Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization

Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2009; 106(42):17910-5. DOI: 10.1073/pnas.0909353106
Source: PubMed


HIF-1 is a heterodimeric transcription factor that mediates adaptive responses to hypoxia and plays critical roles in cancer progression. Using a cell-based screening assay we have identified acriflavine as a drug that binds directly to HIF-1alpha and HIF-2alpha and inhibits HIF-1 dimerization and transcriptional activity. Pretreatment of mice bearing prostate cancer xenografts with acriflavine prevented tumor growth and treatment of mice bearing established tumors resulted in growth arrest. Acriflavine treatment inhibited intratumoral expression of angiogenic cytokines, mobilization of angiogenic cells into peripheral blood, and tumor vascularization. These results provide proof of principle that small molecules can inhibit dimerization of HIF-1 and have potent inhibitory effects on tumor growth and vascularization.

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    • "In vivo, digoxin prevents and reverses the development of chronic hypoxia-induced PH in mice (Abud et al., 2012). Acriflavine, which is the most potent inhibitor of HIF subunit dimerization (Lee et al., 2009), leads to reduced hypoxia-induced PH in rats (Abud et al., 2012). Finally, the HIF-PHD axis can be directly targeted by iron supplementation, since PHD activity is iron sensitive (Smith et al., 2008). "
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    ABSTRACT: Oxygen (O2 ) is essential for the viability and function of most metazoan organisms and thus is closely monitored at both the organismal and the cellular levels. However, alveoli often encounter decreased O2 levels (hypoxia), leading to activation of physiological or pathophysiological responses in the pulmonary arteries. Such changes are achieved by activation of transcription factors. The hypoxia-inducible factors (HIFs) are the most prominent hypoxia-regulated transcription factors in this regard. HIFs bind to hypoxia-response elements (HREs) in the promoter region of target genes, whose expression and translation allows the organism, amongst other factors, to cope with decreased environmental O2 partial pressure (pO2 ). However, prolonged HIF activation can contribute to major structural alterations, especially in the lung, resulting in the development of pulmonary hypertension (PH). PH is characterized by a rise in pulmonary arterial pressure associated with pulmonary arterial remodeling, concomitant with a reduced intravascular lumen area. Patients with PH develop right heart hypertrophy and eventually die from right heart failure. Thus, understanding the molecular mechanisms of HIF regulation in PH is critical for the identification of novel therapeutic strategies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    The Journal of Physiology 07/2015; DOI:10.1113/JP270689 · 5.04 Impact Factor
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    • "Despite the initial failure of topotecan monotherapy [28], the pre-clinical data of its combination with anti-angiogenic TKIs (such as pazopanib) look promising [29]. Small molecules, like Acriflavine that directly binds to HIF1a and HIF2a, can inhibit HIF1 dimerization with potent inhibitory effects on tumor growth and vascularization [30]. Despite the difficulties to directly inhibit HIF itself, several agents have been developed to indirectly down-regulate HIF, including mTOR inhibitors, HSP90 inhibitors and HDAC inhibitors [31]. "
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    ABSTRACT: Renal cell carcinoma (RCC) is a metabolic disease, being characterized by the dysregulation of metabolic pathways involved in oxygen sensing (VHL/HIF pathway alterations and the subsequent up-regulation of HIF-responsive genes such as VEGF, PDGF, EGF, and glucose transporters GLUT1 and GLUT4, which justify the RCC reliance on aerobic glycolysis), energy sensing (fumarate hydratase-deficient, succinate dehydrogenase-deficient RCC, mutations of HGF/MET pathway resulting in the metabolic Warburg shift marked by RCC increased dependence on aerobic glycolysis and the pentose phosphate shunt, augmented lipogenesis, and reduced AMPK and Krebs cycle activity) and/or nutrient sensing cascade (deregulation of AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR pathways). We analyzed the key metabolic abnormalities underlying RCC carcinogenesis, highlighting those altered pathways that may represent potential targets for the development of more effective therapeutic strategies. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Cancer Treatment Reviews 07/2015; 41(9). DOI:10.1016/j.ctrv.2015.07.002 · 7.59 Impact Factor
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    • "A large number of natural products have been shown to inhibit HIF by different mechanisms such as proteasomal degradation as in the case of curcumin [111], moracin O and P [112]; increased HIF degradation such as in the case of resveratrol [113] [114] and Sibiriquinone A [115]. HIF1α can be inhibited by preventing its dimerization to HIF1β as in the case of the antibacterial agent acriflavine [116], by inhibiting Fig. (3). Generation of ROS by endogenous or exogenous stimuli (red) and their major detoxifying mechanisms (green). "
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    ABSTRACT: Hypoxia and Inflammation are strictly interconnected with important consequences at clinical and therapeutic level. While cell and tissue damage due to acute hypoxia mostly leads to cell necrosis, in chronic hypoxia, cells that are located closer to vessels are able to survive adapting their phenotype through the expression of a number of genes, including proinflammatory receptors for alarmins. These receptors are activated by alarmins released by necrotic cells and generate signals for master transcription factors such as NFkB, AP1, etc. which control hundreds of genes for innate immunity and damage repair. Clinical consequences of chronic inflammatory reparative response activation include cell and tissue remodeling, damage in the primary site and, the systemic involvement of distant organs and tissues. Thus every time a tissue environment become stably hypoxic, inflammation can be activated followed by chronic damage and cell death or repair with vessel proliferation and fibrosis. This pathway can occur in cancer, myocardial infarction and stroke, diabetes, obesity, neurodegenerative diseases, chronic and autoimmune diseases and age-related diseases. Interestingly, proinflammatory gene expression can be observed earlier in hypoxic tissue cells and, in addition, in activated resident or recruited leukocytes. Herewith, the reciprocal relationships between hypoxia and inflammation will be shortly reviewed to underline the possible therapeutic targets to control hypoxia-related inflammation in a number of epidemiologically important human diseases and conditions.
    03/2015; 15(3). DOI:10.2174/1871530315666150316120112
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