The antimycotic ciclopirox olamine induces HIF‐1α stability, VEGF expression, and angiogenesis

Linden, Tobias; Katschinski, Dörthe M.; Eckhardt, Katrin; Scheid, Annette; Pagel, Horst; Wenger, Roland H.

doi:10.1096/fj.02-0586fje

Cited by 94 publications

(89 citation statements)

References 56 publications

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“…It is most useful against tinea versicolor (Niewerth et al, 2003). Antimycotic ciclopirox olamine also acts as a bidentate iron chelator capable of stabilizing HIF-1α and then activating endogenous HIF-1 target genes, including VEGF to promote angiogenesis remodeling (Linden et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Expression profiling analysis of hypoxic pulmonary disease

Zhou

Wang²,

Song³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Exposure of humans to low levels of environmental oxygen results in alveolar hypoxia and normally causes chronic pulmonary hypertension and morphological alterations of precapillary pulmonary vessels. In this study, the microarray dataset GSE11341 was used to identify potential differentially expressed genes related with human lung microvascular endothelial cell hypoxia. In addition, gene ontology term enrichment analysis was performed to explore their underlying functions. In addition, we also investigated the small molecules by comparing with the Connectivity Map. We found that hypoxia samples of 3, 24, and 48 h relative to 0 h displayed 22, 21, and 29 differentially expressed genes, respectively. Among them, six genes (ADM, HMOX1, VEGFA, EGLN3, APOLD1, and ANGPTL4) were closely related to pulmonary microvascular endothelial cell hypoxia response. Three drugs (pindolol, sulfapyridine, and ciclopirox) were selected as candidates to treat hypoxia-related pulmonary diseases. In conclusion, our results provide some underlying drug targets for treatment of hypoxic pulmonary patients.

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Section: Discussionmentioning

confidence: 99%

Expression profiling analysis of hypoxic pulmonary disease

Zhou

Wang²,

Song³

et al. 2013

Genet. Mol. Res.

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“…However, none of the previously studied iron chelators (desferrioxamine, desferri-exochelin, ciclopirox olamine, 2,2′-dipyridyl, and dibenzoylmethane) that activate HIF-1 under normoxic conditions inhibit hypoxic activation of HIF-1. 19,[21][22][23] Compound 1 (ECG) appears to play dual opposing roles that differentially regulate HIF-1 activity, depending on the concentration of oxygen in the cellular environment. While screening small molecule natural products for HIF-1 inhibitors, we observed that certain green tea catechins activate HIF-1 under normoxic conditions in a T47D human breast tumor cell-based reporter assay.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Inducible Factor-1 Activation by (−)-Epicatechin Gallate: Potential Adverse Effects of Cancer Chemoprevention with High-Dose Green Tea Extracts

Zhou

Kim

et al. 2004

J. Nat. Prod.

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Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that induces oxygen-regulated genes in response to reduced oxygen conditions (hypoxia). Expression of the oxygen regulated HIF-1α subunit correlates positively with advanced disease stages and poor prognosis in cancer patients. Green tea catechins are believed to be responsible for the cancer chemopreventive activities of green tea. We found that (−)-epicatechin-3-gallate (ECG, 1), one of the major green tea catechins, strongly activates HIF-1 in T47D human breast carcinoma cells. Among the green tea catechins tested, 1 demonstrated the strongest HIF-1 inducing activity while (−)-epigallocatechin-3-gallate (EGCG, 2), was significantly less active. However, 2 is relatively unstable in the in vitro system studied. Compound 1 also increases the expression of HIF-1 target genes including GLUT-1, VEGF, and CDKN1A. In T47D cells, 1 induces nuclear HIF-1α protein without affecting HIF-1α mRNA. Both the induction of HIF-1α protein and activation of HIF-1 by 1 can be blocked by iron and ascorbate, indicating that 1 may activate HIF-1 through the chelation of iron. These results suggest that intended cancer chemoprevention with high-dose green tea extracts may be compromised, by the ability of tea catechins to promote tumor cell survival pathways associated with HIF-1 activation.Rapid tumor growth often outstrips the ability of blood vessels to supply oxygen and nutrients, leaving many regions inside solid tumors low in oxygen (hypoxia). In cancer patients, the extent of tumor hypoxia correlates positively with advanced disease stages, poor prognosis, and treatment resistance. 1 Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays a critical role in hypoxia activated gene expression. 2 In tumor cells, HIF-1 activates the transcription of genes involved in anaerobic metabolism, angiogenesis, survival, invasion/metastasis and treatment resistance, thus promoting cellular This study investigates the effects of green tea catechins and related compounds on HIF-1 activity in vitro. Among the compounds tested [1-4, (+)-catechin (5), and gallic acid (6)], only catechins that contain the 3-gallate moiety (1 and 2) activate HIF-1 in a T47D cellbased reporter assay. In addition, 1 inhibits HIF-1 activation under hypoxic conditions. Apart from one hydroxyl group, 1 and 2 are structurally identical. However, 2 is chemically less stable than 1. The focus of this study is the regulation of HIF-1 activity by ECG (1). The pathways and mechanisms involved in HIF-1 activation have been extensively studied. 1,2,9 In the presence of oxygen, the HIF-1α subunit is prolyl hydroxylated, recognized by an E3 ubiquitin ligase complex that contains the von Hippel-Lindau tumor suppressor protein (pVHL), polyubiquitylated, and degraded by the 26S proteosome. [15][16][17] The HIF-1α protein is also asparaginyl hydroxylated to prevent HIF-1 activation. 18 At reduced cellular oxygen levels, inhibition of HIF-1α protein prolyl hydroxylation and degradation leads to an ...

