Systemic hypoxia potentiates anti-tumor effects of metformin in hepatocellular carcinoma in mice

2020 ◽  
Vol 52 (4) ◽  
pp. 421-429
Author(s):  
Hui Lin ◽  
Wenfang Zhou ◽  
Yonghong Huang ◽  
Min Ren ◽  
Fangyun Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Progression ◽  
Tumor Volume ◽  
Combined Treatment ◽  
Hypoxia Inducible Factor ◽  
Inhibitory Effect ◽  
Whole Body ◽  
Matrix Metalloproteinase 2 ◽  
Systemic Hypoxia ◽  
Novel Strategy

Abstract Local hypoxia is a universal phenomenon in most solid tumors. The role of local hypoxia in the tumor microenvironment and cancer growth and metastasis has been well established. However, the effect of acute systemic hypoxia (exposing the whole body to 10% O2 environment) on cancer has not yet been investigated. In this study, we investigated the potential effects of acute systemic hypoxia itself and in combination with metformin on hepatocellular carcinoma (HCC) growth and metastasis in a mouse model of HCC. Acute systemic hypoxia significantly decreased tumor volume and weight in H22 tumor-bearing mice. Interestingly, the combined treatment of acute systemic hypoxia and metformin showed a more pronounced effect in reducing tumor volume and weight. Moreover, acute systemic hypoxia and metformin in combination had a potent inhibitory effect on tumor progression. More importantly, the expressions of hypoxia response genes including hypoxia-inducible factor-1 α, vascular endothelial growth factor, and matrix metalloproteinase 2 were significantly decreased in the tumor tissues with combination treatment. Our study demonstrated that acute systemic hypoxia repressed tumor progression of the HCC and potentiated the anti-tumor activities of metformin. This study supports that combination of systemic hypoxia and metformin treatment may represent a novel strategy for HCC.

scholarly journals Upregulation of histamine receptor H1 promotes tumor progression and contributes to poor prognosis in hepatocellular carcinoma

Oncogene ◽  
2019 ◽  
Vol 39 (8) ◽  
pp. 1724-1738 ◽  
Author(s):  
Jing Zhao ◽  
Yiran Hou ◽  
Chun Yin ◽  
Jing Hu ◽  
Tian Gao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Progression ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Histamine Receptor ◽  
Matrix Metalloproteinase 2 ◽  
Mice Model ◽  
Hcc Cells

AbstractH1 histamine receptor (H1HR) belongs to the family of rhodopsin-like G-protein-coupled receptors. Recent studies have shown that H1HR expression is increased in several types of cancer. However, its functional roles in tumor progression remain largely unknown, especially in hepatocellular carcinoma (HCC). We found that H1HR is frequently unregulated in HCC, which is significantly associated with both recurrence-free survival and overall survival in HCC patients. Functional experiments revealed that H1HR promoted both the growth and metastasis of HCC cells by inducing cell cycle progression, formation of lamellipodia, production of matrix metalloproteinase 2, and suppression of cell apoptosis. Activation of cyclic adenosine monophosphate-dependent protein kinase A was found to be involved in H1HR-mediated HCC cell growth and metastasis. In addition, we found that overexpression of H1HR was mainly due to the downregulation of miR-940 in HCC cells. Moreover, the H1HR inhibitor terfenadine significantly suppressed tumor growth and metastasis in an HCC xenograft nude mice model. Our findings demonstrate that H1HR plays a critical role in the growth and metastasis of HCC cells, which provides experimental evidence supporting H1HR as a potential drug target for the treatment of HCC.

scholarly journals The inhibitory effect and mechanism of quetiapine on tumor progression in hepatocellular carcinoma in vivo

2021 ◽  
Author(s):  
Chun‐Min Su ◽  
Song‐Shei Lin ◽  
Hsiao‐Chia Wang ◽  
Fei‐Ting Hsu ◽  
Jing Gung Chung ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Progression ◽  
Inhibitory Effect

scholarly journals Manuka honey enhanced sensitivity of HepG2, hepatocellular carcinoma cells, for Doxorubicin and induced apoptosis through inhibition of Wnt/β-catenin and ERK1/2

2021 ◽  
Vol 54 (1) ◽  
Author(s):  
Heba R. Al Refaey ◽  
Al-Sayeda A. Newairy ◽  
Mayssaa M. Wahby ◽  
Chris Albanese ◽  
Mohamed Elkewedi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Apoptotic Cell ◽  
Combined Treatment ◽  
Inhibitory Effect ◽  
Hep G2 ◽  
Hep G2 Cells ◽  
Manuka Honey ◽  
Anticancer Properties ◽  
Hep3b Cells ◽  
Induced Apoptosis

Abstract Background Recently, there is increasing awareness focused on the identification of naturally occurring anticancer agents derived from natural products. Manuka honey (MH) has been recognized for its biological properties as antimicrobial, antioxidant, and anticancer properties. However, its antiproliferative mechanism in hepatocellular carcinoma is not investigated. The current study focused mainly on investigating the molecular mechanism and synergistic effect of anticancer properties of MH on Doxorubicin (DOX)-mediated apoptotic cell death, using two different p53 statuses (HepG2 and Hep3B) and one non-tumorigenic immortalized liver cell line. Results MH treatment showed a proliferative inhibitory effect on tested cells in a dose-dependent manner with IC50 concentration of (6.92 ± 0.005%) and (18.62 ± 0.07%) for HepG2 and Hep3B cells, respectively, and induced dramatic morphological changes of Hep-G2 cells, which considered as characteristics feature of apoptosis induction after 48 h of treatment. Our results showed that MH or combined treatments induced higher cytotoxicity in p53-wild type, HepG2, than in p53-null, Hep3B, cells. Cytotoxicity was not observed in normal liver cells. Furthermore, the synergistic effect of MH and Dox on apoptosis was evidenced by increased annexin-V-positive cells and Sub-G1 cells in both tested cell lines with a significant increase in the percentage of Hep-G2 cells at late apoptosis as confirmed by the flow cytometric analysis. Consistently, the proteolytic activities of caspase-3 and the degradation of poly (ADP-ribose) polymerase were also higher in the combined treatment which in turn accompanied by significant inhibitory effects of pERK1/2, mTOR, S6K, oncogenic β-catenin, and cyclin D1 after 48 h. In contrast, the MH or combined treatment-induced apoptosis was accompanied by significantly upregulated expression of proapoptotic Bax protein and downregulated expression of anti-apoptotic Bcl-2 protein after 48 h. Conclusions Our data showed a synergistic inhibitory effect of MH on DOX-mediated apoptotic cell death in HCC cells. To our knowledge, the present study provides the first report on the anticancer activity of MH and its combined treatment with DOX on HCC cell lines, introducing MH as a promising natural and nontoxic anticancer compound.

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