Metabolic Profiling of the Novel Hypoxia-Inducible Factor 2<i>α</i> Inhibitor PT2385 In Vivo and In Vitro

Xie, Cen; Gao, Xiaoxia; Sun, Dongxue; Zhang, You-Bo; Krausz, Kristopher W.; Qin, Xuemei; Gonzalez, Frank J.

doi:10.1124/dmd.117.079723

Cited by 26 publications

(19 citation statements)

References 48 publications

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“…Accordingly, HIF-1α silencing in H/SB3 cells was ineffective on transcript levels of Myc, p53, and p21 ( Figure S8B). Such a SB-3-related and HIF-2α-dependent regulation of p53, p21, and c-Myc resulted in a shift of cell cycle towards S phase (increase in S phase ratio up to 96 h), then indicating that H/SB3 cells are more proliferative than control H/3.1 cells ( Figure 7C), with cells in G2/M phase increasing later on at 72 and 96 h. In addition, performing soft agar colony formation assay [9], the most stringent tests for malignant transformation in cells which measures the ability of cells to proliferate in semi-solid matrices, we demonstrated that the increase in colony formation and dimension of H/SB3 was prevented by using the HIF-2α specific inhibitor (PT-2385 10 µM [38,39], Figure 7D) that efficiently down-regulated in H/SB3 cells HIF-2α and c-myc protein levels ( Figure 7E,F). Moreover, HIF-2α target genes involved in tumor progression such as metalloproteinase 9 (MMP-9), C-X-C chemokine receptor type 4 (CXCR4, receptor of the chemokine SDF-1), and the more generic target gene erythropoietin (EPO) are up-regulated in H/SB3 cells and decrease by using HIF-2α specific siRNA ( Figure 7G).…”

Section: Serpinb3 Up-regulated Hif-α Subunits Are Biologically Activementioning

confidence: 83%

SerpinB3 Differently Up-Regulates Hypoxia Inducible Factors -1α and -2α in Hepatocellular Carcinoma: Mechanisms Revealing Novel Potential Therapeutic Targets

Cannito

Foglia

Villano

et al. 2019

Cancers

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Background: SerpinB3 (SB3) is a hypoxia and hypoxia-inducible factor (HIF)-2α-dependent cysteine-protease inhibitor up-regulated in hepatocellular carcinoma (HCC), released by cancer cells and able to stimulate proliferation and epithelial-to-mesenchymal-transition. Methods: In the study we employed transgenic and knock out SerpinB3 mice, liver cancer cell line, human HCC specimens, and mice receiving diethyl-nitrosamine (DEN) administration plus choline-deficient L-amino acid refined (CDAA) diet (DEN/CDAA protocol). Results: We provide detailed and mechanistic evidence that SB3 can act as a paracrine mediator able to affect the behavior of surrounding cells by differentially up-regulating, in normoxic conditions, HIF-1α and HIF-2α. SB3 acts by (i) up-regulating HIF-1α transcription, facilitating cell survival in a harsh microenvironment and promoting angiogenesis, (ii) increasing HIF-2α stabilization via direct/selective NEDDylation, promoting proliferation of liver cancer cells, and favoring HCC progression. Moreover (iii) the highest levels of NEDD8-E1 activating enzyme (NAE1) mRNA were detected in a subclass of HCC patients expressing the highest levels of HIF-2α transcripts; (iv) mice undergoing DEN/CDAA carcinogenic protocol showed a positive correlation between SB3 and HIF-2α transcripts with the highest levels of NAE1 mRNA detected in nodules expressing the highest levels of HIF-2α transcripts. Conclusions: These data outline either HIF-2α and NEDDylation as two novel putative therapeutic targets to interfere with the procarcinogenic role of SerpinB3 in the development of HCC.

