Cargando…

Mebendazole Treatment Disrupts the Transcriptional Activity of Hypoxia-Inducible Factors 1 and 2 in Breast Cancer Cells

SIMPLE SUMMARY: Mebendazole (MBZ), an orally available, FDA-approved anthelmintic, has demonstrated efficacy in reducing solid tumor growth and preventing or treating metastasis in multiple preclinical models of cancer. MBZ was also well tolerated in a recently completed phase I clinical trial. Give...

Descripción completa

Detalles Bibliográficos
Autores principales: Joe, Natalie S., Wang, Yuanfeng, Oza, Harsh H., Godet, Inês, Milki, Nubaira, Riggins, Gregory J., Gilkes, Daniele M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954103/
https://www.ncbi.nlm.nih.gov/pubmed/36831670
http://dx.doi.org/10.3390/cancers15041330
_version_ 1784894043763769344
author Joe, Natalie S.
Wang, Yuanfeng
Oza, Harsh H.
Godet, Inês
Milki, Nubaira
Riggins, Gregory J.
Gilkes, Daniele M.
author_facet Joe, Natalie S.
Wang, Yuanfeng
Oza, Harsh H.
Godet, Inês
Milki, Nubaira
Riggins, Gregory J.
Gilkes, Daniele M.
author_sort Joe, Natalie S.
collection PubMed
description SIMPLE SUMMARY: Mebendazole (MBZ), an orally available, FDA-approved anthelmintic, has demonstrated efficacy in reducing solid tumor growth and preventing or treating metastasis in multiple preclinical models of cancer. MBZ was also well tolerated in a recently completed phase I clinical trial. Given the success of MBZ, we aimed to identify additional mechanisms of action for MBZ beyond those that have been previously reported, which include tubulin disruption, inhibiting angiogenesis, promoting apoptosis, and maintaining cell stemness. We demonstrate that MBZ can inhibit the transcriptional activity of HIFs in breast cancer cell lines and in preclinical models of breast cancer by preventing the induction of HIF-1α, HIF-2α, and HIF-1β at the protein level under hypoxic conditions. We show that MBZ treatment has dual use as a chemotherapeutic agent as well as blocking the hypoxia-induced phenotype that promotes chemoresistance. ABSTRACT: Breast cancer is the most diagnosed cancer in women in the world. Mebendazole (MBZ) has been demonstrated to have preclinical efficacy across multiple cancers, including glioblastoma multiforme, medulloblastoma, colon, breast, pancreatic, and thyroid cancers. MBZ was also well tolerated in a recent phase I clinical trial of adults diagnosed with glioma. The mechanisms of action reported so far for MBZ include tubulin disruption, inhibiting angiogenesis, promoting apoptosis, and maintaining stemness. To elucidate additional mechanisms of action for mebendazole (MBZ), we performed RNA sequencing of three different breast cancer cell lines treated with either MBZ or vehicle control. We compared the top genes downregulated upon MBZ treatment with expression profiles of cells treated with over 15,000 perturbagens using the clue.io online analysis tool. In addition to tubulin inhibitors, the gene expression profile that correlated most with MBZ treatment matched the profile of cells treated with known hypoxia-inducible factor (HIF-1α and -2α) inhibitors. The HIF pathway is the main driver of the cellular response to hypoxia, which occurs in solid tumors. Preclinical data support using HIF inhibitors in combination with standard of care to treat solid tumors. Therefore, we tested the hypothesis that MBZ could inhibit the hypoxia response. Using RNA sequencing and HIF-reporter assays, we demonstrate that MBZ inhibits the transcriptional activity of HIFs in breast cancer cell lines and in mouse models of breast cancer by preventing the induction of HIF-1α, HIF-2α, and HIF-1β protein under hypoxia. Taken together, our results suggest that MBZ treatment has additional therapeutic efficacy in the setting of hypoxia and warrants further consideration as a cancer therapy.
format Online
Article
Text
id pubmed-9954103
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-99541032023-02-25 Mebendazole Treatment Disrupts the Transcriptional Activity of Hypoxia-Inducible Factors 1 and 2 in Breast Cancer Cells Joe, Natalie S. Wang, Yuanfeng Oza, Harsh H. Godet, Inês Milki, Nubaira Riggins, Gregory J. Gilkes, Daniele M. Cancers (Basel) Article SIMPLE SUMMARY: Mebendazole (MBZ), an orally available, FDA-approved anthelmintic, has demonstrated efficacy in reducing solid tumor growth and preventing or treating metastasis in multiple preclinical models of cancer. MBZ was also well tolerated in a recently completed phase I clinical trial. Given the success of MBZ, we aimed to identify additional