Chronic administration of diethylnitrosamine to induce hepatocarcinogenesis and to evaluate its synergistic effect with other hepatotoxins in mice

Fuentes-Hernández, Sergio; Alarcón-Sánchez, Brisa Rodope; Guerrero-Escalera, Dafne; Montes-Aparicio, Alexia Viridiana; Castro-Gil, María Paulette; Idelfonso-García, Osiris Germán; Rosas-Madrigal, Sandra; Aparicio‐Bautista, Diana Ivette; Pérez-Hernández, J.L.; Reyes‐Gordillo, Karina; Lakshman, M; Vásquez-Garzón, Verónica Rocío; Baltiérrez-Hoyos, Rafael; Sierra-Santoyo, Adolfo; Villa‐Treviño, Saúl; Pérez‐Carreón, Julio Isael; Arellanes‐Robledo, Jaime

doi:10.1016/j.taap.2019.114611

Cited by 12 publications

(8 citation statements)

References 47 publications

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“…Our findings revealed that CGDCM treatment decreased the levels of the liver proliferative marker Ki-67 in DEN-induced HCC rats, implying anti-proliferative activity against liver cancer. DEN has been reported to enhance the proliferation and initiation of hepatocyte tumors by activating the G1/S phase of the cell cycle 96 , 119 , 120 . The enhanced proliferation of liver cells after DEN treatment supports compensatory responses for the development of primary HCC following DNA damage and necrotic cell death in the liver 3 , 88 , 121 .…”

Section: Discussionmentioning

confidence: 99%

Calotropis gigantea stem bark extracts inhibit liver cancer induced by diethylnitrosamine

Sawong

Pekthong

Suknoppakit

et al. 2022

Sci Rep

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Several fractions of Calotropis gigantea extracts have been proposed to have potential anticancer activity in many cancer models. The present study evaluated the anticancer activity of C. gigantea stem bark extracts in liver cancer HepG2 cells and diethylnitrosamine (DEN)-induced primary liver cancer in rats. The carcinogenesis model induced by DEN administration has been widely used to study pathophysiological features and responses in rats that are comparable to those seen in cancer patients. The dichloromethane (CGDCM), ethyl acetate, and water fractions obtained from partitioning crude ethanolic extract were quantitatively analyzed for several groups of secondary metabolites and calactin contents. A combination of C. gigantea stem bark extracts with doxorubicin (DOX) was assessed in this study to demonstrate the enhanced cytotoxic effect to cancer compared to the single administration. The combination of DOX and CGDCM, which had the most potential cytotoxic effect in HepG2 cells when compared to the other three fractions, significantly increased cytotoxicity through the apoptotic effect with increased caspase-3 expression. This combination treatment also reduced ATP levels, implying a correlation between ATP and apoptosis induction. In a rat model of DEN-induced liver cancer, treatment with DOX, C. gigantea at low (CGDCM-L) and high (CGDCM-H) doses, and DOX + CGDCM-H for 4 weeks decreased the progression of liver cancer by lowering the liver weight/body weight ratio and the occurrence of liver hyperplastic nodules, fibrosis, and proliferative cells. The therapeutic applications lowered TNF-α, IL-6, TGF-β, and α-SMA inflammatory cytokines in a similar way, implying that CGDCM had a curative effect against the inflammation-induced liver carcinogenesis produced by DEN exposure. Furthermore, CGDCM and DOX therapy decreased ATP and fatty acid synthesis in rat liver cancer, which was correlated with apoptosis inhibition. CGDCM reduced cleaved caspase-3 expression in liver cancer rats when used alone or in combination with DOX, implying that apoptosis-inducing hepatic carcinogenesis was suppressed. Our results also verified the low toxicity of CGDCM injection on the internal organs of rats. Thus, this research clearly demonstrated a promising, novel anticancer approach that could be applied in future clinical studies of CGDCM and combination therapy.