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Section: Serpinb3 Up-regulated Hif-α Subunits Are Biologically Activementioning

confidence: 83%

SerpinB3 Differently Up-Regulates Hypoxia Inducible Factors -1α and -2α in Hepatocellular Carcinoma: Mechanisms Revealing Novel Potential Therapeutic Targets

Cannito

Foglia

Villano

et al. 2019

Cancers

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“…Metabolomics is a powerful tool for the comprehensive profiling of drug metabolites (Fang et al, 2012; Lv et al, 2017; Yang et al, 2017b) and identification of endogenous metabolic pathways associated with liver injury (Li et al, 2011; Liu et al, 2015a; Xie et al, 2018). By using this strategy, a series of hydroxylated, demethylated, hydroformylated and glucuronidated metabolites of pazopanib were found in this study.…”

Section: Discussionmentioning

confidence: 99%

A metabolomic perspective of pazopanib-induced acute hepatotoxicity in mice

Wang

Yang

Liang³

et al. 2018

Xenobiotica

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To elucidate the metabolism of pazopanib, a metabolomics approach was performed based on ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry. A total of 22 pazopanib metabolites were identified in vitro and in vivo. Among these metabolites, 17 were novel, including several cysteine adducts and aldehyde derivatives. By screening using recombinant CYPs, CYP3A4 and CYP1A2 were found to be the main forms involved in the pazopanib hydroxylation. Formation of a cysteine conjugate (M3), an aldehyde derivative (M15) and two N-oxide metabolites (M18 and M20) from pazopanib could induce the oxidative stress that may be responsible in part for pazopanib-induced hepatotoxicity. Morphological observation of the liver suggested that pazopanib (300 mg/kg) could cause liver injury. The aspartate transaminase and alanine aminotransferase in serum significantly increased after pazopanib (150, 300 mg/kg) treatment; this liver injury could be partially reversed by the broad-spectrum CYP inhibitor 1-aminobenzotriazole (ABT). Metabolomics analysis revealed that pazopanib could significantly change the levels of L-carnitine, proline and lysophosphatidylcholine 18:1 in liver. Additionally, drug metabolism-related gene expression analysis revealed that hepatic Cyp2d22 and Abcb1a (P-gp) mRNAs were significantly lowered by pazopanib treatment. In conclusion, this study provides a global view of pazopanib metabolism and clues to its influence on hepatic function.

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“…Although having low systemic bioavailability, these compounds effectively inhibited NEU3 in the intestine and reduced the severity of HFD-induced metabolic disorders 88 . PT2385 administration to mice shifted the metabolism of bile acids via hepatic cholesterol 7α-monooxygenase (CYP7A1), the key enzyme in bile acid biosynthesis 110 . Thus, this selective HIF2α antagonist shows great potential in the treatment of metabolic disease.…”

Section: Hif2α In Metabolic Diseasementioning

confidence: 99%

The role of hypoxia-inducible factors in metabolic diseases

2018

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Hypoxia-inducible factors (HIFs), a family of transcription factors activated by hypoxia, consist of three α-subunits (HIF1α, HIF2α and HIF3α) and one β-subunit (HIF1β), which serves as a heterodimerization partner of the HIFα subunits. HIFα subunits are stabilized from constitutive degradation by hypoxia largely through lowering the activity of the oxygen-dependent prolyl hydroxylases that hydroxylate HIFα, leading to their proteolysis. HIF1α and HIF2α are expressed in different tissues and regulate target genes involved in angiogenesis, cell proliferation and inflammation, and their expression is associated with different disease states. HIFs have been widely studied because of their involvement in cancer, and HIF2α-specific inhibitors are being investigated in clinical trials for the treatment of kidney cancer. Although cancer has been the major focus of research on HIF, evidence has emerged that this pathway has a major role in the control of metabolism and influences metabolic diseases such as obesity, type 2 diabetes mellitus and non-alcoholic fatty liver disease. Notably increased HIF1α and HIF2α signalling in adipose tissue and small intestine, respectively, promotes metabolic diseases in diet-induced disease models. Inhibition of HIF1α and HIF2α decreases the adverse diet-induced metabolic phenotypes, suggesting that they could be drug targets for the treatment of metabolic diseases.

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Metabolic Profiling of the Novel Hypoxia-Inducible Factor 2α Inhibitor PT2385 In Vivo and In Vitro

Cited by 26 publications

References 48 publications

SerpinB3 Differently Up-Regulates Hypoxia Inducible Factors -1α and -2α in Hepatocellular Carcinoma: Mechanisms Revealing Novel Potential Therapeutic Targets

SerpinB3 Differently Up-Regulates Hypoxia Inducible Factors -1α and -2α in Hepatocellular Carcinoma: Mechanisms Revealing Novel Potential Therapeutic Targets

A metabolomic perspective of pazopanib-induced acute hepatotoxicity in mice

The role of hypoxia-inducible factors in metabolic diseases

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