scholarly journals Disulfiram Chelated With Copper Inhibits the Growth of Gastric Cancer Cells by Modulating Stress Response and Wnt/β-catenin Signaling

2020 ◽  
Vol 10 ◽  
Author(s):  
Ling Wang ◽  
Xiaoke Chai ◽  
Run Wan ◽  
Hong Zhang ◽  
Cong Zhou ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Stress Response ◽  
Aerobic Glycolysis ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Gastric Cancer Cells ◽  
Cu Complex ◽  
Induced Apoptosis

Disulfiram (DSF) is a well-known drug for alcohol abuse. In recent decades, DSF has been demonstrated to exhibit anti-tumor activity; DSF chelated with copper shows enhanced anti-tumor effect. Our goal was to explore the effect of DSF/Cu complex on the growth and metastasis of gastric cancer (GC) in vitro and in vivo. DSF/Cu complex suppressed the proliferation, migration of MKN-45 and BGC-823 GC cells. Furthermore, DSF/Cu treatment reduced the tumor volume in GC mouse models with a tumor suppression rate of 48.24%. Additionally, DSF/Cu induced apoptosis in vitro in MKN-45 and BGC-823 GC cells in a dose- and time-dependent manner as well as in vivo in the xenograft tumor mouse model. Furthermore, DSF/Cu induced autophagy and autophagic flux in MKN-45 and BGC-823 cells, increased the expression of autophagy-related Beclin-1 and LC3 proteins in vivo. Additionally, DSF/Cu suppressed aerobic glycolysis and oxidative phosphorylation by reducing oxygen consumption rate and extracellular acidification rate, respectively, in MKN-45 and BGC-823 cells. Treatment with DSF/Cu induced oxidative stress and DNA damage response by elevating the reactive oxygen species levels; increasing the expression of P53, P21, and γ-H2AX proteins; and inhibiting Wnt/β-catenin signaling in vitro and in vivo. Thus, DSF/Cu suppressed the growth and metastasis of GC cells via modulating the stress response and Wnt/β-catenin signaling. Hence, DSF may be used as a potential therapeutic agent for the treatment of GC.

scholarly journals Periplocin Extracted from Cortex Periplocae Induced Apoptosis of Gastric Cancer Cells via the ERK1/2-EGR1 Pathway

2016 ◽  
Vol 38 (5) ◽  
pp. 1939-1951 ◽  
Author(s):  
Lei Li ◽  
Lian-Mei Zhao ◽  
Su-li Dai ◽  
Wen-Xuan Cui ◽  
Hui-Lai Lv ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Viability ◽  
Cancer Cells ◽  
Inhibitory Effect ◽  
Tunel Staining ◽  
Dependent Manner ◽  
Gastric Cancer Cells ◽  
Induced Apoptosis

Background/Aims: Periplocin is extracted from the traditional herbal medicine cortex periplocae, which has been reported to suppress the growth of cancer cells. However, little is known about its effect on gastric cancer cells. Methods: Gastric cancer cells were treated with periplocin, and cell viability was assessed using MTS assay. Flow cytometry and TUNEL staining were performed to evaluate apoptosis, and protein expression was examined by western blotting. Microarray analysis was used to screen for changes in related genes. Results: We found that periplocin had an inhibitory effect on gastric cancer cell viability in a dose-dependent manner. Periplocin inhibited cell viability via the ERK1/2-EGR1 pathway to induce apoptosis. Periplocin also inhibited the growth of tumor xenografts and induced apoptosis in vivo. Conclusion: Our results show that periplocin inhibits the proliferation of gastric cancer cells and induces apoptosis in vitro and in vivo, indicating its potential to be used as an antitumor drug.

Celastrus Orbiculatus Extract Potentiates the Sensitivity of Cisplatin Via Caspase-Depenent Apoptosis in Gastric Cancer

2019 ◽  
Vol 18 (15) ◽  
pp. 2206-2211 ◽  
Author(s):  
Weimin Wang ◽  
Yan Zhou ◽  
Qiang Yao ◽  
Weihua Liu ◽  
Liangliang Xiang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cisplatin Resistance ◽  
Annexin V ◽  
Apoptotic Cells ◽  
Dependent Manner ◽  
Celastrus Orbiculatus ◽  
Gastric Cancer Cells ◽  
Synergistic Cytotoxicity

