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Methods in Cell Biology 2021Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer related mortality with a 10 year survival rate of merely... (Review)
Review
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer related mortality with a 10 year survival rate of merely 22-35%. Tumorigenesis frequently occurs in patients with chronic liver disease where continued liver cell damage, compensatory proliferation and inflammation provide the basis for tumor initiation, promotion and progression. Animal models of HCC are particularly useful to better understand molecular events underlying liver tumorigenesis. To this end, chemical carcinogenesis protocols based on the injection of genotoxic compounds such as diethylnitrosamine (DEN) are widely used to model liver tumorigenesis in rodents. DEN injection into 2 week old mice is sufficient to cause liver tumorigenesis after 8-10 months. When injected into older mice, DEN has to be combined with administration of tumor promoting agents such as phenobarbital or feeding high fat diet. Such protocols allow to dissect the different steps of tumor formation (i.e., tumor initiation and promotion) experimentally and to model liver pathologies in mice which frequently lead to HCC in human patients such as non-alcoholic fatty liver disease. Here, we review several established chemical carcinogenesis protocols based on DEN injection into mice and discuss their advantages as well as potential limitations.
Topics: Animals; Carcinogenesis; Carcinoma, Hepatocellular; Diethylnitrosamine; Humans; Liver; Liver Neoplasms; Mice; Mice, Inbred C57BL
PubMed: 33785162
DOI: 10.1016/bs.mcb.2020.08.006 -
Human & Experimental Toxicology 2022Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Piperlongumine (PL) has been claimed to have cytotoxic and HCC inhibitory...
BACKGROUND
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Piperlongumine (PL) has been claimed to have cytotoxic and HCC inhibitory effects in various cancer cell lines and xenograft models, but the chemopreventive potential of PL has not been studied in experimentally induced HCC yet.
RESEARCH DESIGN
Twenty-four Wistar male rats were divided into four groups of six each, Group A: untreated control; Group B: Diethylnitrosamine (DEN) control (200 mg/kg), Group C: DEN + PL 10 mg/kg; and Group D: DEN + PL 20 mg/kg. Rats from all groups were assessed for liver cancer progression or inhibition by evaluating biochemical, cytokines, tumor markers, lipid peroxidation, and histological profiles.
RESULTS
The liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) levels, and lipid peroxidation were significantly decreased in Group C and Group D compared to Group B. Upregulation in the level of pro-inflammatory cytokines IL-1B, TNF-α, inflammatory mediator (NF-κB) and tumour marker alpha-fetoprotein (AFP) in Group B were brought down upon treatment with piperlongumine in a dose-dependent manner. Antitumor cytokine (IL-12) was upregulated in PL-treated rats compared to DEN control rats. DEN treated group (Group B) showed histological features of HCC, and in rats treated with PL (Groups C, D) partial to complete reversal to normal liver histoarchitecture was observed.
CONCLUSIONS
The potential chemopreventive actions of piperlongumine may be due to its free radical scavenging and antiproliferative effect. Therefore, piperlongumine may serve as a novel therapeutic agent for the treatment of hepatocellular carcinoma.
Topics: Animals; Carcinoma, Hepatocellular; Diethylnitrosamine; Dioxolanes; Disease Models, Animal; Humans; Liver Neoplasms; Male; Rats
PubMed: 35113675
DOI: 10.1177/09603271211073593 -
International Journal of Molecular... May 2022Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor involved in protection against initiation of carcinogenesis in normal cells. Notably,...
Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor involved in protection against initiation of carcinogenesis in normal cells. Notably, recent studies have demonstrated that aberrant activation of NRF2 accelerates the proliferation and progression of cancer cells. The differential effects of NRF2 on multi-stage carcinogenesis have raised a concern about the validity of NRF2 activators for chemoprevention. This prompted us to assess the effects of sulforaphane (SFN), a prototypic NRF2 activating chemopreventive phytochemical, on experimentally induced carcinogenesis. In the present study, SFN was daily injected intraperitoneally (25 mg/kg) for 3 months to male C57BL/6 mice at 6 months after single intraperitoneal administration of a hepatocarcinogen, diethylnitrosamine (DEN). The liver to body weight ratio, tumor growth, and the number and the size of hepatomas measured at 9 months after DEN administration were significantly higher in SFN-treated mice than those in vehicle-treated mice. Moreover, the expression of NRF2, its target protein NAD(P)H:quinone oxidoreductase 1, and the cell proliferation marker, proliferating cell nuclear antigen was further elevated in DEN plus SFN-treated mice. These results suggest that once hepatocarcinogenesis is initiated, SFN may stimulate tumor progression.
Topics: Animals; Carcinogenesis; Diethylnitrosamine; Isothiocyanates; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Sulfoxides
PubMed: 35628208
DOI: 10.3390/ijms23105397 -
Biological & Pharmaceutical Bulletin 2023This study was designed to evaluate the potential protective impact of estrogen and estrogen receptor against diethylnitrosamine (DEN)-induced hepatocellular carcinoma...
This study was designed to evaluate the potential protective impact of estrogen and estrogen receptor against diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in rats. The levels of liver injury serum biomarkers, liver content of interleukin-6 (IL-6), relative liver weight and distortion of liver histological pictures were significantly increased in ovariectomized (OVX) rats and SHAM rats that received DEN alone and were further exaggerated when DEN was combined with fulvestrant (F) compared to non-DEN treated rats. The OVX rats showed higher insults than SHAM rats. The tapering impact on these parameters was clear in OVX rats that received estradiol benzoate (EB), silymarin (S) or orlistat (ORS). The immunohistochemistry and/or Western blot analysis of liver tissues showed a prominent increase in fatty acid synthase (FASN) and cluster of differentiation 36 (CD36) expressions in OVX and SHAM rats who received DEN and/ or F compared to SHAM rats. In contrast to S, treatment of OVX rats with EB mitigated DEN-induced expression of FASN and CD36 in liver tissue, while ORS improved DEN-induced expression of FASN. In conclusion, the protective effect against HCC was mediated via estrogen receptor alpha (ER-α) which abrogates its downstream genes involved in lipid metabolism namely FASN and CD36 depriving the tumor from survival vital energy source. In addition, ORS induced similar mitigating effect against DEN-induced HCC which could be attributed to FASN inhibition and anti-inflammatory effect. Furthermore, S alleviated DEN-induced HCC, independent of its estrogenic effect.
Topics: Animals; Female; Rats; Carcinoma, Hepatocellular; Diethylnitrosamine; Estrogens; Fatty Acid Synthases; Interleukin-6; Liver; Liver Neoplasms; Receptors, Estrogen
PubMed: 37914358
DOI: 10.1248/bpb.b23-00342 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Sep 2019To explore the renal metabolic markers relavant to the renal toxicity of diethylnitrosamine and the metabolic pathways involved in the renal metabolic markers. ...
To explore the renal metabolic markers relavant to the renal toxicity of diethylnitrosamine and the metabolic pathways involved in the renal metabolic markers. Methods: Nineteen Sprague Dawley rats were assigned into 2 groups: A normal control group (n=9) and a diethylnitrosamine (DEN) administration group (n=10). The rats in the normal control group were given sterilized water for free drinking. The rats in the DEN administration group were given 0.1 mg/mL DEN solution for free drinking. After 18 weeks, the kidney tissues were collected and tested for nuclear magnetic resonance detection and pathological examination. Results: The content of kidneys metabolites in the rats with the DEN administration was changed significantly. The levels of alanine, taurine, pyruvate, acetate, and choline were significantly reduced compared with rat in the normal control group, while the levels of creatine, glycine, TMAO, methionine, proline, lactate, valine, leucine and isoleucine were significantly increased. Conclusion: Metabolicomics studies have revealed significant differences in five metabolic pathways, including valine, leucine and isoleucine biosynthesis, glycine serine and threonine metabolism, pyruvate metabolism, glycolysis or gluconeogenesis, cysteine and methionine metabolism.
