scholarly journals Microenvironment and Radiation Therapy

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Michio Yoshimura ◽  
Satoshi Itasaka ◽  
Hiroshi Harada ◽  
Masahiro Hiraoka
Keyword(s):  
Radiation Therapy ◽  
Tumor Microenvironment ◽  
Antiangiogenic Therapy ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Tumor Oxygenation ◽  
Therapeutic Effects ◽  
Antitumor Effects ◽  
Hypoxia Inducible Factor 1 ◽  
Effects Of Radiation

Dependency on tumor oxygenation is one of the major features of radiation therapy and this has led many radiation biologists and oncologists to focus on tumor hypoxia. The first approach to overcome tumor hypoxia was to improve tumor oxygenation by increasing oxygen delivery and a subsequent approach was the use of radiosensitizers in combination with radiation therapy. Clinical use of some of these approaches was promising, but they are not widely used due to several limitations. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that is activated by hypoxia and induces the expression of various genes related to the adaptation of cellular metabolism to hypoxia, invasion and metastasis of cancer cells and angiogenesis, and so forth. HIF-1 is a potent target to enhance the therapeutic effects of radiation therapy. Another approach is antiangiogenic therapy. The combination with radiation therapy is promising, but several factors including surrogate markers, timing and duration, and so forth have to be optimized before introducing it into clinics. In this review, we examined how the tumor microenvironment influences the effects of radiation and how we can enhance the antitumor effects of radiation therapy by modifying the tumor microenvironment.

TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Cancer Progression ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Human Lung Cancer ◽  
Regulatory Subunit ◽  
Patients With Cancer ◽  
Hypoxia Inducible Factor 1 ◽  
Chemically Induced ◽  
Induced Tumors ◽  
Patient Prognosis

Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activationare associated with cancer progression. Here, we demonstrate thatthe transcription factor TAp73 opposes HIF-1 activity through anontranscriptional mechanism, thus affecting tumor angiogenesis.TAp73-deficient mice have an increased incidence of spontaneousand chemically induced tumors that also display enhanced vascularization.Mechanistically, TAp73 interacts with the regulatory subunit(α) of HIF-1 and recruits mouse double minute 2 homolog intothe protein complex, thus promoting HIF-1α polyubiquitination andconsequent proteasomal degradation in an oxygen-independentmanner. In human lung cancer datasets, TAp73 strongly predictsgood patient prognosis, and its expression is associated with lowHIF-1 activation and angiogenesis. Our findings, supported by invivo and clinical evidence, demonstrate a mechanism for oxygenindependentHIF-1 regulation, which has important implicationsfor individualizing therapies in patients with cancer.

Anticancer Activity of Natural Flavonoids: Inhibition of HIF-1α Signaling Pathway

2020 ◽  
Vol 23 (26) ◽  
pp. 2945-2959 ◽  
Author(s):  
Xiangping Deng ◽  
Yijiao Peng ◽  
Jingduo Zhao ◽  
Xiaoyong Lei ◽  
Xing Zheng ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Secondary Metabolites ◽  
Anticancer Agents ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Pharmacological Activities ◽  
Hypoxia Inducible Factor 1 ◽  
The Past ◽  
Low Toxicity ◽  
Tumor Blood Vessels

Rapid tumor growth is dependent on the capability of tumor blood vessels and glycolysis to provide oxygen and nutrients. Tumor hypoxia is a common characteristic of many solid tumors, and it essentially happens when the growth of the tumor exceeds the concomitant angiogenesis. Hypoxia-inducible factor 1 (HIF-1) as the critical transcription factor in hypoxia regulation is activated to adapt to this hypoxia situation. Flavonoids, widely distributed in plants, comprise many polyphenolic secondary metabolites, possessing broadspectrum pharmacological activities, including their potentiality as anticancer agents. Due to their low toxicity, intense efforts have been made for investigating natural flavonoids and their derivatives that can be used as HIF-1α inhibitors for cancer therapy during the past few decades. In this review, we sum up the findings concerning the inhibition of HIF-1α by natural flavonoids in the last few years and propose the idea of designing tumor vascular and glycolytic multi-target inhibitors with HIF-1α as one of the targets.

