Targeted therapy of chronic liver diseases with the inhibitors of angiogenesis

Srivastava, Ankita; Shukla, Vanistha; Tiwari, Deepika Pandey; Gupta, Jaya; Kumar, Sunil; Kumar, Awanish

doi:10.1016/j.biopha.2018.05.102

Cited by 9 publications

(8 citation statements)

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“…Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and ranks the fourth cause of lethal tumor (Bray et al, 2018). HCC is a typical hypervascular tumor and commonly associated with hypervascularity (Srivastava et al, 2018;Morse et al, 2019). Therefore, inhibiting angiogenesis is believed to be a potential strategy to control HCC (Taketomi, 2016;Barbhuiya et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Dandelion Polysaccharide Exerts Anti-Angiogenesis Effect on Hepatocellular Carcinoma by Regulating VEGF/HIF-1α Expression

Ren

Yang

et al. 2020

Front. Pharmacol.

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Recent studies have revealed that natural plants-derived polysaccharides exhibit potent anti-tumor activity. Our earlier studies suggest that dandelion polysaccharide (DP) inhibits hepatocellular carcinoma (HCC) cell proliferation in vitro and in vivo. Here, we investigated the effects of DP on the angiogenesis of HCC and the potential molecular mechanisms by which DP regulates angiogenesis. Wound-healing and transwell invasion assays revealed that DP inhibited HUVECs migration and invasion in vitro, respectively. Tube formation assay, chick chorioallantoic membrane (CAM) assay, and immunohistochemistry (IHC) demonstrated that DP suppressed vasculogenesis in vitro and in vivo. Moreover, Western blot and immunofluorescence staining verified that DP treatment decreased the protein levels of some key factors involved in angiogenesis of HCC, such as hypoxia-inducible factor 1a (HIF-1a), vascular endothelial growth factor (VEGF), p-PI3K, and p-AKT. However, activation of PI3K/AKT pathway with insulin-like growth factor 1 (IGF-1) treatment attenuated the effect of DP on angiogenesis via lowering the expression of HIF-1a and VEGF. In summary, we found that DP treatment inhibited angiogenesis in vivo and in vitro through suppressing expression of VEGF and HIF-1a. Furthermore, we showed that the expression of VEGF and HIF1-a was modulated by PI3K/AKT signaling. Collectively, our study suggests that DP is a promising anti-cancer drug candidate for treating HCC.

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Section: Introductionmentioning

confidence: 99%

Dandelion Polysaccharide Exerts Anti-Angiogenesis Effect on Hepatocellular Carcinoma by Regulating VEGF/HIF-1α Expression

Ren

Yang

et al. 2020

Front. Pharmacol.

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“…In addition, angiogenesis has been significantly involved in liver fibrosis. [ 45 , 46 ] Indeed, our pathway enrichment analysis identified that NOS3 and vascular endothelial growth factor signaling pathways are significantly associated with α-SMA expression, while the endothelin-1 signaling pathway is significantly pathway is associated with total collagen level. A considerable body of evidence demonstrates that vascular endothelial growth factor signaling promotes liver fibrogenesis by stimulating activated stellate cells growth, migration, and collagen production.…”

Section: Discussionmentioning

confidence: 97%

Integrative omics analysis identifies macrophage migration inhibitory factor signaling pathways underlying human hepatic fibrogenesis and fibrosis

Liu

Chalasani²,

et al. 2019

J Bio-X Res

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The genetic basis underlying liver fibrosis remains largely unknown. We conducted a study to identify genetic alleles and underlying pathways associated with hepatic fibrogenesis and fibrosis at the genome-wide level in 121 human livers. By accepting a liberal significance level of P <1e-4, we identified 73 and 71 candidate loci respectively affecting the variability in alpha-smooth muscle actin (α-SMA) levels (fibrogenesis) and total collagen content (fibrosis). The top genetic loci associated with the two markers were BAZA1 and NOL10 for α-SMA expression and FAM46A for total collagen content ( P <1e-6). We further investigated the relationship between the candidate loci and the nearby gene transcription levels (cis-expression quantitative trait loci) in the same liver samples. We found that 44 candidate loci for α-SMA expression and 44 for total collagen content were also associated with the transcription of the nearby genes ( P <0.05). Pathway analyses of these genes indicated that macrophage migration inhibitory factor (MIF) related pathway is significantly associated with fibrogenesis and fibrosis, though different genes were enriched for each marker. The association between the single nucleotide polymorphisms, MIF and α-SMA showed that decreased MIF expression is correlated with increased α-SMA expression, suggesting that variations in MIF locus might affect the susceptibility of fibrogenesis through controlling MIF gene expression. In summary, our study identified candidate alleles and pathways underlying both fibrogenesis and fibrosis in human livers. Our bioinformatics analyses suggested MIF pathway as a strong candidate involved in liver fibrosis, thus further investigation for the role of the MIF pathway in liver fibrosis is warranted. The study was reviewed and approved by the Institutional Review Board (IRB) of Wayne State University (approval No. 201842) on May 17, 2018.

