Designing carbonic anhydrase inhibitors for the treatment of breast cancer

Supuran, Claudiu T.; Winum, Jean‐Yves

doi:10.1517/17460441.2015.1038235

Cited by 51 publications

(46 citation statements)

References 33 publications

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“…We also show for the first time evidence using patient-derived tumor cells in the presence of appropriate stromal components, CAFs, 3D spheroid size and proliferation are dramatically reduced upon combination treatment with APE1/Ref-1 inhibitor, APX3330 and CA9 inhibitor, SLC-0111 (Clinical Trial NCT02215850) (30, 31). Upon blockade of multiple hypoxia signaling pathways with APX3330 and SLC-0111, we observe a dramatic effect on 3D tumor spheroid growth even in the presence of the protective environment of the CAFs.…”

Section: Introductionmentioning

confidence: 71%

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

Logsdon

Grimard

Luo

et al. 2016

Molecular Cancer Therapeutics

133

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Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistance, including hypoxia, which creates a more aggressive phenotype with increased metastatic potential and impaired therapeutic efficacy. AP Endonuclease-1/Redox Effector Factor 1 (APE1/Ref-1) is a multi-functional protein possessing a DNA repair function in base excision repair and the ability to reduce oxidized transcription factors, enabling them to bind to their DNA target sequences. APE1/Ref-1 regulates several transcription factors involved in survival mechanisms, tumor growth, and hypoxia signaling. Here, we explore the mechanisms underlying PDAC cell responses to hypoxia and modulation of APE1/Ref-1 redox signaling activity, which regulates the transcriptional activation of hypoxia inducible factor 1 alpha (HIF1α). Carbonic anhydrase IX (CA9) is regulated by HIF1α and functions as part of the cellular response to hypoxia to regulate intracellular pH, thereby promoting cell survival. We hypothesized that modulating APE1/Ref-1 function will block activation of downstream transcription factors, STAT3 and HIF1α, interfering with hypoxia-induced gene expression. We demonstrate APE1/Ref-1 inhibition in patient-derived and established PDAC cells results in decreased HIF1α–mediated induction of CA9. Furthermore, an ex vivo 3D tumor co-culture model demonstrates dramatic enhancement of APE1/Ref-1-induced cell killing upon dual-targeting of APE1/Ref-1 and CA9. Both APE1/Ref-1 and CA9 are under clinical development, therefore these studies have the potential to direct novel PDAC therapeutic treatment.

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Section: Introductionmentioning

confidence: 71%

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

Logsdon

Grimard

Luo

et al. 2016

Molecular Cancer Therapeutics

133

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“…HCO À 3 + H + is slow at physiological pH and thus, in biological systems, the reaction is accelerated by enzymatic catalysts, called carbonic anhydrases (CAs, EC 4.2.1.1). The conversion of CO 2 to bicarbonate and protons is a physiologically relevant reaction in all life kingdoms 8,10,14,[16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

A new procedure for the cloning, expression and purification of the β-carbonic anhydrase from the pathogenic yeastMalassezia globosa, an anti-dandruff drug target

Prete

Luca

Vullo

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Malassezia yeasts are almost exclusively the single eukaryotic members of the fungal flora of the skin. Malassezia globosa and Malassezia restricta are found on the skin of practically all humans. Malassezia globosa is highly implicated in the pathogenesis of dandruff and its genome encodes for only one carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the b-class (MgCA). It has been indeed demonstrated that in many pathogenic microorganisms, CAs are essential for their life cycle and their inhibition can lead to growth impairment and defects. In the previous work, the recombinant MgCA was investigated for its inhibition profile with sulfonamides, which in models of dandruff infection were able to protect animals from the fungal infection, allowing us to propose this enzyme as a new antidandruff target. MgCA was cloned as GST-fusion protein, but the yield was rather low and the protein was often found in inclusion bodies. Here, we propose an alternative procedure consisting in cloning the recombinant MgCA as His-Tag fusion protein. This procedure resulted in a good method to express and purify the active recombinant MgCA, and the protein recovery was better with respect to that used for preparing MG-CA (b-CA cloned as GST-fusion protein).

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“…The metal ion from the enzyme active site is coordinated by three His residues in the α-, γ-,δ-and θ-classes, by one His, and two Cys residues in β-and ζ-CAs or by two His and one Gln residues in η-class with the fourth ligand being a water molecule/hydroxide ion acting as nucleophile in the catalytic cycle of the enzyme [9,12,17,25]. The α-, β-, δ-and, probably η-and θ-CAs use Zn(II) ions at the active site, γ-CAs are Fe(II) enzymes but they are active also with bound Zn(II) or Co(II) ions, whereas ζ-class uses Cd(II) or Zn(II) to perform the physiologic reaction catalysis [6,9,12,17,26,27]. The α-, β-, γ-and ζ-CAs have been crystallized, but not δ-, η-and θ-CAs.…”

Section: Carbonic Anhydrasesmentioning

confidence: 99%

Inhibition of Bacterial Carbonic Anhydrases as a Novel Approach to Escape Drug Resistance

Capasso

Supuran

2017

CTMC

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Background: Clinically used antibiotics act through one of these four mechanisms: cell wall biosynthesis inhibition, inhibition of protein biosynthesis, interference with DNA and RNA synthesis and the folate pathway. Objective:The metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) widespread in microorganisms and present as three genetically distinct families may be considered for the design of antiinfective agents with a different mechanism of action compared to the clinically used antibiotics. CAs are crucial for the life cycle of the pathogen, interfering with pH regulation and biosynthetic processes in which CO 2 or bicarbonate are substrates. CA inhibition was shown to lead to debilitation or growth defects of several pathogenic bacteria. Method:CAs catalyzes the interconversion between carbon dioxide to bicarbonate, leading to the formation of protons, and thus affecting pH homeostasis. Several classes of CA inhibitors (CAIs) are known to date, among which the metal complexing anions, the unsubstituted sulfonamides, the dithiocarbamates, etc., which bind to the Zn(II) ion of the enzyme either by substituting the non-protein zinc ligand or add to the metal coordination sphere.Results: Effective inhibitors for many bacterial CAs belonging to the α-, β-, and γ-CA classes were detected, some of which inhibited bacterial growth in vivo. Few of the inhibitors investigated so far were also selective for the bacterial over the human CA isoforms, which may pose problems for their wide clinical applications. Conclusion:Structure-based drug design campaigns might lead to the achievement of the desired selectivity/potency for preferentially inhibiting bacterial but not the host CAs.

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Designing carbonic anhydrase inhibitors for the treatment of breast cancer

Cited by 51 publications

References 33 publications

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

A new procedure for the cloning, expression and purification of the β-carbonic anhydrase from the pathogenic yeastMalassezia globosa, an anti-dandruff drug target

Inhibition of Bacterial Carbonic Anhydrases as a Novel Approach to Escape Drug Resistance

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