinoma.

The molecular background of hepatocellular carcinoma (HCC) is highly heterogeneous, and biomarkers predicting response to treatments are an unmet clinical need. We investigated miR-30e-3p contribution to HCC phenotype and response to sorafenib, as well as the mutual modulation of TP53/MDM2 pathway, in HCC tissues and preclinical models. MiR-30e-3p was downregulated in human and rat HCCs, and its downregulation associated with TP53 mutations. TP53 contributed to miR-30e-3p biogenesis, and MDM2 was identified among its target genes, establishing an miR-30e-3p/TP53/MDM2 feedforward loop and accou

Targeting super enhancers for liver disease: a review.

BackgroundSuper enhancers (SEs) refer to the ultralong regions of a gene accompanied by multiple transcription factors and cofactors and strongly drive the expression of cell-type-related genes. Recent studies have demonstrated that SEs play crucial roles in regulating gene expression related to cell cycle progression and transcription. Aberrant activation of SEs is closely related to the occurrence and development of liver disease. Liver disease, especially liver failure and hepatocellular carcinoma (HCC), constitutes a major class of diseases that seriously endanger human health. Currently,

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… protein 4 C/EBPs CCAAT/enhancer-binding proteins CDK7 cyclin-dependent kinase 7 Target model | Factors for SE identification | Target gene | Interference tools | Liver disease | Main results | References Mouse | C/EBP | SEs component C/EBP α | C/EBP- α gene knock-in | Hepatocellular Carcinoma (using diethylnitrosamine … Transcription coactivator PBP/MED1-deficient hepatocytes are not susceptible to diethylnitrosamine-induced hepatocarcinogenesis in the mouse. Carcinogenesis. 2010;31(2):318–325. doi: 10.1093/carcin/bgp306. Mei et al. (2007) Mei S, Wang X, Zhang J, Qian J, Ji J. …

Essential oils and their constituents as anticancer agents: a mechanistic view.

Exploring natural plant products as an option to find new chemical entities as anticancer agents is one of the fastest growing areas of research. Recently, in the last decade, essential oils (EOs) have been under study for their use in cancer therapy and the present review is an attempt to collect and document the available studies indicating EOs and their constituents as anticancer agents. This review enlists nearly 130 studies of EOs from various plant species and their constituents that have been studied so far for their anticancer potential and these studies have been classified as in vitr

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… Varying concentrations of Allium sativum (garlic) EO were administered to mouse having diethylnitrosamine induced gastric cancer with basic diet and this EO affected phase I enzymes, SOD, CAT, and GPx activities. … H Liang L Activities of ten essential oils towards Propionibacterium acnes and PC-3, A-549 and MCF-7 cancer cells Molecules 2010 15 5 3200 3210 2-s2.0-77952819145 20657472 10.3390/molecules15053200 PMC6263286 29 Jayakumar S Madankumar A Asokkumar S Potential preventive effect of carvacrol against diethylnitrosamine-induced …

Does DPP-IV Inhibition Offer New Avenues for Therapeutic Intervention in Malignant Disease?

Dipeptidyl peptidase IV (DPP-IV, CD26) is frequently dysregulated in cancer and plays an important role in regulating multiple bioactive peptides with the potential to influence cancer progression and the recruitment of immune cells. Therefore, it represents a potential contributing factor to cancer pathogenesis and an attractive therapeutic target. Specific DPP-IV inhibitors (gliptins) are currently used in patients with type 2 diabetes mellitus to promote insulin secretion by prolonging the activity of the incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypep

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… In addition, vildagliptin prevented diethylnitrosamine-induced hepatocarcinogenesis in rats fed a high-fat diet. … Tumor Type | Model | Gliptin | Reference Hepatocellular carcinoma | Diethylnitrosamine + high-fat diet-induced carcinogenesis in rats | Vildagliptin | [ 112 ] Thiacetamide-induced carcinogenesis in rats | Saxagliptin | [ 117 ] Hepatocellular carcinoma associated with nonalcoholic steatohepatitis | Melanocortin …

Anticancer Potential of Whey Proteins-A Systematic Review of Bioactivity and Functional Mechanisms.