Background: Cisplatin-based treatment often leads to therapeutic failure because the acquisition of cisplatin resistance. The combination of cisplatin with other agents has been recognized as a promising strategy to overcome cisplatin resistance. Objective: Celastrus orbiculatus is a traditional Chinese medicine from Celastraceae family with multiple pharmacological activities. We previously found that the ethyl acetate extract of Celastrus orbiculatus (COE) exhibited significant antitumor activity in gastric cancer. Here, we asked whether COE could increase the sensitivity of cisplatin. Methods: We use CCK8 assay to show synergistic cytotoxicity of COE and cisplatin. Then, PI single staining and FITC-Annexin V/PI double staining were used to observe apoptotic cells through flow cytometry. The proteins of caspase signaling pathway were examined by Western blotting. Results: COE and cisplatin showed synergistic cytotoxicity in a dose-dependent manner in BGC 823 and SGC 7901 gastric cancer cells, and COE could increase the number of apoptotic cells upon cisplatin treatment in vitro. Moreover, our results indicated that COE could enhance cisplatin–induced activation of caspase-8 or caspase- 9/caspase-3/PARP1 signaling pathways. The xenograft study further confirmed that COE increased the sensitivity of cisplatin in vivo. Conclusion: Our findings provided new evidence that COE could increase the sensitivity of cisplatin on the antitumor effect.

scholarly journals Knockdown of Kremen2 Inhibits Tumor Growth and Migration in Gastric Cancer

2021 ◽  
Vol 10 ◽  
Author(s):  
Beibei Chen ◽  
Sai-Qi Wang ◽  
Jinxi Huang ◽  
Weifeng Xu ◽  
Huifang Lv ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Xenograft Model ◽  
Gastric Cancer Cells ◽  
And Migration ◽  
Induced Apoptosis ◽  
Gastric Cancer Patients

Kremen2 (Krm2) plays an important role in embryonic development, bone formation, and tumorigenesis as a crucial regulator of classical Wnt/β-catenin signaling pathway. However, the role of Krm2 in gastric cancer is not clear. The aim of this study was to explore the regulatory role of Krm2 in the tumorigenesis and metastasis of gastric cancer. It was demonstrated that, compared to para-cancerous tissues, Krm2 was significantly up-regulated in gastric cancer tissues and was positively correlated with the pathological grade of gastric cancer patients. Given that Krm2 is abundantly expressed in most tested gastric cancer cell lines, Krm2 knockdown cell models were established and further used to construct mice xenograft model. After knocking down Krm2, both the cell survival in vitro and tumorigenesis in vivo of gastric cancer cells were inhibited. At the same time, knockdown of Krm2 induced apoptosis, cell cycle arrest at G2/M phase and repression of migration in gastric cancer cells in vitro. Mechanistically, we found that knockdown of Krm2 suppressed PI3K/Akt pathway. Therefore, we revealed the novel role and the molecular mechanism of Krm2 in promoting the tumorigenesis and metastasis in gastric cancer. Krm2 can be a potent candidate for designing of targeted therapy.

scholarly journals Berberine Suppressed Tumor Growth through Regulating Fatty Acid Metabolism and Triggering Cell Apoptosis via Targeting FABPs

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Lingli Li ◽  
Ze Peng ◽  
Qian Hu ◽  
Lijun Xu ◽  
Xin Zou ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Fatty Acid ◽  
Protein Expression ◽  
Cell Viability ◽  
Human Gastric Cancer ◽  
Dependent Manner ◽  
Xenograft Models ◽  
Induced Apoptosis

Aim. To further investigate the mechanism behind the antitumor properties of berberine regarding lipid metabolism. Methods. Cell viability, proliferation, and apoptosis assays were performed to determine the antigrowth effects of berberine in vitro. Ectopic xenograft models in Balb/c nude mice were established to determine the antitumor effects of berberine in vivo. Results. Berberine inhibited cell viability and proliferation of MGC803 human gastric cancer cell lines in a time- and dose-dependent manner. Berberine induced apoptosis of MGC803 and increased the apoptotic rate with higher doses. Berberine induced the accumulation of fatty acid of MGC803 and suppressed the protein expression of FABPs and PPARα. The FABP inhibitor BMS309403 recapitulated the effects of berberine on MGC803 cells. In the xenograft model, berberine significantly decreased the tumor volume and tumor weight and induced apoptosis in tumor tissues. Berberine significantly elevated the fatty acid content and inhibited the expression of FABPs and PPARα in the MGC803 xenograft models. Conclusion. Berberine exerted anticancer effects on human gastric cancer both in vitro and in vivo by inducing apoptosis, which was due to the reduced protein expression of FABPs and the accumulation of fatty acid.

