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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    • "Selective knockdown of PHDs enhances HIF-dependent gene expression in vitro [25]. PHDs lose their activity under hypoxic conditions, leading to accumulation and nuclear translocation of HIF-í µí»¼ and activation of HIF target genes by binding to HREs [26]. The first identified function of PHDs was to hydroxylate human HIF-1í µí»¼ hsubunits at Pro402 and Pro564 under normoxic conditions, resulting in their recognition, pVHL ubiquitylation, and degradation by 26S proteasomes. "
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    ABSTRACT: Oxygen homeostasis reflects the constant body requirement to generate energy. Hypoxia (0.1–1% O 2 ), physioxia or physoxia (∼1–13%), and normoxia (∼20%) are terms used to define oxygen concentration in the cellular environment. A decrease in oxygen (hypoxia) or excess oxygen (hyperoxia) could be deleterious for cellular adaptation and survival. Hypoxia can occur under both physiological (e.g., exercise, embryonic development, underwater diving, or high altitude) and pathological conditions (e.g., inflammation, solid tumor formation, lung disease, or myocardial infarction). Hypoxia plays a key role in the pathophysiology of heart disease, cancers, stroke, and other causes of mortality. Hypoxia inducible factor(s) (HIFs) are key oxygen sensors that mediate the ability of the cell to cope with decreased oxygen tension. These transcription factors regulate cellular adaptation to hypoxia and protect cells by responding acutely and inducing production of endogenous metabolites and proteins to promptly regulate metabolic pathways. Here, we review the role of the HIF pathway as a metabolic adaptation pathway and how this pathway plays a role in cell survival. We emphasize the roles of the HIF pathway in physiological adaptation, cell death, pH regulation, and adaptation during exercise.
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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.
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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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