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“…It was shown that these sequences are necessary, but not sufficient for HIF-1 mediated transcription as surrounding nucleotides are also important. Several HIF-1-dependent reporter systems, that used the HREcontaining portions of promoters/enhancers or multimerized HIF-1 binding sites, were previously described (Forsythe et al, 1996;Shibata et al, 1998Shibata et al, , 2000Koshikawa et al, 2000;Post and Van Meir, 2001;Rapisarda et al, 2002;Su et al, 2002;Burroughs et al, 2003;Hanze et al, 2003;Linden et al, 2003). However it was noticed that a large portion of upstream region from HIF-1-responsive gene can be responsible for HIF-1-independent activation of a reporter gene expression (Burroughs et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Virus-based reporter systems for monitoring transcriptional activity of hypoxia-inducible factor 1

Razorenova

Ivanov

Budanov

et al. 2005

Gene

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Being key regulator of oxygen homeostasis hypoxia-inducible factor 1 (HIF-1) plays significant roles in cancer progression as well as in cardiovascular diseases. The modulation of HIF-1a activity in vivo may represent a valuable therapeutic approach to these disorders [Hofer, T., Desbaillets, I., Hopfl, G., Wenger, R.H., Gassmann, M., 2002. Characterization of HIF-1 alpha overexpressing HeLa cells and implications for gene therapy. Comp. Biochem. Physiol., Toxicol. Pharmacol. 133,[475][476][477][478][479][480][481]. In order to monitor HIF-1 transcriptional activity, we have developed HIF-1a-responsive reporter constructs, in which lacZ gene expression is driven by minimal Hsp70 gene promoter or minimal immediate early promoter of cytomegalovirus (CMV) and a combination of hypoxia response elements from regulatory regions of PGK1, ENO1 and LDHA genes. For the efficient delivery to a wide variety of cell types we chose retroviral and lentiviral vectors as carriers of the reporter cassette. We demonstrate that the obtained reporter system i) has a high inducibility in response to treatments leading to HIF-1a activation, ii) shows upregulation in response to HIF-1 activation and downregulation following inhibition of HIF-1a expression by small interfering RNA, iii) follows the dynamics of endogenous HIF-1 target gene expression. The retrovirus-and lentivirusbased reporters can be used for high-throughput screening of HIF-1a modulators and for the study of crosstalk between HIF-1 and different related signal transduction pathways. Potential applications for the reporters are discussed.

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The antimycotic ciclopirox olamine induces HIF‐1α stability, VEGF expression, and angiogenesis

Cited by 94 publications

References 56 publications

Expression profiling analysis of hypoxic pulmonary disease

Expression profiling analysis of hypoxic pulmonary disease

Hypoxia-Inducible Factor-1 Activation by (−)-Epicatechin Gallate: Potential Adverse Effects of Cancer Chemoprevention with High-Dose Green Tea Extracts

Virus-based reporter systems for monitoring transcriptional activity of hypoxia-inducible factor 1

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