Thymoquinone inhibits growth and augments 5-fluorouracil-induced apoptosis in gastric cancer cells both in vitro and in vivo

2012 ◽  
Vol 417 (2) ◽  
pp. 864-868 ◽  
Author(s):  
Xiaofei Lei ◽  
Xiaoguang Lv ◽  
Meng Liu ◽  
Zirong Yang ◽  
Mengyao Ji ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Gastric Cancer Cells ◽  
Induced Apoptosis

scholarly journals Zuo Jin Wan Reverses DDP Resistance in Gastric Cancer through ROCK/PTEN/PI3K Signaling Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Meng-Yao Sun ◽  
Jian Sun ◽  
Jie Tao ◽  
Yu-Xia Yuan ◽  
Zhen-Hua Ni ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Chemotherapy Resistance ◽  
Underlying Mechanism ◽  
Pi3k Signaling ◽  
Gastric Cancer Cells ◽  
Poor Overall Survival ◽  
Mitochondrial Translocation ◽  
Induced Apoptosis

Gastric cancer (GC) is the third leading cause of cancer-related death. Chemotherapy resistance remains the major reason for GC treatment failure and poor overall survival of patients. Our previous studies have proved that Zuo Jin Wan (ZJW), a traditional Chinese medicine (TCM) formula, could significantly enhance the sensitivity of cisplatin (DDP)-resistant gastric cancer cells to DDP by inducing apoptosis via mitochondrial translocation of cofilin-1. However, the underlying mechanism remains poorly understood. This study aimed to evaluate the effects of ROCK/PTEN/PI3K on ZJW-induced apoptosis in vitro and in vivo. We found that ZJW could significantly activate the ROCK/PTEN pathway, inhibit PI3K/Akt, and promote the apoptosis of SGC-7901/DDP cells. Inhibition of ROCK obviously attenuated ZJW-induced apoptosis as well as cofilin-1 mitochondrial translocation, while inhibition of PI3K had the opposite effects. In vivo, combination treatment of DDP and ZJW (2000 mg/kg) significantly reduced tumor growth compared with DDP alone. Moreover, the combined administration of ZJW and DDP increased the expression of cleaved ROCK and p-PTEN while it decreased p-PI3K and p-cofilin-1, which was consistent with our in vitro results. These findings indicated that ZJW could effectively inhibit DDP resistance in GC by regulating ROCK/PTEN/PI3K signaling and provide a promising treatment strategy for gastric cancer.

scholarly journals Rosiglitazone Suppresses the Growth and Invasiveness of SGC-7901 Gastric Cancer Cells and Angiogenesis In Vitro via PPARγ Dependent and Independent Mechanisms

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-9 ◽  
Author(s):  
Qing He ◽  
Ruiping Pang ◽  
Xin Song ◽  
Jie Chen ◽  
Huixin Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Dependent Manner ◽  
Gastric Cancer Cells ◽  
Independent Manner ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Induced Apoptosis ◽  
Dose Dependent

Although thiazolidinediones (TZDs) were found to be ligands for peroxisome proliferators-activated receptorγ (PPARγ), the mechanism by which TZDs exert their anticancer effect remains unclear. Furthermore, the effect of TZDs on metastatic and angiogenesis potential of cancer cells is unknown. Our results in this paper show that rosiglitazone inhibited SGC-7901 gastric cancer cells growth, caused G1 cell cycle arrest and induced apoptosis in a dose-dependent manner. The effects of rosiglitazone on SGC-7901 cancer cells were completely reversed by treatment with PPARγ antagonist GW9662. Rosiglitazone inhibited SGC-7901 cell migration, invasiveness, and the expression of MMP-2 in dose-dependent manner via PPARγ-independent manner. Rosiglitazone reduced the VEGF induced angiogenesis of HUVEC in dose-dependent manner through PPARγ-dependent pathway. Moreover, rosiglitazone did not affect the expression of VEGF by SGC-7901 cells. Our results demonstrated that by PPARγ ligand, rosiglitazone inhibited growth and invasiveness of SGC-7901 gastric cancer cells and angiogenesis in vitro via PPARγ-dependent or -independent pathway.

scholarly journals m6A Methylation Mediates LHPP Acetylation as a Tumour Aerobic Glycolysis Suppressor to Improve the Prognosis of Gastric Cancer

2021 ◽  
Author(s):  
Jian-Xian Lin ◽  
Ning-Zi Lian ◽  
You-Xin Gao ◽  
Qing-Zhu Qiu ◽  
Hua-Gen Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cox Regression ◽  
Aerobic Glycolysis ◽  
Prognostic Significance ◽  
Predictive Biomarker ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells ◽  
Cox Regression Analysis

Abstract BackgroundLHPP, a histidine phosphatase, has been implicated in tumor progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. MethodsWe obtained GC tissues and corresponding normal tissues from 8 patients and identified LHPP as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine LHPP levels in normal and GC tissues. The prognostic value of LHPP was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of LHPP in GC growth and metastasis were evaluated in vitro and in vivo. ResultsThe results showed that LHPP expression was significantly decreased in GC tissues at both the mRNA and protein level. Multivariate Cox regression analysis revealed that LHPP was an independent prognostic factor and effective predictor in patients with GC. The low expression of LHPP was significantly related to the poor prognosis and chemotherapy sensitivity of gastric cancer patients. Moreover, elevated LHPP expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, the m6A modification of LHPP mRNA by METTL14 represses its expression; LHPP inhibits the phosphorylation of GSK3b through acetylation, and mediates HIF1A to inhibit glycolysis, proliferation, invasion and metastasis of gastric cancer cells. ConclusionLHPP is regulated by m6A methylation and regulates the metabolism of GC by changing the acetylation level. Thus, LHPP is a potential predictive biomarker and therapeutic target for GC.

