T-32 In vivo and in vitro models support the therapeutic effects of acycloguanosyl 5’-thymidyltriphosphate for the hepatocellular carcinoma via telomerase activation

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death globally. HCC is a complex multistep disease and usually emerges in the setting of chronic liver diseases. The molecular pathogenesis of HCC varies according to the etiology, mainly caused by chronic hepatitis B and C virus infections, chronic alcohol consumption, aflatoxin-contaminated food, and non-alcoholic fatty liver disease associated with metabolic syndrome or diabetes mellitus. The establishment of HCC models has become essential for both basic and translational research to improve our understanding of the pathophysiology and unravel new molecular drivers of this disease. The ideal model should recapitulate key events observed during hepatocarcinogenesis and HCC progression in view of establishing effective diagnostic and therapeutic strategies to be translated into clinical practice. Despite considerable efforts currently devoted to liver cancer research, only a few anti-HCC drugs are available, and patient prognosis and survival are still poor. The present paper provides a state-of-the-art overview of in vivo and in vitro models used for translational modeling of HCC with a specific focus on their key molecular hallmarks.

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Hypoxic hepatocellular carcinoma cells acquire arsenic trioxide resistance through upregulating HIF-1α expression

10.21203/rs.2.18624/v3 ◽

2020 ◽

Author(s):

Yaoting Chen ◽

Huiqing Li ◽

Dong Chen ◽

Xiongying Jiang ◽

Weidong Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Protein Expression ◽

Arsenic Trioxide ◽

Therapeutic Effects ◽

Advanced Hepatocellular Carcinoma ◽

Antitumor Effects ◽

P Glycoprotein ◽

Hcc Cells

Abstract Background : Although arsenic trioxide (ATO) is used in the treatment of advanced hepatocellular carcinoma (HCC) in clinical trials, it is not satisfactory in terms of improving HCC patients’ overall survival. Intratumoral hypoxia and overexpression of hypoxia-inducible-1α (HIF-1α) may result in ATO-resistance and tumor progression. We investigated the mechanisms involving HIF-1α expression and acquired ATO chemoresistance in HCC cells and mice. Methods: The therapeutic effects of ATO in normoxic and hypoxic HCC cells were assessed using cell viability and apoptosis assays in vitro and a xenograft model in vivo . mRNA and protein expression of HIF-1α, P-glycoprotein, and VEGF were measured by qRT-PCR and western blotting. HIF-1α inhibition was performed to investigate the mechanism of ATO-resistance. VEGF secretion was tested using ELISA and tube-formation assays. Results : Compared to normoxic cells, hypoxic HCC cells were more resistant to ATO, with higher IC 50 values and less apoptosis, and upregulated HIF-1α protein expression, accompanied with the enhancement of P-glycoprotein and VEGF synthesis after ATO treatment. VEGF secretion was elevated in the supernatant of ATO-treated HCC cells, and this change can potentiate angiogenesis in vitro . HIF-1α inhibition attenuated ATO-resistance and angiogenesis, and promoted the anticancer effects of ATO both in vitro and in vivo by downregulating therapy-induced P-glycoprotein and VEGF overexpression. Conclusions : Hypoxic HCC cells acquire ATO resistance by upregulating HIF-1α levels; thus, combining ATO with a HIF-1α-targeting agent may lead to enhanced antitumor effects in HCC.

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A novel peptide with a potential to enhance sorafenib’s therapeutic effects in hepatocellular carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e13505 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e13505-e13505

Author(s):

