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WP1234—A Novel Anticancer Agent with Bifunctional Activity in a Glioblastoma Model

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis. Despite significant progress in drug development, the blood–brain barrier (BBB) continues to limit the use of novel chemotherapeutics. Thus, our attention has been focused on the design, s...

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Autores principales: Pająk, Beata, Siwiak-Niedbalska, Ewelina, Jaśkiewicz, Anna, Sołtyka, Maja, Domoradzki, Tomasz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9687458/
https://www.ncbi.nlm.nih.gov/pubmed/36359318
http://dx.doi.org/10.3390/biomedicines10112799
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author Pająk, Beata
Siwiak-Niedbalska, Ewelina
Jaśkiewicz, Anna
Sołtyka, Maja
Domoradzki, Tomasz
author_facet Pająk, Beata
Siwiak-Niedbalska, Ewelina
Jaśkiewicz, Anna
Sołtyka, Maja
Domoradzki, Tomasz
author_sort Pająk, Beata
collection PubMed
description Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis. Despite significant progress in drug development, the blood–brain barrier (BBB) continues to limit the use of novel chemotherapeutics. Thus, our attention has been focused on the design, synthesis, and testing of small-molecule anticancer agents that are able to penetrate the BBB. One such compound is the D-glucose analog, 2-deoxy-D-glucose (2-DG), which inhibits glycolysis and induces GBM cell death. 2-DG has already been tested in clinical trials but was not approved as a drug, in part due to inadequate pharmacokinetics. To improve the pharmacokinetic properties of 2-DG, a series of novel derivatives was synthesized. Herein, we report the biological effects of WP1234, a 2-ethylbutyric acid 3,6-diester of 2-DG that can potentially release 2-ethylbutyrate and 2-DG inside the cells when metabolized. Using biochemical assays and examining cell viability, proliferation, protein synthesis, and apoptosis induction, we assessed the cytotoxic potential of WP1234. WP1234 significantly reduced the viability of GBM cells in a dose- and time-dependent manner. The lactate and ATP synthesis assays confirmed the inhibition of glycolysis elicited by released 2-DG. Furthermore, an evaluation of histone deacetylases (HDAC) activity revealed that the 2-ethylbutyrate action resulted in HDAC inhibition. Overall, these results demonstrated that WP1234 is a bifunctional molecule with promising anticancer potential. Further experiments in animal models and toxicology studies are needed to evaluate the efficacy and safety of this new 2-DG derivative.
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spelling pubmed-96874582022-11-25 WP1234—A Novel Anticancer Agent with Bifunctional Activity in a Glioblastoma Model Pająk, Beata Siwiak-Niedbalska, Ewelina Jaśkiewicz, Anna Sołtyka, Maja Domoradzki, Tomasz Biomedicines Article Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis. Despite significant progress in drug development, the blood–brain barrier (BBB) continues to limit the use of novel chemotherapeutics. Thus, our attention has been focused on the design, synthesis, and testing of small-molecule anticancer agents that are able to penetrate the BBB. One such compound is the D-glucose analog, 2-deoxy-D-glucose (2-DG), which inhibits glycolysis and induces GBM cell death. 2-DG has already been tested in clinical trials but was not approved as a drug, in part due to inadequate pharmacokinetics. To improve the pharmacokinetic properties of 2-DG, a series of novel derivatives was synthesized. Herein, we report the biological effects of WP1234, a 2-ethylbutyric acid 3,6-diester of 2-DG that can potentially release 2-ethylbutyrate and 2-DG inside the cells when metabolized. Using biochemical assays and examining cell viability, proliferation, protein synthesis, and apoptosis induction, we assessed the cytotoxic potential of WP1234. WP1234 significantly reduced the viability of GBM cells in a dose- and time-dependent manner. The lactate and ATP synthesis assays confirmed the inhibition of glycolysis elicited by released 2-DG. Furthermore, an evaluation of histone deacetylases (HDAC) activity revealed that the 2-ethylbutyrate action resulted in HDAC inhibition. Overall, these results demonstrated that WP1234 is a bifunctional molecule with promising anticancer potential. Further experiments in animal models and toxicology studies are needed to evaluate the efficacy and safety of this new 2-DG derivative. MDPI 2022-11-03 /pmc/articles/PMC9687458/ /pubmed/36359318 http://dx.doi.org/10.3390/biomedicines10112799 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pająk, Beata
Siwiak-Niedbalska, Ewelina
Jaśkiewicz, Anna
Sołtyka, Maja
Domoradzki, Tomasz
WP1234—A Novel Anticancer Agent with Bifunctional Activity in a Glioblastoma Model
title WP1234—A Novel Anticancer Agent with Bifunctional Activity in a Glioblastoma Model
title_full WP1234—A Novel Anticancer Agent with Bifunctional Activity in a Glioblastoma Model
title_fullStr WP1234—A Novel Anticancer Agent with Bifunctional Activity in a Glioblastoma Model
title_full_unstemmed WP1234—A Novel Anticancer Agent with Bifunctional Activity in a Glioblastoma Model
title_short WP1234—A Novel Anticancer Agent with Bifunctional Activity in a Glioblastoma Model
title_sort wp1234—a novel anticancer agent with bifunctional activity in a glioblastoma model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9687458/
https://www.ncbi.nlm.nih.gov/pubmed/36359318
http://dx.doi.org/10.3390/biomedicines10112799
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