Cancer remains a primary global health concern, with treatment-related side effects and malnutrition posing significant challenges to patient care and recovery. In recent years, there has been growing interest in the therapeutic potential of functional food components, especially whey proteins (WPs), due to their notable antioxidant, immunomodulatory, and anticancer properties. This systematic review explores the effects of WPs across various cancer types and assesses their value as supportive nutritional agents. A thorough literature search was conducted in PubMed, Scopus, and Web of Science

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… Antihepatocarcinogenic activity of whey protein concentrate and lactoferrin in diethylnitrosamine-treated male albino mice. Environ. Toxicol. 2019;34:1025–1033. doi: 10.1002/tox.22773. 27. …

Antioxidant Food Supplementation in Cancer: Lessons from Clinical Trials and Insights from Preclinical Studies.

Food antioxidant supplementation has been widely proposed for cancer prevention and adjuvant therapy due to the pleiotropic role of antioxidants. Herein, particular attention is given to recent clinical trials based on the use of dietary supplements in cancer patients, both as monotherapy and in combination with standard treatments, exploring both their potential benefits and risks. This review focuses on the efficacy of the most important food antioxidants, highlighting how their action may change depending on different factors such as cancer type, dose, timing of administration and antioxida

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… Interestingly, in regard to GSH, it has been demonstrated that GSH and selenium supplementation markedly reduced the diethylnitrosamine-induced DNA damage by reducing malondialdehyde levels and by increasing GSH levels and the activities of GSH-related enzymes, such as glutathione peroxidase and glutathione …

Linoleate-pazopanib conjugation as active pharmacological ingredient to abolish hepatocellular carcinoma growth.

Small molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma (HCC). Nonetheless, despite the beneficial effects of multikinase inhibitors (MKIs), a lack of boosting adjuvant limits their objective response rate. Lipid conjugates have been used to improve delivery efficacy or pharmaceutical benefits for decades. However, the feasibility of utilizing lipid-drug conjugates (LDCs) in HCC regimens remains untested. In this study, oral feeding of linoleate-fluorescein isothiocyanate conjugates show

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… HBVtg-HCC mice were induced with a subminimal diethylnitrosamine injection. The drug was dissolved in a sunflower oil and phosphate-buffered saline mixture (1:1:8) and fed to 42–45-week-old mice thrice weekly at 10 mg/kg. (A) The LAPC preclinical trial using HBVtg-HCC mouse model. …

Deciphering the Causal Relationship between Sodium-glucose Cotransporter 2 Inhibition and Cancer Risks: A Comprehensive Mendelian Randomization Study.

Background: Controversy persists regarding the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cancer. The underlying causal relationship remains unclear. Method: A two-sample Mendelian randomization (MR) strategy was employed to investigate the causal associations between SGLT2 inhibitors and 26 site-specific malignancies. Instrumental variants strongly associated with SLC5A2 gene expression and glycated hemoglobin A1c levels were identified as the genetic proxy for SGLT2 inhibition. Cancer-related outcome datasets sourced from the OpenGWAS project were separated into discover

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… Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice. Oncotarget. 2017;8:58353–63. doi: 10.18632/oncotarget.16874. 10. Saito T, Okada S, Yamada E, Shimoda Y, Osaki A, Tagaya Y. et al. …

Glutathione Transferase P1-1 an Enzyme Useful in Biomedicine and as Biomarker in Clinical Practice and in Environmental Pollution.

Glutathione transferase P1-1 (GSTP1-1) is expressed in some human tissues and is abundant in mammalian erythrocytes (here termed e-GST). This enzyme is able to detoxify the cell from endogenous and exogenous toxic compounds by using glutathione (GSH) or by acting as a ligandin. This review collects studies that propose GSTP1-1 as a useful biomarker in different fields of application. The most relevant studies are focused on GSTP1-1 as a biosensor to detect blood toxicity in patients affected by kidney diseases. In fact, this detoxifying enzyme is over-expressed in erythrocytes when unusual amo

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… Lee et al. [ 167 ] found, in the rat liver, increased expression of EGF-R (transmembrane tyrosine kinase receptor) and reduced expression of receptor tyrosine-protein kinase ErbB4 during diethylnitrosamine (DEN)-induced hepatocarcinogenesis. …

Recent Progress of Exosomes in Multiple Myeloma: Pathogenesis, Diagnosis, Prognosis and Therapeutic Strategies.