Joline Sijing Lim ◽

Todor Dimitrov ◽

Kol Jia Yong ◽

Chong Gao ◽

Daniel G Tenen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Stem Cell ◽

Tumor Growth ◽

Mechanism Of Action ◽

Stem Cell Factor ◽

Tumor Burden ◽

Therapeutic Effects ◽

Novel Approach

e13505 Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide, with chemotherapy or targeted therapy such as sorafenib achieving limited success. Recently stem cell factor SALL4 has emerged as a novel oncogene associated with leukemogenesis and is also implicated in many solid tumors. We have observed that SALL4 is not expressed in adult human liver tissues, but expressed in 30-40% of liver cancer, and this is associated with poorer prognosis and overall survival. We further tested whether inhibition of SALL4 function could be used for HCC treatment. Methods: A novel peptide blocking SALL4 function was designed and used to treat HCC lines with or without SALL4 expression. This is followed by evaluation for binding affinity, tumor growth inhibitory activity and mechanism of action. Treated cells were then transplanted in vivo into NOD/SCID mice and monitored for tumor growth. Comparison and/or combination of peptide with sorafenib were also carried out. Further modification of the peptide was done to allow for in vivo administration. Results: The peptide can effectively block SALL4 function. When used to treat HCC cell lines, it showed inhibitory effects in SNU398 cells (SALL4 expression), but not SNU387 cells (non-SALL4 expression). Post-xenotransplant, mice which received cells treated with peptide had slower rate of tumor growth (p=0.028) and lower tumor burden at dissection 26 days post transplant (p=0.048). Searching for its mechanism of action, we discovered that the peptide could affect the PTEN/AKT pathway, which was validated by western blot. When the peptide was combined with sorafenib, decreased cell viability was observed (p=0.03), suggestive of at least an additive effect between the peptide and sorafenib. Modification of peptide with TAT-protein showed similar inhibition of growth in vitro and was tested for further in-vivo usage through intraperitoneal injection. Conclusions: Our proof-of-principle studies have showed that a peptide blocking the function of stem cell factor SALL4 can be used as a novel approach for treating HCC. Combined with sorafenib, it may be able to enhance cell death and potentially lead to better outcomes in HCC patients.

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Blockade of AMPK-Mediated cAMP–PKA–CREB/ATF1 Signaling Synergizes with Aspirin to Inhibit Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13071738 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1738

Author(s):

Hongying Zhang ◽

Songpeng Yang ◽

Jiao Wang ◽

Yangfu Jiang

Keyword(s):

Hepatocellular Carcinoma ◽

Protein Phosphatase ◽

Protein Phosphatase 2A ◽

Therapeutic Effects ◽

Carbamoyl Phosphate ◽

Cycle Enzyme ◽

Phosphatase 2A ◽

Hcc Cells

Aspirin can prevent or inhibit inflammation-related cancers, such as colorectal cancer and hepatocellular carcinoma (HCC). However, the effectiveness of chemotherapy may be compromised by activating oncogenic pathways in cancer cells. Elucidation of such chemoresistance mechanisms is crucial to developing novel strategies to maximize the anti-cancer effects of aspirin. Here, we report that aspirin markedly induces CREB/ATF1 phosphorylation in HCC cells, which compromises aspirin’s anti-HCC effect. Inhibition of AMP-activated protein kinase (AMPK) abrogates the induction of CREB/ATF1 phosphorylation by aspirin. Mechanistically, activation of AMPK by aspirin results in decreased expression of the urea cycle enzyme carbamoyl-phosphate synthase 1 (CPS1) in HCC cells and xenografts. Treatment with aspirin or CPS1 knockdown stimulates soluble adenylyl cyclase expression, thereby increasing cyclic AMP (cAMP) synthesis and stimulating PKA–CREB/ATF1 signaling. Importantly, abrogation of aspirin-induced CREB/ATF1 phosphorylation could sensitize HCC to aspirin. The bis-benzylisoquinoline alkaloid berbamine suppresses the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), leading to protein phosphatase 2A-mediated downregulation of CREB/ATF1 phosphorylation. The combination of berbamine and aspirin significantly inhibits HCC in vitro and in vivo. These data demonstrate that the regulation of cAMP-PKA-CREB/ATF1 signaling represents a noncanonical function of CPS1. Targeting the PKA–CREB/ATF1 axis may be a strategy to improve the therapeutic effects of aspirin on HCC.

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Circ_0015756 aggravates hepatocellular carcinoma development by regulating FGFR1 via sponging miR-610

10.21203/rs.2.23658/v1 ◽

2020 ◽

Author(s):