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Section: Discussionmentioning

confidence: 99%

Calotropis gigantea stem bark extracts inhibit liver cancer induced by diethylnitrosamine

Sawong

Pekthong

Suknoppakit

et al. 2022

Sci Rep

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“…Iron content is about 45 mg/kg in the iron control diet, and <6 mg/kg in the iron-deficient diet, as confirmed by flame atomic absorption detection. After four weeks of feeding, mice were treated with three times alcohol (5 g/kg, 24 h interval, gavage) to mimic mild liver damage ( Ambade et al, 2014 ) (n = 6 in each group), and five times DEN (50 mg/kg, 24 h interval, i. p. injection) to mimic acute liver failure ( Fuentes-Hernandez et al, 2019 ) (n = 10 in each group). Mice in the control group were treated with the same dose of PBS.…”

Section: Methodsmentioning

confidence: 99%

An iron-deficient diet prevents alcohol- or diethylnitrosamine-induced acute hepatotoxicity in mice by inhibiting ferroptosis

Gao

Wang

Zhang

et al. 2022

Current Research in Food Science

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“…Additionally, ethanol was administered in combination either with LPS (EL), DEN at 5 mg/kg (ED5) or LPS plus DEN at 5 mg/kg (ELD5), as illustrated in Figure 1. DEN doses were selected according to a previous study reporting that while the chronic administration of DEN at 20 mg/kg induces HCC, DEN at 5 mg/kg induces mild liver damage that might be potentiated in combination with other hepatotoxins 28 . Thus, while DEN at 20 mg/kg was used as a positive control of hepatocarcinogenesis, its lower dose (5 mg/kg) was used to determine its synergistic effect along with LPS and ethanol.…”

Section: Methodsmentioning

confidence: 99%

Nucleoredoxin interaction with flightless‐I/actin complex is differentially altered in alcoholic liver disease

Alarcón-Sánchez

Guerrero-Escalera

Rosas-Madrigal

et al. 2020

Basic Clin Pharma Tox

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Alcoholic liver disease (ALD) may be attributed to multiple hits driving several alterations. The aim of this work was to determine whether nucleoredoxin (NXN) interacts with flightless-I (FLII)/actin complex and how this ternary complex is altered during ALD progression induced by different ALD models. ALD was recapitulated in C57BL/6J female mice by the well-known ALD Lieber-DeCarli model, and by an in vitro human co-culture system overexpressing NXN. The effects of ethanol and low doses of lipopolysaccharides (LPS) and diethylnitrosamine (DEN) were also evaluated in vivo as a first approach of an ALD multi-hit protocol. We demonstrated that NXN interacts with FLII/actin complex. This complex was differentially altered in ALD in vivo and in vitro, and NXN overexpression partially reverted this alteration. We also showed that ethanol, LPS and DEN synergistically induced liver structural disarrangement, steatosis and inflammatory infiltration accompanied by increased levels of proliferation (Ki67), ethanol metabolism (CYP2E1), hepatocarcinogenesis (GSTP1) and LPS-inducible (MYD88 and TLR4) markers. In summary, we provide evidence showing that NXN/FLII/actin complex is involved in ALD progression and that NXN might be involved in the regulation of FLII/actin-dependent cellular functions. Moreover, we present a promising first approach of a multi-hit protocol to better recapitulate ALD pathogenesis.

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Chronic administration of diethylnitrosamine to induce hepatocarcinogenesis and to evaluate its synergistic effect with other hepatotoxins in mice

Cited by 12 publications

References 47 publications

Calotropis gigantea stem bark extracts inhibit liver cancer induced by diethylnitrosamine

Calotropis gigantea stem bark extracts inhibit liver cancer induced by diethylnitrosamine

An iron-deficient diet prevents alcohol- or diethylnitrosamine-induced acute hepatotoxicity in mice by inhibiting ferroptosis

Nucleoredoxin interaction with flightless‐I/actin complex is differentially altered in alcoholic liver disease

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