Multiple myeloma (MM) is a hematological malignancy that is still incurable. The bone marrow microenvironment (BMM), with cellular and non-cellular components, can create a favorable environment for the survival, proliferation and migration of MM cells, which is the main reason for the failure of MM therapies. Many studies have demonstrated that exosomes play an important role in the tumor-supportive BMM. Exosomes are nanoscale vesicles that can be released by various cells. Some exosomes contribute to the pathogenesis and progression of MM. MM-derived exosomes act on different cells in the BM

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… Zhen et al. developed ectopic, orthotopic and diethylnitrosamine (DENA)-induced autochthonous hepatocellular carcinoma (HCC) mouse models. …

What Zebrafish and Nanotechnology Can Offer for Cancer Treatments in the Age of Personalized Medicine.

Cancer causes millions of deaths each year and thus urgently requires the development of new therapeutic strategies. Nanotechnology-based anticancer therapies are a promising approach, with several formulations already approved and in clinical use. The evaluation of these therapies requires efficient in vivo models to study their behavior and interaction with cancer cells, and to optimize their properties to ensure maximum efficacy and safety. In this way, zebrafish is an important candidate due to its high homology with the human genoma, its large offspring, and the ease in developing specifi

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… Maid, a protein involved in cell proliferation, is abundantly expressed in the liver hepatocytes’ cytoplasm of zebrafish; its role as a regulator of hepatocarcinogenesis was explored by treating adult zebrafish with Diethylnitrosamine (DEN) for 8 weeks. … retinoic acid AuNPs | Golden nanoparticles BC | Breast cancer BPC-ALL | B-cell precursor acute lymphoblastic leukemia CAR-T cell | Chimeric antigen receptor T cell CR | Complete response CRC | Colorectal cancer NSCLC | Non-small-cell lung cancer CTLA-4 | Cytotoxic T-lymphocyte-associated antigen-4 DEN | Diethylnitrosamine …

Inflammasomes in Cancer Progression and Anti-Tumor Immunity.

The inflammasomes are critical regulators of innate immunity, inflammation and cell death and have emerged as important regulators of cancer development and control. Inflammasomes are assembled by pattern recognition receptors (PRR) following the sensing of microbial- or danger-associated molecular patterns (MAMPs/DAMPs) and elicit inflammation through the oligomerization and activation of inflammatory caspases. These cysteinyl-aspartate proteases cleave the proinflammatory cytokines IL-1β and IL-18 into their biologically active mature form. The roles of the inflammasomes and associated pro-i

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… This was demonstrated using the diethylnitrosamine (DEN) mouse model of hepatocellular carcinoma (HCC), in which the mitophagy effector FUNDC1 was specifically deleted in hepatocytes leading to aberrant activation of the Nlrp3 inflammasome and IL-1β-driven hepatocyte hyperproliferation ( Wenhui Li et …

Ketogenic Diet in Cancer Prevention and Therapy: Molecular Targets and Therapeutic Opportunities.

Although cancer is still one of the most significant global challenges facing public health, the world still lacks complementary approaches that would significantly enhance the efficacy of standard anticancer therapies. One of the essential strategies during cancer treatment is following a healthy diet program. The ketogenic diet (KD) has recently emerged as a metabolic therapy in cancer treatment, targeting cancer cell metabolism rather than a conventional dietary approach. The ketogenic diet (KD), a high-fat and very-low-carbohydrate with adequate amounts of protein, has shown antitumor effe

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… 1 Some of the preclinical studies for the effect of ketogenic diet on cancer (tumor) cells. 2-DG: 2-deoxyglucose, AcAc: acetoacetate, BHB: b-hydroxybutyrate, CD: control diet, CHO: carbohydrate, CR-CD: calorie-restricted control diet, CR-KD: calorie-restricted ketogenic diet, CT: chemotherapy, DEN: diethylnitrosamine …

Novel Investigations of Flavonoids as Chemopreventive Agents for Hepatocellular Carcinoma.

We would like to highlight the application of natural products to hepatocellular carcinoma (HCC). We will focus on the natural products known as flavonoids, which target this disease at different stages of hepatocarcinogenesis. In spite of the use of chemotherapy and radiotherapy in treating HCC, patients with HCC still face poor prognosis because of the nature of multidrug resistance and toxicity derived from chemotherapy and radiotherapy. Flavonoids can be found in many vegetables, fruits, and herbal medicines that exert their different anticancer effects via different intracellular signalin

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… Mandal has demonstrated that nanoencapsulated quercetin downregulates rat hepatic MMP-13 and controls diethylnitrosamine-induced hepatocarcinogenesis [ 244 ]. At present, quercetin is considered safe only based on in vitro studies [ 245 ]. …