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“…Angiogenesis is a vital process through which vascular endothelial cells sprout from pre-existing vessels and form capillaries during cell growth and development that and supply oxygen and nutrients to every cell in the body under physiological and pathological stress conditions. Recent studies indicate that angiogenesis is dysregulated in various pathological processes, leading to various diseases, including cancer, cardiovascular disease, inflammation, and obesity (Carmeliet and Jain, 2000;Carmeliet, 2003;Srivastava et al, 2018). It has been established that the abnormal formation of blood vessels is effective as a treatment for patients with cancer, chronic liver disease, cardiovascular disease or other diseases; therefore, using anti-angiogenic agents as inhibitors has become a major therapeutic strategy (Liao et al, 2014;Chen et al, 2018;Srivastava et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies indicate that angiogenesis is dysregulated in various pathological processes, leading to various diseases, including cancer, cardiovascular disease, inflammation, and obesity (Carmeliet and Jain, 2000;Carmeliet, 2003;Srivastava et al, 2018). It has been established that the abnormal formation of blood vessels is effective as a treatment for patients with cancer, chronic liver disease, cardiovascular disease or other diseases; therefore, using anti-angiogenic agents as inhibitors has become a major therapeutic strategy (Liao et al, 2014;Chen et al, 2018;Srivastava et al, 2018). Currently, several angiogenesis inhibitors that specifically target VEGF, VEGFR, or other specific genes that are involved in angiogenesis can prolong life expectancy in patients with advanced colon cancer and are now being investigated in clinical trials alone or in combination with conventional therapeutic approaches of both cancer and retinal disease (Hurwitz et al, 2004;Avery et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Angiogenesis plays a key role in a variety of pathological processes, including cancer, cardiovascular disease, inflammation, and obesity (Carmeliet and Jain, 2000;Carmeliet, 2003;Carmeliet, 2005;Srivastava et al, 2018). It is a multi-step process that relies on endothelial cell proliferation, migration to surrounding tissues and differentiation into new capillaries.…”

Section: Introductionmentioning

confidence: 99%

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A Bromodomain-Containing Protein 4 (BRD4) Inhibitor Suppresses Angiogenesis by Regulating AP-1 Expression

Zhou

Liu

et al. 2020

Front. Pharmacol.

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Angiogenesis dysregulation contributes to inflammation, infections, immune disorders, and carcinogenesis. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader that recognizes histone proteins and acts as a transcriptional regulator to trigger tumor growth and the inflammatory response. The pan-bromodomain and extra-terminal domain (BET) inhibitor, (+)-JQ1 (1), was reported to inhibit angiogenesis. However, owing to the non-selectivity action of (+)-JQ1 towards all BET family members, the role of BRD4 and that of its bromodomains (BD1 and BD2) in angiogenesis remains elusive. Herein, we identified a potent BRD4 inhibitor, ZL0513 (7), which exhibited significant antiangiogenic effects in chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models. This inhibitor also directly suppressed the viability and tube formation of human umbilical vascular endothelial cells (HUVECs). Moreover, ZL0513 (7) was found to inhibit the phosphorylation of c-jun and c-fos, important members of activating protein-1 (AP-1) transcription factor complexes that enhance angiogenesis. The findings on this novel BRD4 inhibitor indicate that, in addition to being a powerful pharmacological tool for further elucidating the roles and functions of BRD4 and its BD domains in angiogenesis, it may serve as a potential therapeutic strategy for targeting the vasculature in various angiogenesis-dysregulated human diseases.

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Targeted therapy of chronic liver diseases with the inhibitors of angiogenesis

Cited by 9 publications

References 100 publications

Dandelion Polysaccharide Exerts Anti-Angiogenesis Effect on Hepatocellular Carcinoma by Regulating VEGF/HIF-1α Expression

Dandelion Polysaccharide Exerts Anti-Angiogenesis Effect on Hepatocellular Carcinoma by Regulating VEGF/HIF-1α Expression

Integrative omics analysis identifies macrophage migration inhibitory factor signaling pathways underlying human hepatic fibrogenesis and fibrosis

A Bromodomain-Containing Protein 4 (BRD4) Inhibitor Suppresses Angiogenesis by Regulating AP-1 Expression

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