mechanisms of action for MBZ beyond those that have been previously reported, which include tubulin disruption, inhibiting angiogenesis, promoting apoptosis, and maintaining cell stemness. We demonstrate that MBZ can inhibit the transcriptional activity of HIFs in breast cancer cell lines and in preclinical models of breast cancer by preventing the induction of HIF-1α, HIF-2α, and HIF-1β at the protein level under hypoxic conditions. We show that MBZ treatment has dual use as a chemotherapeutic agent as well as blocking the hypoxia-induced phenotype that promotes chemoresistance. ABSTRACT: Breast cancer is the most diagnosed cancer in women in the world. Mebendazole (MBZ) has been demonstrated to have preclinical efficacy across multiple cancers, including glioblastoma multiforme, medulloblastoma, colon, breast, pancreatic, and thyroid cancers. MBZ was also well tolerated in a recent phase I clinical trial of adults diagnosed with glioma. The mechanisms of action reported so far for MBZ include tubulin disruption, inhibiting angiogenesis, promoting apoptosis, and maintaining stemness. To elucidate additional mechanisms of action for mebendazole (MBZ), we performed RNA sequencing of three different breast cancer cell lines treated with either MBZ or vehicle control. We compared the top genes downregulated upon MBZ treatment with expression profiles of cells treated with over 15,000 perturbagens using the clue.io online analysis tool. In addition to tubulin inhibitors, the gene expression profile that correlated most with MBZ treatment matched the profile of cells treated with known hypoxia-inducible factor (HIF-1α and -2α) inhibitors. The HIF pathway is the main driver of the cellular response to hypoxia, which occurs in solid tumors. Preclinical data support using HIF inhibitors in combination with standard of care to treat solid tumors. Therefore, we tested the hypothesis that MBZ could inhibit the hypoxia response. Using RNA sequencing and HIF-reporter assays, we demonstrate that MBZ inhibits the transcriptional activity of HIFs in breast cancer cell lines and in mouse models of breast cancer by preventing the induction of HIF-1α, HIF-2α, and HIF-1β protein under hypoxia. Taken together, our results suggest that MBZ treatment has additional therapeutic efficacy in the setting of hypoxia and warrants further consideration as a cancer therapy. MDPI 2023-02-20 /pmc/articles/PMC9954103/ /pubmed/36831670 http://dx.doi.org/10.3390/cancers15041330 Text en © 2023 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
Joe, Natalie S.
Wang, Yuanfeng
Oza, Harsh H.
Godet, Inês
Milki, Nubaira
Riggins, Gregory J.
Gilkes, Daniele M.
Mebendazole Treatment Disrupts the Transcriptional Activity of Hypoxia-Inducible Factors 1 and 2 in Breast Cancer Cells
title Mebendazole Treatment Disrupts the Transcriptional Activity of Hypoxia-Inducible Factors 1 and 2 in Breast Cancer Cells
title_full Mebendazole Treatment Disrupts the Transcriptional Activity of Hypoxia-Inducible Factors 1 and 2 in Breast Cancer Cells
title_fullStr Mebendazole Treatment Disrupts the Transcriptional Activity of Hypoxia-Inducible Factors 1 and 2 in Breast Cancer Cells
title_full_unstemmed Mebendazole Treatment Disrupts the Transcriptional Activity of Hypoxia-Inducible Factors 1 and 2 in Breast Cancer Cells
title_short Mebendazole Treatment Disrupts the Transcriptional Activity of Hypoxia-Inducible Factors 1 and 2 in Breast Cancer Cells
title_sort mebendazole treatment disrupts the transcriptional activity of hypoxia-inducible factors 1 and 2 in breast cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954103/
https://www.ncbi.nlm.nih.gov/pubmed/36831670
http://dx.doi.org/10.3390/cancers15041330
work_keys_str_mv AT joenatalies mebendazoletreatmentdisruptsthetranscriptionalactivityofhypoxiainduciblefactors1and2inbreastcancercells
AT wangyuanfeng mebendazoletreatmentdisruptsthetranscriptionalactivityofhypoxiainduciblefactors1and2inbreastcancercells
AT ozaharshh mebendazoletreatmentdisruptsthetranscriptionalactivityofhypoxiainduciblefactors1and2inbreastcancercells
AT godetines mebendazoletreatmentdisruptsthetranscriptionalactivityofhypoxiainduciblefactors1and2inbreastcancercells
AT milkinubaira mebendazoletreatmentdisruptsthetranscriptionalactivityofhypoxiainduciblefactors1and2inbreastcancercells
AT rigginsgregoryj mebendazoletreatmentdisruptsthetranscriptionalactivityofhypoxiainduciblefactors1and2inbreastcancercells
AT gilkesdanielem mebendazoletreatmentdisruptsthetranscriptionalactivityofhypoxiainduciblefactors1and2inbreastcancercells