Cargando…
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...
Autores principales: | , , , , |
---|---|
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 |
_version_ | 1784836010270523392 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9687458 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT pajakbeata wp1234anovelanticanceragentwithbifunctionalactivityinaglioblastomamodel AT siwiakniedbalskaewelina wp1234anovelanticanceragentwithbifunctionalactivityinaglioblastomamodel AT jaskiewiczanna wp1234anovelanticanceragentwithbifunctionalactivityinaglioblastomamodel AT sołtykamaja wp1234anovelanticanceragentwithbifunctionalactivityinaglioblastomamodel AT domoradzkitomasz wp1234anovelanticanceragentwithbifunctionalactivityinaglioblastomamodel |