HIF-1 stabilization exerts anticancer effects in breast cancer cells in vitro and in vivo

Kachamakova‐Trojanowska, Neli; Podkalicka, Paulina; Bogacz, Tomasz; Barwacz, Szymon; Józkowicz, Alicja; Dulak, Józef; Łoboda, Agnieszka

doi:10.1016/j.bcp.2020.113922

Cited by 32 publications

(26 citation statements)

References 31 publications

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“…Among the enriched KEGG pathways, the HIF-1 signalling pathway is most closely related to TNBC [ 38 ]. An increase in HIF-1 expression is one of the main molecular characteristics of TNBC [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

The Shuganhuazheng Formula in Triple-Negative Breast Cancer: A Study Based on Network Pharmacology and In Vivo Experiments

Wang

Fei

Yang

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Breast cancer is the most common cancer in women. Among breast cancer subtypes, triple-negative breast cancer (TNBC) has the highest degree of malignancy and the worst prognosis. The Shuganhuazheng formula (SGHZF) is a traditional Chinese herbal formula for the treatment of TNBC, but the mechanism of SGHZF in the treatment of TNBC remains unclear. In this study, the therapeutic effect and mechanism of SGHZF against TNBC were preliminarily determined based on in vivo experimental verification and network pharmacology. In terms of therapeutic effects, the antitumour effect was verified by measuring and calculating tumour volume, and the expression of proto-oncogene c-Myc was verified by PCR. In terms of the mechanism, potential therapeutic targets were identified by overlapping the SGHZF-related and TNBC-related targets. After comprehensively analysing the results of the protein-protein interaction (PPI), gene ontology (GO) function, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, Akt and HIF-1α were selected for verification by using immunohistochemical and Western blot analyses. The results of the study indicated that SGHZF can inhibit breast tumour growth in mice and that the mechanism may be related to the inhibition of Akt and HIF-1α expression.

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Section: Discussionmentioning

confidence: 99%

The Shuganhuazheng Formula in Triple-Negative Breast Cancer: A Study Based on Network Pharmacology and In Vivo Experiments

Wang

Fei

Yang

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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“…In vitro, a dramatic reduction in cell viability was shown in comparison to control, PHD inhibitor alone, or gemcitabine alone. Although the authors reported an increase in VEGF, both in gene expression and protein release into the culture media, it resulted in no significant changes in angiogenesis, other than dramatic anticancer effects in vivo [151]. Conflicts of Interest: The authors declare that no relevant conflicts of interest exist.…”

Section: Roxadustatmentioning

confidence: 96%

“…-In vivo impaired tumor growth without altering angiogenesis in an MDA-MB-231 [151], but with enhanced normalization in LLC tumors [146] 1. Roxadustat (FG-4592) is a 2-OG analog and was developed as an inhibitor of HIF-PHDs by FibroGen, AstraZeneca, and Astellas Pharma [145].…”

Section: Roxadustatmentioning

confidence: 99%

Hif-Prolyl Hydroxylase Domain Proteins (Phds) in Cancer – Potential Targets for Anti-Tumor Therapy?

Gaete¹,

Rodríguez²,

Watts³

et al. 2020

Preprint

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Solid tumors are typically associated with unbridled proliferation of malignant cells, accompanied by an immature and dysfunctional tumor-associated vascular network. Consequent impairment in transport of nutrients and oxygen eventually leads to a hypoxic environment wherein cells must adapt to survive and overcome these stresses. Hypoxia inducible factors (HIFs) are central transcription factors in the hypoxia response and drive the expression of a vast number of survival genes in cancer cells and in cells in the tumor microenvironment. HIFs are tightly controlled by a class of oxygen sensors, the HIF-prolyl hydroxylase domain proteins (PHDs), which hydroxylate HIFs, thereby marking them for proteasomal degradation. Remarkable and intense research during the past decade has revealed that, contrary to expectations, PHDs are often overexpressed in many tumor types and that inhibition of PHDs can lead to decreased tumor growth, impaired metastasis and diminished tumor-associated immune-tolerance. Therefore, PHDs represent an attractive therapeutic target in cancer research. Multiple PHD inhibitors have been developed that have either been recently accepted in China as erythropoiesis stimulating agents (ESA) or are currently in phase III trials. We review here the function of HIFs and PHDs in cancer and related therapeutic opportunities.

