NG, a novel PABA/NO-based oleanolic acid derivative, induces Human hepatoma cell apoptosis via a ROS/MAPK-dependent mitochondrial pathway

Liu, Ling; Fu, Junjie; Li, Tingting; Cui, Ran; Ling, Jingjing; Yu, Xiao; Ji, Hui; Zhang, Yihua

doi:10.1016/j.ejphar.2012.07.031

Cited by 45 publications

(25 citation statements)

References 26 publications

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“…It is hypothesized that ERK is important for cell survival, while JNK and p38 have been characterized as stress-responsive factors, thus serving important roles in apoptosis (12–16). In addition, the phosphorylation of c-Jun is required for apoptosis following survival signal withdrawal (24–27). These conclusions were obtained in the present study.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress regulates mitogen-activated protein kinases and c-Jun activation involved in heat stress and lipopolysaccharide-induced intestinal epithelial cell apoptosis

Liu

Wang

Xie

et al. 2017

Molecular Medicine Reports

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Heat stress and gut-derived endotoxinemia are common causes of multiple organ dysfunction syndrome in heat stroke patients. Evidence has demonstrated that cell apoptosis in the small intestine serves an important role in the pathogenesis of heatstroke, which leads to increased intestinal permeability to endotoxin or lipopolysaccharides (LPS) from the gut entering the circulation. However, little is known about the potential underlying mechanisms mediating heat stress combined with LPS-induced intestinal epithelial cell apoptosis. In the present study, LPS combined with heat stress induced production of reactive oxygen species (ROS), mitochondrial membrane potential disruption and cell apoptosis, which eventually led to increased intestinal permeability and reduced epithelial resistance in the IEC-6 cell line. Inductions in ROS, mitochondrial membrane potential disruption and cell apoptosis were detected by using an ROS assay kit, 5,5′,6,6′-tetrachloro-1,1′,3,3′tetraethylbenzimidazo carbocyanine iodide dye kit and annexin V-fluorescein isothiocyanate apoptosis kit, respectively. The effect of ROS on mitogen activated protein kinases (MAPKs) and c-Jun activation was investigated using the antioxidant drug, butylated hydroxyanisole (BHA) by western blotting. The results of the present study demonstrated that ROS is essential to activate p38, extracellular signal-regulated kinase (ERK) and c-Jun, but not c-Jun N-terminal kinase (JNK), in LPS combined with heat stress treated cells. Furthermore, ROS, and activation of p38, JNK and c-Jun, were revealed to serve pro-apoptosis roles which aggravated damage to epithelial barrier integrity, as assessed by flow cytometry using Annexin V-fluorescein isothiocyanate staining and pretreatment of cells with specific inhibitors of ROS, JNK, p38 and c-Jun (BHA, SP600125, SB203580 and c-Jun peptide, respectively). Transepithelial electrical resistance and horseradish peroxidase permeability were detected in cells treated with LPS combined with heat stress, which revealed that ERK serves an anti-apoptosis role, as determined by pretreatment of cells with PD98059, a specific inhibitor of ERK. In conclusion, these findings suggested a novel role of the ROS signaling pathway which involved activation of MAPKs and c-Jun, following LPS combined with heat stress-induced IEC-6 cell apoptosis and impairment of the epithelial barrier. These results may facilitate understanding of pathological conditions involving ROS, such as heat stroke.

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Section: Discussionmentioning

confidence: 99%

Oxidative stress regulates mitogen-activated protein kinases and c-Jun activation involved in heat stress and lipopolysaccharide-induced intestinal epithelial cell apoptosis

Liu

Wang

Xie

et al. 2017

Molecular Medicine Reports

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“…Therefore, HCC is also acknowledged to be a result of an inflammatory accumulation of hepatocyte leading to cirrhosis [6]. In addition, biomolecule targets of oxidative stress conduce to nuclear fragmentation membrane disruption and lipid peroxidation which may trigger carcinogenesis [7]. Liver, the major organ which metabolizes ingested material, thus is more susceptible to carcinogenic insult.…”

Section: Introductionmentioning

confidence: 99%

Antihepatocarcinoma Effect of Portulaca oleracea L. in Mice by PI3K/Akt/mTOR and Nrf2/HO‐1/NF‐κB Pathway

