Biology subjects

Kalderen, C.

Publications and source records attributed to Kalderen, C..

3 recordsLinked to original sources

bioRxiv2022

OGG1 inhibitor TH5487 alleviates allergic airway inflammation in mice

Allergic asthma is a complex disease characterized by dyspnea, coughing, chest tightness and airway remodeling, for which there is no cure and is symptomatically treated with inhaled {beta}2-agonist and/or corticosteroids. Molecular mechanisms underlying its complex pathogenesis are not fully understood. However, the 8-oxoguanine DNA glycosylase-1 (OGG1), a DNA repair protein may play a central role, as OGG1 deficiency decreases both innate and allergic inflammatory responses. In this study, administration of TH5487 to mice with OVA-induced allergic airway inflammation significantly decreased goblet cell hyperplasia and mucus production. TH5487 treatment also decreased levels of activated NF-{kappa}B and expression of proinflammatory cytokines resulting in significantly lower recruitment of eosinophils and other immune cells to the lungs. Gene expression profiling of asthma and allergy-related proteins after TH5487 treatment revealed down regulation of Arg1, Mcp1 and Ccl11, and upregulation of the negative regulator of TH2, Bcl6. In addition, the OVA-induced airway hyperresponsiveness was significantly reduced by TH5487 treatment. Taken together, the data presented in this study suggest a clinically relevant utilization of TH5487 for the treatment of allergic inflammation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/492235v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@2985cdorg.highwire.dtl.DTLVardef@f642corg.highwire.dtl.DTLVardef@79bb1aorg.highwire.dtl.DTLVardef@1eab483_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2021

Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis

Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues together with aberrant repair processes. Despite substantial advancement in our understanding of IPF progression, numerous questions remain concerning disease pathology. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to treat underlying causes of disease. The DNA repair enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) is upregulated following TGF-{beta} exposure in several fibrosis-associated cell types. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study, a novel small molecule OGG1 inhibitor, TH5487, decreased myofibroblast transition and associated pro-fibrotic markers in fibroblast cells. In addition, TH5487 decreased pro-inflammatory cytokine production, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis. Taken together, these data strongly suggest that TH5487 is a potent, specific, and clinically-relevant treatment for IPF.

pharmacology and toxicology↗

bioRxiv2019

MTH1 promotes mitotic progression to avoid oxidative DNA damage in cancer cells

BACKGROUNDWe developed MTH1 inhibitors (MTH1i) TH588 and TH1579 showing broad anti-cancer activity, while structurally distinct MTH1i fail to kill cancer cells. Here, we describe a new role of MTH1 in mitosis and the detailed mechanism of action of TH1579 (karonudib) and other structurally distinct MTH1i.\n\nMATERIALS AND METHODSCancer cell lines or zebrafish embryos were treated with MTH1i or siRNA targeting MTH1 and analysed primarily by live cell and immunofluorescence microscopy, survival assays, DNA fibre or COMET assays. MTH1 and tubulin interactions were analysed in vitro using co-immunoprecipitation and tubulin polymerisation assays.\n\nRESULTSHere, we describe a mitotic role for the MTH1 protein, which binds to tubulin, is required for microtubule polymerisation, correct spindle assembly, mitosis progression and suppression reactive oxygen species (ROS) generation in mitosis. Potent MTH1i display differential abilities to break the MTH1-tubulin interaction and cause mitotic arrest, demonstrating 8-oxodGTPase and mitotic function of MTH1 are mechanistically distinct. TH588 and TH1579 have more profound effect on mitotic arrest than other MTH1i explained by additional direct inhibition of tubulin polymerisation. MTH1i only inhibiting 8-oxodGTPase activity synergize with mitotic poisons.\n\nCONCLUSIONSEfficient MTH1 have a dual mechanism of action: inhibiting mitosis (to generate ROS) and promoting 8-oxodGTP incorporation into DNA during mitotic replication, dependent on ROS generation. Direct inhibition of tubulin polymerisation of TH588 and TH1579 increase their ability to arrest cells and generate ROS in mitosis. Furthermore, non-cytotoxic MTH1 can become effective and increase incorporation of oxidised nucleotides into DNA when combined with sub-therapeutic concentrations of mitotic inhibitors or challenged directly by 8-oxodGTP.

cancer biology↗