Selective Small Molecule Probes for the Hypoxia Inducible Factor (HIF) Prolyl Hydroxylases

Chowdhury, Rasheduzzaman; Candela-Lena, J I; Chan, Mun Chiang; Greenald, David; Yeoh, Kar Kheng; Tian, Ya-Min; McDonough, Michael A.; Tumber, Anthony; Rose, Nathan R.; Conejo‐García, Ana; Demetriades, Marina; Mathavan, Sinnakaruppan; Kawamura, Akane; Lee, Myung Kyu; Eeden, Freek van; Pugh, Christopher W.; Ratcliffe, Peter J.; Schofield, Christopher J.

doi:10.1021/cb400088q

Cited by 103 publications

(140 citation statements)

References 40 publications

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“…To study whether pharmacological inhibition of PHD2 copied key phenotypes of PHD2 haplodeficiency (more in particular, whether it impaired CAF activation by reducing TGF-b1 secretion by cancer cells), we used IOX2, a pharmacological prolyl-hydroxylase inhibitor with higher specificity for PHD2 (Chowdhury et al, 2013). Treatment of PyMT cancer cells with 50 mM IOX2 for 48 hr, a concentration that upregulated HIF1a and HIF2a levels ( Figure S7B), decreased TGF-b1 secretion ( Figure 7T).…”

Section: Possible Translational Implicationsmentioning

confidence: 99%

The Cancer Cell Oxygen Sensor PHD2 Promotes Metastasis via Activation of Cancer-Associated Fibroblasts

et al. 2015

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Several questions about the role of the oxygen sensor prolyl-hydroxylase 2 (PHD2) in cancer have not been addressed. First, the role of PHD2 in metastasis has not been studied in a spontaneous tumor model. Here, we show that global PHD2 haplodeficiency reduced metastasis without affecting tumor growth. Second, it is unknown whether PHD2 regulates cancer by affecting cancer-associated fibroblasts (CAFs). We show that PHD2 haplodeficiency reduced metastasis via two mechanisms: (1) by decreasing CAF activation, matrix production, and contraction by CAFs, an effect that surprisingly relied on PHD2 deletion in cancer cells, but not in CAFs; and (2) by improving tumor vessel normalization. Third, the effect of concomitant PHD2 inhibition in malignant and stromal cells (mimicking PHD2 inhibitor treatment) is unknown. We show that global PHD2 haplodeficiency, induced not only before but also after tumor onset, impaired metastasis. These findings warrant investigation of PHD2's therapeutic potential.

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Section: Possible Translational Implicationsmentioning

confidence: 99%

The Cancer Cell Oxygen Sensor PHD2 Promotes Metastasis via Activation of Cancer-Associated Fibroblasts

et al. 2015

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“…The heterodimer binds to specific DNA sequences and upregulates transcription of target genes (Semenza, 2013). Thus hypoxia is reflected by stabilisation of HIF α-subunits, which themselves can also be stabilised by chemical compounds such as dimethyloxalylglycine (DMOG) (Elvidge et al, 2006) and a glycine-linked dipeptidylquinolone derivative, IOX2 (Chowdhury et al, 2013). Both compounds block oxygen-dependent prolyl-hydroxylation, thus inhibiting degradation of HIF α-subunits and activating the HIF pathway.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia promotes production of neural crest cells in the embryonic head

et al. 2016

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Hypoxia is encountered in either pathological or physiological conditions, the latter of which is seen in amniote embryos prior to the commencement of a functional blood circulation. During the hypoxic stage, a large number of neural crest cells arise from the head neural tube by epithelial-to-mesenchymal transition (EMT). As EMTlike cancer dissemination can be promoted by hypoxia, we investigated whether hypoxia contributes to embryonic EMT. Using chick embryos, we show that the hypoxic cellular response, mediated by hypoxia-inducible factor (HIF)-1α, is required to produce a sufficient number of neural crest cells. Among the genes that are involved in neural crest cell development, some genes are more sensitive to hypoxia than others, demonstrating that the effect of hypoxia is gene specific. Once blood circulation becomes fully functional, the embryonic head no longer produces neural crest cells in vivo, despite the capability to do so in a hypoxia-mimicking condition in vitro, suggesting that the oxygen supply helps to stop emigration of neural crest cells in the head. These results highlight the importance of hypoxia in normal embryonic development.

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“…PHDs utilize α-ketoglutarate as a cosubstrate and contain Fe(II) in their active site, and they are inhibited by α-ketoglutarate analogs or by rather unspecific iron chelators and metal ions (Scholz and Taylor 2013). IOX2 represents a synthetic cell-permeable hydroxylase inhibitor with pronounced selectivity for PHD-2 (Chowdhury et al 2013;Murray et al 2010;Tian et al 2011). In NHEK and NHDF, we showed that IOX2 efficiently blocks the constitutive HIF-1α degradation under normoxic conditions.…”

Section: Discussionmentioning

confidence: 90%

Impairment of hypoxia-induced HIF-1α signaling in keratinocytes and fibroblasts by sulfur mustard is counteracted by a selective PHD-2 inhibitor

et al. 2015

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Skin exposure to sulfur mustard (SM) provokes long-term complications in wound healing. Similar to chronic wounds, SM-induced skin lesions are associated with low levels of oxygen in the wound tissue. Normally, skin cells respond to hypoxia by stabilization of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1α). HIF-1α modulates expression of genes including VEGFA, BNIP3, and MMP2 that control processes such as angiogenesis, growth, and extracellular proteolysis essential for proper wound healing. The results of our studies revealed that exposure of primary normal human epidermal keratinocytes (NHEK) and primary normal human dermal fibroblasts (NHDF) to SM significantly impaired hypoxia-induced HIF-1α stabilization and target gene expression in these cells. Addition of a selective inhibitor of the oxygen-sensitive prolyl hydroxylase domain-containing protein 2 (PHD-2), IOX2, fully recovered HIF-1α stability, nuclear translocation, and target gene expression in NHEK and NHDF. Moreover, functional studies using a scratch wound assay demonstrated that the application of IOX2 efficiently counteracted SM-mediated deficiencies in monolayer regeneration under hypoxic conditions in NHEK and NHDF. Our findings describe a pathomechanism by which SM negatively affects hypoxia-stimulated HIF-1α signaling in keratinocytes and fibroblasts and thus possibly contributes to delayed wound healing in SM-injured patients that could be treated with PHD-2 inhibitors.

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Selective Small Molecule Probes for the Hypoxia Inducible Factor (HIF) Prolyl Hydroxylases

Cited by 103 publications

References 40 publications

The Cancer Cell Oxygen Sensor PHD2 Promotes Metastasis via Activation of Cancer-Associated Fibroblasts

The Cancer Cell Oxygen Sensor PHD2 Promotes Metastasis via Activation of Cancer-Associated Fibroblasts

Hypoxia promotes production of neural crest cells in the embryonic head

Impairment of hypoxia-induced HIF-1α signaling in keratinocytes and fibroblasts by sulfur mustard is counteracted by a selective PHD-2 inhibitor

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