Topics: Alkylating Agents; Animals; Diethylnitrosamine; Glycine; Kidney; Metabolic Networks and Pathways; Rats; Rats, Sprague-Dawley
PubMed: 31645487
DOI: 10.11817/j.issn.1672-7347.2019.180518 -
Experimental and Toxicologic Pathology... Dec 2014Animal models, namely mice, have been used to study chemically induced carcinogenesis due to their similarity to the histological and genetic features of human patients....
Animal models, namely mice, have been used to study chemically induced carcinogenesis due to their similarity to the histological and genetic features of human patients. Hepatocellular carcinoma (HCC) is a common malignancy with poor clinical outcome. The high incidence of HCC might be related to exposure to known risk factors, including carcinogenic compounds, such as N-nitrosamines, which cause DNA damage. N-nitrosamines affect cell mitochondrial metabolism, disturbing the balance between reactive oxygen species (ROS) and antioxidants, causing oxidative stress and DNA damage, potentially leading to carcinogenesis. This work addresses the progressive histological changes in the liver of N-diethylnitrosamine (DEN)-exposed mice and its correlation with oxidative stress. Male ICR mice were randomly divided into five DEN-exposed and five matched control groups. DEN was IP administered, once a week, for eight consecutive weeks. Samples were taken 18 h after the last DEN injection (8 weeks post-exposure). The following sampling occurred at weeks 15th, 22nd, 29th and 36th after the first DEN injection. DEN resulted in early toxic lesions and, from week 29 onwards, in progressive proliferative lesions. Between 15 and 29 weeks, DEN-exposed animals showed significant changes in hepatic antioxidant (glutathione, glutathione reductase, and catalase) status (p<0.05) compared with controls. These results point to an association between increased DEN-induced oxidative stress and the early histopathological alterations, suggesting that DEN disrupted the antioxidant defense mechanism, thereby triggering liver carcinogenesis.
Topics: Alkylating Agents; Animals; Diethylnitrosamine; Liver; Male; Mice; Mice, Inbred ICR; Oxidative Stress; Time
PubMed: 25097018
DOI: 10.1016/j.etp.2014.07.002 -
Chinese Medical Journal Jun 2021
Topics: Animals; Diethylnitrosamine; Liver; Liver Neoplasms; Rats
PubMed: 34116526
DOI: 10.1097/CM9.0000000000001504 -
Molecules (Basel, Switzerland) Feb 2023Therapeutics, based on small interfering RNA (siRNA), have demonstrated tremendous potential for treating cancer. However, issues such as non-specific targeting,...
Therapeutics, based on small interfering RNA (siRNA), have demonstrated tremendous potential for treating cancer. However, issues such as non-specific targeting, premature degradation, and the intrinsic toxicity of the siRNA, have to be solved before they are ready for use in translational medicines. To address these challenges, nanotechnology-based tools might help to shield siRNA and ensure its specific delivery to the target site. Besides playing a crucial role in prostaglandin synthesis, the cyclo-oxygenase-2 (COX-2) enzyme has been reported to mediate carcinogenesis in various types of cancer, including hepatocellular carcinoma (HCC). We encapsulated COX-2-specific siRNA in membrane lipid-based liposomes (subtilosomes) and evaluated their potential in the treatment of diethylnitrosamine (DEN)-induced hepatocellular carcinoma. Our findings suggested that the subtilosome-based formulation was stable, releasing COX-2 siRNA in a sustained manner, and has the potential to abruptly release encapsulated material at acidic pH. The fusogenic property of subtilosomes was revealed by FRET, fluorescence dequenching, content-mixing assay, etc. The subtilosome-based siRNA formulation was successful in inhibiting TNF-α expression in the experimental animals. The apoptosis study indicated that the subtilosomized siRNA inhibits DEN-induced carcinogenesis more effectively than free siRNA. The as-developed formulation also suppressed COX-2 expression, which in turn up-regulated the expression of wild-type p53 and Bax on one hand and down-regulated Bcl-2 expression on the other. The survival data established the increased efficacy of subtilosome-encapsulated COX-2 siRNA against hepatocellular carcinoma.