Zheng

Peng

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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The purpose of the present study was to evaluate the pharmacological effects of Portulaca oleracea L. (Purslane) (PL) on N-nitrosodiethylamine- (NDEA-) induced hepatocellular carcinomas (HCC) and explore its potential mechanism. Mice were randomly assigned to four groups: control group, NDEA group, NDEA + Purslane (100 mg/kg) group, and NDEA + Purslane (200 mg/kg) group. The animal of each group was given NDEA (100 ppm) in drinking water. 1 h later, Purslane dissolved in PBS was intragastrically administered for continuous seven days. The results showed that Purslane reduced the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in liver and serum. Purslane also reduced the contents of interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α), and methane dicarboxylic aldehyde (MDA) and restored the activity of superoxygen dehydrogenises (SOD) in serum. Purslane could obviously attenuate the hepatic pathological alteration. Furthermore, treatment with Purslane effectively inhibited the phosphorylations of phosphatidylinositol 3 kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), nuclear factor-kappa B (NF-κB), and inhibitor of NF-κBα (IκBα) and upregulated the expressions of NF-E2-related factor 2 (Nrf2) and heme oxygenase- (HO-) 1. In conclusion, our research suggested that Purslane exhibited protective effects on NDEA-induced hepatocellular carcinomas by anti-inflammatory and antioxidative properties via the PI3K/Akt/mTOR and Nrf2/HO-1/NF-κB pathway.

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“…In recent years, a series of pentacyclic triterpenoid compounds, including ursolic acid (5), oleanolic acid (6) and betulinic acid (7), were reported to exhibit anti-tumor activity, and therefore, triterpene acids are thought to have great potential as novel drugs for the treatment of malignant tumors. Asiatic acid (AA) is a pentacyclic triterpenoid derived from the medicinal plant Centella asiatica (family, Apiaceae).…”

Section: Introductionmentioning

confidence: 99%

Apoptosis of HL-60 human leukemia cells induced by Asiatic acid through modulation of B-cell lymphoma 2 family proteins and the mitogen-activated protein kinase signaling pathway

Yan

et al. 2012

Molecular Medicine Reports

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Abstract. The toxicities of conventional chemotherapeutic agents to normal cells restrict their dosage and clinical efficacy in acute leukemia; therefore, it is important to develop novel chemotherapeutics, including natural products, which selectively target cancer-specific pathways. The present study aimed to explore the effect of the chemopreventive agent asiatic acid (AA) on the proliferation and apoptotic rate of the leukemia cell line HL-60 and investigated the mechanisms underlying its anti-tumor activity. The effect of AA on the proliferation of HL-60 cells was evaluated using the MTT assay. Annexin V-fluorescein isothiocyanate/propidium iodide double staining followed by flow cytometric analysis as well as Hoechst 33258 staining were used to analyze the apoptotic rate of the cells. Furthermore, changes of survivin, B-cell lymphoma 2 (Bcl-2), myeloid cell leukemia 1 (Mcl-1), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 expressions were detected by western blot analysis. AA blocked the growth of HL-60 cells in a dose-and time-dependent manner. The IC 50 -value of AA on HL-60 cells was 46.67±5.08 µmol/l for 24 h. AA induced apoptosis in a dose-dependent manner, which was inhibited in the presence of Z-DEVD-FMK, a specific inhibitor of caspase. The anti-apoptotic proteins Bcl-2, Mcl-1 and survivin were downregulated by AA in a dose-dependent manner. Concurrently, AA inhibited ERK and p38 phosphorylation in a dose-dependent manner, while JNK phosphorylation was not affected. In conclusion, the present study indicated that the p38 and ERK pathways, as well as modulation of Bcl-2 family and survivin proteins were key regulators of apoptosis induced in HL-60 cells in response to AA.

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NG, a novel PABA/NO-based oleanolic acid derivative, induces Human hepatoma cell apoptosis via a ROS/MAPK-dependent mitochondrial pathway

Cited by 45 publications

References 26 publications

Oxidative stress regulates mitogen-activated protein kinases and c-Jun activation involved in heat stress and lipopolysaccharide-induced intestinal epithelial cell apoptosis

Oxidative stress regulates mitogen-activated protein kinases and c-Jun activation involved in heat stress and lipopolysaccharide-induced intestinal epithelial cell apoptosis

Antihepatocarcinoma Effect of Portulaca oleracea L. in Mice by PI3K/Akt/mTOR and Nrf2/HO‐1/NF‐κB Pathway

Apoptosis of HL-60 human leukemia cells induced by Asiatic acid through modulation of B-cell lymphoma 2 family proteins and the mitogen-activated protein kinase signaling pathway

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