scholarly journals Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

Metabolites ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 412 ◽  
Author(s):  
Andrea Angeli ◽  
Fabrizio Carta ◽  
Alessio Nocentini ◽  
Jean-Yves Winum ◽  
Raivis Zalubovskis ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Carbonic Anhydrase ◽  
Drug Targets ◽  
Ph Regulation ◽  
Hypoxia Inducible Factor ◽  
Lead Compounds ◽  
Hypoxia Inducible Factor 1 ◽  
Ca Ix ◽  
Activation Of Transcription ◽  
Hif Pathway

The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence the outcome of anticancer therapies. The biochemical rationale behind many of these phenomena resides in the activation of transcription factors such as hypoxia-inducible factor 1 and 2 (HIF-1/2). In turn, the HIF pathway activates a number of genes including those involved in glucose metabolism, angiogenesis, and pH regulation. Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX and XII, actively participate in these processes and were validated as antitumor/antimetastatic drug targets. Here, we review the field of CA inhibitors (CAIs), which selectively inhibit the cancer-associated CA isoforms. Particular focus was on the identification of lead compounds and various inhibitor classes, and the measurement of CA inhibitory on-/off-target effects. In addition, the preclinical data that resulted in the identification of SLC-0111, a sulfonamide in Phase Ib/II clinical trials for the treatment of hypoxic, advanced solid tumors, are detailed.

scholarly journals Albendazole regulates radiosensitivity of human pancreatic cancer cells by inhibiting HIF-1α and basic fibroblast growth factor

2020 ◽  
Author(s):  
Haifeng Chen ◽  
Xiaochong Zhou ◽  
Zhen Weng ◽  
Xing Wei ◽  
Chunfang Xu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factor ◽  
Tumor Microenvironment ◽  
Fibroblast Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Human Pancreatic Cancer ◽  
Fibroblast Growth ◽  
Hypoxia Inducible Factor 1 ◽  
Pancreatic Cancer Cells

Abstract Background Albendazole, a clinical antiparasitic drug, has been shown to have antitumor activity and supress expression of hypoxia-inducible factor 1-alpha. While hypoxia, the most prominent feature of tumor microenvironment, is associated with radiotherapy tolerance. Herein, we aimed to identify Albendazole as a candidates that improves tumor microenvironment and enhances the radiosensitivity of human pancreatic cancer cells. Methods MTT assay, clone formation and flow cytometry were performed to assess the effect of ABZ and radiation on PC cell line proliferation and apoptosis induction. In addition, the expression levels of hypoxia-inducible factor 1-alpha (HIF-1α) and basic fibroblast growth factor (bFGF) were assessed using western blotting. Finally, the effects of ABZ on tumor growth and radiosensitivity were examined using nude mice xenograft model. Results ABZ significantly improved hypoxia-induced radiation resistance in PC cell line PATU8988 and SW1990 as evidenced by decreased absorbance of MTT, reduced colony number, and increased apoptotic cell ratio. Furthermore, the in vivo results confirmed that ABZ suppressed tumor growth. On mechanisms, treatment with ABZ decreased HIF-1α and bFGF expression levels, which correlated with radioresistance in cells exposed to hypoxia in vitro and tumor to radiation in vivo. Conclusion Taken together, our datas show that HIF-1α and bFGF regulate radiation sensitivity in PC cells under hypoxic conditions. And ABZ enhances radiosensitivity of pancreatic cancer by suppression of HIF-1α and bFGF expression.

scholarly journals Induction of Vascular Endothelial Growth Factor by Hypoxia Is Modulated by a Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in Ha-ras-Transformed Cells Through a Hypoxia Inducible Factor-1 Transcriptional Element