Topics: Animals; Carcinoma, Hepatocellular; Liver Neoplasms; Diethylnitrosamine; RNA, Small Interfering; Cyclooxygenase 2; Apoptosis; Carcinogenesis
PubMed: 36903437
DOI: 10.3390/molecules28052191 -
Current Drug Delivery 2021Madhuca longifolia has been used for the treatment of renal cancer. Therefore, the current study describes the protective effects of biofabricated silver nanoparticles...
OBJECTIVE
Madhuca longifolia has been used for the treatment of renal cancer. Therefore, the current study describes the protective effects of biofabricated silver nanoparticles (MLAg- NPs) using Madhuca longifolia aqueous leaves extract against diethylnitrosamine (DEN) induced Renal Cell Carcinoma (RCC) in rats.
METHODS
Animals were categorized into five groups and treated with doses of silver nanoparticles for 16 weeks. Antineoplastic effect in renal cancer was dose dependent to control the macroscopical variations when compared to DEN induced group. Significant changes were observed in biochemical parameters and dose graded improvement in the level of antioxidants parameters were accountable for its protective nature.
RESULTS
Silver nanoparticles in dose dependent manner was effective to modify the raised levels of pro-inflammatory cytokines and inflammatory mediators during renal cancer. Alteration in renal histopathology were also detected in the silver nanoparticles treated group, which show its safety concern. Biofabricated silver nanoparticles (MLAgNPs) using Madhuca longifolia can convey significant chemo-protective effect against renal cancer by suppressing the IL-6, TNF-α and IL-1β by nuclear factor-kappa B (NF-κB) pathway.
CONCLUSION
Our outcomes implicates that biofabricated MLAgNPs exhibited a chemoprotective potential in the prevention and intervention of RCC.
Topics: Animals; Diethylnitrosamine; Kidney Neoplasms; Madhuca; Metal Nanoparticles; Oxidative Stress; Plant Extracts; Rats; Rats, Wistar; Silver
PubMed: 32914714
DOI: 10.2174/1567201817666200910154301 -
Biomedical Mass Spectrometry May 1980N-nitrosodiethanolamine is believed to be a weakly carcinogenic chemical, and as it occurs widely--in consumer products for example--it may constitute a significant...
N-nitrosodiethanolamine is believed to be a weakly carcinogenic chemical, and as it occurs widely--in consumer products for example--it may constitute a significant hazard to humans. However, the chemical evidence concerning the identity, purity and properties of N-nitrosodiethanolamine is incomplete, and this casts some doubt on the basis of the current interest in this substance. In the present paper a purification procedure of synthetic N-nitrosodiethanolamine based on high-performance liquid chromatography is given. Other fractionation procedures such as gas liquid chromatography, ambient pressure column chromatography and distillation are shown to be inadequate. The purity and identity of purified N-nitrosodiethanolamine is established by means of electron impact and field ionization mass spectrometry, including metastable defocusing and collision induced decomposition techniques. Furthermore, 1H and 13C nuclear magnetic resonance and, to a lesser extent, infrared and ultraviolet spectroscopy are used. Deuterium labelled analogues of N-nitrosodiethanolamine and the parent diethanolamine are employed in rationalizing the results obtained.
Topics: Carcinogens; Chemical Phenomena; Chemistry, Physical; Diethylnitrosamine; Magnetic Resonance Spectroscopy; Mass Spectrometry; Nitrosamines
PubMed: 7417697
DOI: 10.1002/bms.1200070506