Article

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

ABSTRACT

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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    • "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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