Blood ◽  
1997 ◽  
Vol 90 (9) ◽  
pp. 3322-3331 ◽  
Author(s):  
Nathalie M. Mazure ◽  
Eunice Y. Chen ◽  
Keith R. Laderoute ◽  
Amato J. Giaccia
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tumor Microenvironment ◽  
Kinase Activity ◽  
Hypoxia Inducible Factor ◽  
Transformed Cells ◽  
Vascular Endothelial ◽  
Phosphatidylinositol 3 Kinase ◽  
Hypoxia Inducible Factor 1 ◽  
Endothelial Growth Factor

Abstract Tumor angiogenesis, the development of new blood vessels, is a highly regulated process that is controlled genetically by alterations in oncogene and tumor suppressor gene expression and physiologically by the tumor microenvironment. Previous studies indicate that the angiogenic switch in Ras-transformed cells may be physiologically promoted by the tumor microenvironment through the induction of the angiogenic mitogen, vascular endothelial growth factor (VEGF). In this report, we show Ras-transformed cells do not use the downstream effectors c-Raf-1 or mitogen activated protein kinases (MAPK) in signaling VEGF induction by hypoxia as overexpression of kinase-defective alleles of these genes does not inhibit VEGF induction under low oxygen conditions. In contrast to the c-Raf-1/MAP kinase pathway, hypoxia increases phosphatidylinositol 3-kinase (PI 3-kinase) activity in a Ras-dependent manner, and inhibition of PI 3-kinase activity genetically and pharmacologically results in inhibition of VEGF induction. We propose that hypoxia modulates VEGF induction in Ras-transformed cells through the activation of a stress inducible PI 3-kinase/Akt pathway and the hypoxia inducible factor-1 (HIF-1) transcriptional response element.

scholarly journals Hypoxia in Obesity and Diabetes: Potential Therapeutic Effects of Hyperoxia and Nitrate

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Reza Norouzirad ◽  
Pedro González-Muniesa ◽  
Asghar Ghasemi
Keyword(s):  
Diabetes Management ◽  
Hypoxia Inducible Factor ◽  
Antioxidant Properties ◽  
Therapeutic Effects ◽  
Beneficial Effects ◽  
Hypoxia Inducible Factor 1 ◽  
Obesity And Diabetes ◽  
Nitrate Therapy ◽  
Prevalence Of Obesity ◽  
Signaling Components

The prevalence of obesity and diabetes is increasing worldwide. Obesity and diabetes are associated with oxidative stress, inflammation, endothelial dysfunction, insulin resistance, and glucose intolerance. Obesity, a chronic hypoxic state that is associated with decreased nitric oxide (NO) bioavailability, is one of the main causes of type 2 diabetes. The hypoxia-inducible factor-1α(HIF-1α) is involved in the regulation of several genes of the metabolic pathways including proinflammatory adipokines, endothelial NO synthase (eNOS), and insulin signaling components. It seems that adipose tissue hypoxia and NO-dependent vascular and cellular dysfunctions are responsible for other consequences linked to obesity-related disorders. Although hyperoxia could reverse hypoxic-related disorders, it increases the production of reactive oxygen species (ROS) and decreases the production of NO. Nitrate can restore NO depletion and has antioxidant properties, and recent data support the beneficial effects of nitrate therapy in obesity and diabetes. Although it seems reasonable to combine hyperoxia and nitrate treatments for managing obesity/diabetes, the combined effects have not been investigated yet. This review discusses some aspects of tissue oxygenation and the potential effects of hyperoxia and nitrate interventions on obesity/diabetes management. It can be proposed that concomitant use of hyperoxia and nitrate is justified for managing obesity and diabetes.

scholarly journals IFN-γ Mediates the Antitumor Effects of Radiation Therapy in a Murine Colon Tumor

2013 ◽  
Vol 182 (6) ◽  
pp. 2345-2354 ◽  
Author(s):  
Scott A. Gerber ◽  
Abigail L. Sedlacek ◽  
Kyle R. Cron ◽  
Shawn P. Murphy ◽  
John G. Frelinger ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Colon Tumor ◽  
Antitumor Effects ◽  
Ifn Γ ◽  
Effects Of Radiation ◽  
Murine Colon
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