Role of hypoxia-inducible factor-1α as a cancer therapy target

2006 ◽  
Vol 13 (Supplement_1) ◽  
pp. S61-S75 ◽  
Author(s):  
Shalini Patiar ◽  
Adrian L Harris
Keyword(s):  
Anticancer Agents ◽  
Ph Regulation ◽  
Hypoxia Inducible Factor ◽  
Genetic Alterations ◽  
Solid Tumours ◽  
Tumour Suppressor Genes ◽  
Hypoxia Inducible Factor 1 ◽  
And Migration ◽  
Patient Prognosis ◽  
Therapy Target

Hypoxia occurs in solid tumours due to a mismatch between tumour growth and angiogenesis. Hypoxia in solid tumours is associated with an aggressive phenotype and resistance to radiation therapy and chemotherapy leading to poor patient prognosis. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor, which is activated in response to intratumoural hypoxia and as a result of genetic alterations that activate oncogenes and inactivate tumour suppressor genes. It plays a key role in the adaptation of tumour cells to hypoxia by activating the transcription of genes, which regulate several biological processes including angiogenesis, cell proliferation and survival, glucose metabolism, pH regulation and migration. This makes HIF-1 an attractive target for the development of anticancer agents. The success of these agents depends on reliable methods to identify those patients most likely to benefit from HIF-1-targeted therapy. Several novel small molecule inhibitors of HIF-1 have been identified and are moving towards clinical trials, but none of these are specific for HIF-1. Further work is ongoing to identify more selective HIF-1 inhibitors.

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 PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+T cells

2012 ◽  
Vol 199 (6) ◽  
pp. i8-i8 ◽  
Author(s):  
David K. Finlay ◽  
Ella Rosenzweig ◽  
Linda V. Sinclair ◽  
Carmen Feijoo-Carnero ◽  
Jens L. Hukelmann ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
And Migration

scholarly journals An Overview of the Recent Development of Anticancer Agents Targeting the HIF-1 Transcription Factor

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2813
Author(s):  
Yukari Shirai ◽  
Christalle C. T. Chow ◽  
Gouki Kambe ◽  
Tatsuya Suwa ◽  
Minoru Kobayashi ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cancer Therapy ◽  
Characteristic Feature ◽  
Anticancer Agents ◽  
Adaptive Response ◽  
Hypoxia Inducible Factor ◽  
Therapy Resistance ◽  
Relevant Research ◽  
Malignant Phenotype ◽  
Hypoxia Inducible Factor 1

Hypoxia, a characteristic feature of solid tumors, is associated with the malignant phenotype and therapy resistance of cancers. Hypoxia-inducible factor 1 (HIF-1), which is responsible for the metazoan adaptive response to hypoxia, has been recognized as a rational target for cancer therapy due to its critical functions in hypoxic regions. In order to efficiently inhibit its activity, extensive efforts have been made to elucidate the molecular mechanism underlying the activation of HIF-1. Here, we provide an overview of relevant research, particularly on a series of HIF-1 activators identified so far and the development of anticancer drugs targeting them.

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