Weisheng Guo ◽

Lin Zhao ◽

Yaguang Wei ◽

Peng Liu ◽

Yu Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Cell Viability ◽

Colony Formation ◽

Cell Counting ◽

Luciferase Reporter ◽

Circular Rnas ◽

Therapeutic Effects

Abstract Background: Hepatocellular carcinoma (HCC) is the leading threat of cancer-related death in humans with poor therapeutic effects. Circular RNAs (circRNAs) are important indicators in cancer diagnosis and prognosis. This study intended to explore the function and mechanism of circ_0015756 in HCC, providing the additional opinion for HCC treatment.Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to detect the expression of circ_0015756 and miR-610. Cell viability was assessed by cell counting kit-8 (CCK-8) assay, and colony formation capacity was ascertained by colony formation assay. Cell proliferation and invasion were monitored by transwell assay. Cell cycle progression and apoptosis were analyzed by flow cytometry assay. Circ_0015756 oncogenicity was determined by Xenograft models. The prediction of targets was performed using the bioinformatics tools, and the verification of targeted relationship was conducted using RNA pull-down, RNA immunoprecipitation (RIP) and dual-luciferase reporter assays. The expression level of fibroblast growth factor receptor 1 (FGFR1) was measured by western blot.Result: The expression of circ_0015756 was increased in HCC tissues, serums and cells. Circ_0015756 downregulation impaired HCC cell viability, colony formation capacity, invasion and migration, induced cell cycle arrest and apoptosis, and inhibited tumor growth in vivo. MiR-610 was ensured as a target of circ_0015756, and miR-610 absence reversed the effects of circ_0015756 downregulation. Further, FGFR1 was interacted by miR-610, and FGFR1 overexpression overturned the effects of miR-610 restoration in vitro. Circ_0015756 could regulate FGFR1 expression by targeting miR-610.Conclusion: Circ_0015756 played its tumorigenic properties in HCC by activating FGFR1 and sponging miR-610, and circ_0015756 was expected to be a vital indicator in HCC diagnosis and treatment.

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Hypoxic hepatocellular carcinoma cells acquire arsenic trioxide resistance through upregulating HIF-1α expression

10.21203/rs.2.18624/v2 ◽

2020 ◽

Author(s):

Yaoting Chen ◽

Huiqing Li ◽

Dong Chen ◽

Xiongying Jiang ◽

Weidong Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Protein Expression ◽

Arsenic Trioxide ◽

Therapeutic Effects ◽

Advanced Hepatocellular Carcinoma ◽

Antitumor Effects ◽

P Glycoprotein ◽

Hcc Cells

Abstract Background : Although arsenic trioxide (ATO) is used in the treatment of advanced hepatocellular carcinoma (HCC) in clinical trials, it is not satisfactory in terms of improving HCC patients’ overall survival. Intratumoral hypoxia and overexpression of hypoxia-inducible-1α (HIF-1α) may result in ATO-resistance and tumor progression. We investigated the mechanisms involving HIF-1α expression and acquired ATO chemoresistance in HCC cells and mice. Methods: The therapeutic effects of ATO in normoxic and hypoxic HCC cells were assessed using cell viability and apoptosis assays in vitro and a xenograft model in vivo . mRNA and protein expression of HIF-1α, P-glycoprotein, and VEGF were measured by qRT-PCR and western blotting. HIF-1α inhibition was performed to investigate the mechanism of ATO-resistance. VEGF secretion was tested using ELISA and tube-formation assays. Results : Compared to normoxic cells, hypoxic HCC cells were more resistant to ATO, with higher IC 50 values and less apoptosis, and upregulated HIF-1α protein expression, accompanied with the enhancement of P-glycoprotein and VEGF synthesis after ATO treatment. VEGF secretion was elevated in the supernatant of ATO-treated HCC cells, and this change can potentiate angiogenesis in vitro . HIF-1α inhibition attenuated ATO-resistance and angiogenesis, and promoted the anticancer effects of ATO both in vitro and in vivo by downregulating therapy-induced P-glycoprotein and VEGF overexpression. Conclusions : Hypoxic HCC cells acquire ATO resistance by upregulating HIF-1α levels; thus, combining ATO with a HIF-1α-targeting agent may lead to enhanced antitumor effects in HCC.

