Btissame El Hassouni, Marika Franczak, Mjriam Capula, Christian M Vonk, Valentina M Gomez, Ryszard T Smolenski, Carlotta Granchi, Godefridus J Peters, Filippo Minutolo, Elisa Giovannetti
{"title":"Lactate dehydrogenase A inhibition by small molecular entities: steps in the right direction.","authors":"Btissame El Hassouni, Marika Franczak, Mjriam Capula, Christian M Vonk, Valentina M Gomez, Ryszard T Smolenski, Carlotta Granchi, Godefridus J Peters, Filippo Minutolo, Elisa Giovannetti","doi":"10.18632/oncoscience.519","DOIUrl":null,"url":null,"abstract":"<p><p>Direct targeting of energy metabolism to defeat cancer is not a recent strategy. Although quite a few drugs use cellular metabolism for their antitumor effect, no direct inhibitors of energy metabolism have been approved by the FDA. Currently, several inhibitors of lactate dehydrogenase A (LDH-A), a key player in glycolysis, are in development. Earlier, we demonstrated the efficacy of <i>N</i>-hydroxyindole-based LDH-A inhibitors in different cancer types. In this study we describe the efficacy of NHI-Glc-2, which is designed to dual target cancer cells, by exploiting a simultaneous enhanced glucose uptake by overexpressed glucose transporter 1 (GLUT1) and by inhibition of LDH-A. NHI-Glc-2 inhibits LDH-A enzyme activity, PANC-1 cell growth and disrupts spheroid integrity, with an overall effect that is more pronounced when combined with gemcitabine.</p>","PeriodicalId":19508,"journal":{"name":"Oncoscience","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2020-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640902/pdf/","citationCount":"11","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Oncoscience","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.18632/oncoscience.519","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2020/9/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 11
Abstract
Direct targeting of energy metabolism to defeat cancer is not a recent strategy. Although quite a few drugs use cellular metabolism for their antitumor effect, no direct inhibitors of energy metabolism have been approved by the FDA. Currently, several inhibitors of lactate dehydrogenase A (LDH-A), a key player in glycolysis, are in development. Earlier, we demonstrated the efficacy of N-hydroxyindole-based LDH-A inhibitors in different cancer types. In this study we describe the efficacy of NHI-Glc-2, which is designed to dual target cancer cells, by exploiting a simultaneous enhanced glucose uptake by overexpressed glucose transporter 1 (GLUT1) and by inhibition of LDH-A. NHI-Glc-2 inhibits LDH-A enzyme activity, PANC-1 cell growth and disrupts spheroid integrity, with an overall effect that is more pronounced when combined with gemcitabine.
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