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“…Pharmacological studies are also being performed in relation to prolyl hydroxylase domain (PHDs) inhibitors, responsible for the activation of hypoxia-inducible factors (HIFs), the family of transcriptional factors responding to subphysiological concentrations of oxygen [155][156][157]. HIFs activation results in the stimulation of the expression of hypoxia-sensitive genes that are significantly involved in the regulation of cellular metabolism from the level of proliferation or apoptosis [158].…”

Section: Combination Of Anti-angiogenic and Epigenetic Drugs-based Thmentioning

confidence: 99%

“…HIFs activation results in the stimulation of the expression of hypoxia-sensitive genes that are significantly involved in the regulation of cellular metabolism from the level of proliferation or apoptosis [158]. As among HIFs' target genes are erythropoietin, VEGF, and nitric oxide synthase (NOS), the HIF hydroxylases are an interesting target of anticancer therapy [156,157,159]. Currently, we are aware of four PHDs inhibitors in clinical use, mostly in phase II and III: Daprodustat (GSK1278863), Vadadustat, Molidustat, and Roxadustat (FG4592), however, they are tested for anemia (NCT03029247, NCT03140722, NCT03418168) and Roxadustat for chemotherapy-induced anemia (NCT04076943) [155].…”

Section: Combination Of Anti-angiogenic and Epigenetic Drugs-based Thmentioning

confidence: 99%

The Epigenetic Profile of Tumor Endothelial Cells. Effects of Combined Therapy with Antiangiogenic and Epigenetic Drugs on Cancer Progression

Ciesielski

Biesiekierska

Panthu

et al. 2020

IJMS

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Tumors require a constant supply of nutrients to grow which are provided through tumor blood vessels. To metastasize, tumors need a route to enter circulation, that route is also provided by tumor blood vessels. Thus, angiogenesis is necessary for both tumor progression and metastasis. Angiogenesis is tightly regulated by a balance of angiogenic and antiangiogenic factors. Angiogenic factors of the vascular endothelial growth factor (VEGF) family lead to the activation of endothelial cells, proliferation, and neovascularization. Significant VEGF-A upregulation is commonly observed in cancer cells, also due to hypoxic conditions, and activates endothelial cells (ECs) by paracrine signaling stimulating cell migration and proliferation, resulting in tumor-dependent angiogenesis. Conversely, antiangiogenic factors inhibit angiogenesis by suppressing ECs activation. One of the best-known anti-angiogenic factors is thrombospondin-1 (TSP-1). In pathological angiogenesis, the balance shifts towards the proangiogenic factors and an angiogenic switch that promotes tumor angiogenesis. Here, we review the current literature supporting the notion of the existence of two different endothelial lineages: normal endothelial cells (NECs), representing the physiological form of vascular endothelium, and tumor endothelial cells (TECs), which are strongly promoted by the tumor microenvironment and are biologically different from NECs. The angiogenic switch would be also important for the explanation of the differences between NECs and TECs, as angiogenic factors, cytokines and growth factors secreted into the tumor microenvironment may cause genetic instability. In this review, we focus on the epigenetic differences between the two endothelial lineages, which provide a possible window for pharmacological targeting of TECs.Int. J. Mol. Sci. 2020, 21, 2606 2 of 22 organ" spread over an area of approximately 7 m 2 that controls: (i) the flow of blood, (ii) organism nutrition by the passage of metabolites and gases exchange, (iii) immunity by circulating immune cells and antibodies, as well as (iv) trafficking of leukocytes [2][3][4]. Moreover, endothelial cells are involved in several physiological processes including (v) angiogenesis, (vi) blood coagulation and fibrinolysis, (vii) vasomotor and blood pressure regulation, and (viii) inflammatory reactions, which are conditioned by a multitude of synthesized and released hormonal and chemical mediators, including vascular endothelial growth factor (VEGF), nitric oxide (NO • ), or prostaglandin E2 [5][6][7].Dysfunction of the endothelium results in a number of disorders. In tumors, endothelial cells due to chronic stimulation by growth factors and hypoxia, change their phenotype into tumor endothelial cells (TECs), which results in abnormalities in tumor blood vessel morphology. TECs are fragile and leaky as compared to normal vessels, that in consequence alters blood flow. These abnormalities in the tumor endothelium contribute to tumor growth and metastasis [8,9]. Thus, a detailed under...

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HIF-1 stabilization exerts anticancer effects in breast cancer cells in vitro and in vivo

Cited by 32 publications

References 31 publications

The Shuganhuazheng Formula in Triple-Negative Breast Cancer: A Study Based on Network Pharmacology and In Vivo Experiments

The Shuganhuazheng Formula in Triple-Negative Breast Cancer: A Study Based on Network Pharmacology and In Vivo Experiments

Hif-Prolyl Hydroxylase Domain Proteins (Phds) in Cancer – Potential Targets for Anti-Tumor Therapy?

The Epigenetic Profile of Tumor Endothelial Cells. Effects of Combined Therapy with Antiangiogenic and Epigenetic Drugs on Cancer Progression

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