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Therapeutic effects of the PKR inhibitor C16 suppressing tumor proliferation and angiogenesis in hepatocellular carcinoma in vitro and in vivo

Scientific Reports ◽

10.1038/s41598-020-61579-x ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Takao Watanabe ◽

Hiroko Ninomiya ◽

Takashi Saitou ◽

Sota Takanezawa ◽

Shin Yamamoto ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Therapeutic Effects ◽

Tumor Proliferation

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Hypoxic hepatocellular carcinoma cells acquire arsenic trioxide resistance through upregulating HIF-1α expression

10.21203/rs.2.18624/v1 ◽

2019 ◽

Author(s):

Yaoting Chen ◽

Huiqing Li ◽

Dong Chen ◽

Xiongying Jiang ◽

Weidong Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Protein Expression ◽

Arsenic Trioxide ◽

Therapeutic Effects ◽

Advanced Hepatocellular Carcinoma ◽

Antitumor Effects ◽

P Glycoprotein ◽

Hcc Cells

Abstract Background: Although arsenic trioxide (ATO) is used in treatment of advanced hepatocellular carcinoma (HCC) in clinical trials, it is not yet satisfied in improving HCC patients’ overall survival. Intratumoral hypoxia and overexpression of hypoxia-inducible factor-1α (HIF-1α) may result in ATO-resistance and tumor progression. We investigated the mechanisms between HIF-1α expression and acquired ATO-chemoresistance in HCC cells and in mice. Methods: Therapeutic effects of ATO in normoxic and hypoxic HCC cells were assessed using cell viability and apoptosis assays in vitro and xenografts model. mRNA and protein expression of HIF-1α, P-glycoprotein, and VEGF were measured by qRT-PCR and western blotting. HIF-1α inhibition was performed to investigate the mechanism of ATO-resistance. VEGF secretion was tested using ELISA and tube-formation assay. Results: Hypoxic HCC cells showed more resistance to ATO, with higher IC50 values and less apoptosis, than normoxic cells and upregulated HIF-1α protein expression, accompanied with the enhancement of P-glycoprotein and VEGF synthesis after ATO treatment. VEGF secretion was elevated in ATO-treated supernatant to potentiate angiogenesis in vitro. HIF-1α inhibition attenuated ATO-resistance and angiogenesis, and promoted the anticancer effects of ATO both in vitro and in vivo by downregulating therapy-induced P-glycoprotein and VEGF overexpression. Conclusions: Hypoxic HCC cells acquire ATO-resistance by upregulating HIF-1α levels; thus ATO combined with targeting HIF-1α levels may lead to the enhanced antitumor effects in HCC. Keywords: hepatocellular carcinoma, arsenic trioxide, drug resistance, HIF-1α, targeted therapy

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Clinical Trials in Thrombosis: Secondary Prevention of Myocardial Infarction

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647910 ◽

1976 ◽

Vol 35 (01) ◽

pp. 049-056 ◽

Cited By ~ 4

Author(s):

Christian R Klimt ◽

P. H Doub ◽

Nancy H Doub

Keyword(s):

Myocardial Infarction ◽

Secondary Prevention ◽

Case Control ◽

Therapeutic Effects ◽

Case Control Studies ◽

Definitive Answer ◽

Inhibition Of Platelet Aggregation ◽

Prospective Trials

SummaryNumerous in vivo and in vitro experiments, investigating the inhibition of platelet aggregation and the prevention of experimentally-induced thrombosis, suggest that anti-platelet drugs, such as aspirin or the combination of aspirin and dipyridamole or sulfinpyrazone, may be effective anti-thrombotic agents in man. Since 1971, seven randomized prospective trials and two case-control studies have been referenced in the literature or are currently being conducted, which evaluate the effects of aspirin, sulfinpyrazone, or dipyridamole in combination with aspirin in the secondary prevention of myocardial infarction. A critical review of these trials indicates a range of evidence from no difference to a favorable trend that antiplatelet drugs may serve as anti-thrombotic agents in man. To date, a definitive answer concerning the therapeutic effects of these drugs in the secondary prevention of coronary heart disease is not available.

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Modulation of Matrix Metalloproteinases by Plant-Derived Products

Current Cancer Drug Targets ◽

10.2174/1568009620666201120144838 ◽

2020 ◽

Vol 20 ◽

Author(s):

Nur Najmi Mohamad Anuar ◽

Nurul Iman Natasya Zulkafali ◽

Azizah Ugusman

Keyword(s):

Clinical Trials ◽

Natural Products ◽

Matrix Metalloproteinases ◽

Animal Studies ◽

Current Knowledge ◽

In Vitro Models ◽

In Vivo Studies ◽

Extracellular Matrix Components

: Matrix metalloproteinases (MMPs) are a group of zinc-dependent metallo-endopeptidase that are responsible towards the degradation, repair and remodelling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic and food industries. This review summarises the current knowledge on plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signalling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviours, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.

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