scholarly journals Targeting the autophagy promoted antitumor effect of T-DM1 on HER2-positive gastric cancer

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Jinghui Zhang ◽  
Jiajun Fan ◽  
Xian Zeng ◽  
Mingming Nie ◽  
Wei Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Antitumor Effect ◽  
Underlying Mechanism ◽  
Immunoblot Analysis ◽  
Autophagic Flux ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Induced Apoptosis

AbstractTrastuzumab emtansine (T-DM1), an antibody-drug conjugate consisted of the HER2-targeted monoclonal antibody trastuzumab and the tubulin inhibitor emtansine, has shown potent therapeutic value in HER2-positive breast cancer (BC). However, a clinical trial indicated that T-DM1 exerts a limited effect on HER2-positive gastric cancer (GC), but the underlying mechanism is inconclusive. Our research attempted to reveal the probable mechanism and role of autophagy in T-DM1-treated HER2-positive GC. In this study, our results showed that T-DM1 induced apoptosis and exhibited potent therapeutic efficacy in HER2-positive GC cells. In addition, autophagosomes were observed by transmission electron microscopy. Autophagy was markedly activated and exhibited the three characterized gradations of autophagic flux, consisting of the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and the deterioration of autophagosomes in autolysosomes. More importantly, autophagic inhibition by the suppressors 3-methyladenine (3-MA) and LY294002 significantly potentiated cytotoxicity and apoptosis in HER2-positive GC cells in vitro, while the combined use of LY294002 and T-DM1 elicited potent anti-GC efficacy in vivo. In mechanistic experiments, immunoblot analysis indicated the downregulated levels of Akt, mTOR, and P70S6K and confocal microscopy analysis clearly showed that autophagic inhibition promoted the fusion of T-DM1 molecules with lysosomes in GC cells. In conclusion, our research demonstrated that T-DM1 induced apoptosis as well as cytoprotective autophagy, and autophagic inhibition could potentiate the antitumor effect of T-DM1 on HER2-positive GC. Furthermore, autophagic inhibition might increase the fusion of T-DM1 with lysosomes, which might accelerate the release of the cytotoxic molecule emtansine from the T-DM1 conjugate. These findings highlight a promising therapeutic strategy that combines T-DM1 with an autophagy inhibitor to treat HER-positive GC more efficiently.

OSI-027 alleviates oxaliplatin chemoresistance in gastric cancer cells by suppressing P-gp induction

2020 ◽  
Vol 20 ◽  
Author(s):  
En Xu ◽  
Hao Zhu ◽  
Feng Wang ◽  
Ji Miao ◽  
Shangce Du ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Mammalian Target Of Rapamycin ◽  
Cell Counting ◽  
Gastric Cancer Cells ◽  
Ags Cells ◽  
Dual Inhibitor ◽  
Induced Apoptosis

: Gastric cancer is one of the most common malignancies worldwide and the third leading cause of cancer-related death. In the present study, we investigated the potential activity of OSI-027, a potent and selective mammalian target of rapamycin complex 1/2 (mTOR1/2) dual inhibitor, alone or in combination with oxaliplatin against gastric cancer cells in vitro. Cell counting kit-8 assays and EdU staining were performed to examine the proliferation of cancer cells. Cell cycle and apoptosis were detected by flow cytometry. Western blot was used to detect the elements of the mTOR pathway and Pgp in gastric cancer cell lines. OSI-027 inhibited the proliferation of MKN-45 and AGS cells by arresting the cell cycle in the G0/G1 phase. At the molecular level, OSI-027 simultaneously blocked mTORC1 and mTORC2 activation, and resulted in the downregulation of phosphor-Akt, phpspho-p70S6k, phosphor-4EBP1, cyclin D1, and cyclin-dependent kinase4 (CDK4). Additionally, OSI-027 also downregulated P-gp, which enhanced oxaliplatin-induced apoptosis and suppressed multidrug resistance. Moreover, OSI-027 exhibited synergistic cytotoxic effects with oxaliplatin in vitro, while a P-gp siRNA knockdown significantly inhibited the synergistic effect. In summary, our results suggest that dual mTORC1/mTORC2 inhibitors (e.g., OSI-027) should be further investigated as a potential valuable treatment for gastric cancer.

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