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The Cationic Amphiphilic Drug Hexamethylene Amiloride Eradicates Bulk Breast Cancer Cells and Therapy-Resistant Subpopulations with Similar Efficiencies

SIMPLE SUMMARY: A limitation to successful therapeutic outcomes for breast and other cancer patients is the ability of small subsets of tumor cells to resist the apoptotic cell death provoked by currently employed therapeutic agents. These therapy-resistant cancer stem cell populations can then seed...

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Autores principales: Berg, Anastasia L., Rowson-Hodel, Ashley, Hu, Michelle, Keeling, Michael, Wu, Hao, VanderVorst, Kacey, Chen, Jenny J., Hatakeyama, Jason, Jilek, Joseph, Dreyer, Courtney A., Wheeler, Madelyn R., Yu, Ai-Ming, Li, Yuanpei, Carraway, Kermit L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8869814/
https://www.ncbi.nlm.nih.gov/pubmed/35205696
http://dx.doi.org/10.3390/cancers14040949
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author Berg, Anastasia L.
Rowson-Hodel, Ashley
Hu, Michelle
Keeling, Michael
Wu, Hao
VanderVorst, Kacey
Chen, Jenny J.
Hatakeyama, Jason
Jilek, Joseph
Dreyer, Courtney A.
Wheeler, Madelyn R.
Yu, Ai-Ming
Li, Yuanpei
Carraway, Kermit L.
author_facet Berg, Anastasia L.
Rowson-Hodel, Ashley
Hu, Michelle
Keeling, Michael
Wu, Hao
VanderVorst, Kacey
Chen, Jenny J.
Hatakeyama, Jason
Jilek, Joseph
Dreyer, Courtney A.
Wheeler, Madelyn R.
Yu, Ai-Ming
Li, Yuanpei
Carraway, Kermit L.
author_sort Berg, Anastasia L.
collection PubMed
description SIMPLE SUMMARY: A limitation to successful therapeutic outcomes for breast and other cancer patients is the ability of small subsets of tumor cells to resist the apoptotic cell death provoked by currently employed therapeutic agents. These therapy-resistant cancer stem cell populations can then seed recurrent tumors and metastatic lesions, compromising the efficacy of the treatment regimen. The aim of our study was to assess the hypothesis that cationic amphiphilic drugs (CADs), which induce tumor cell death via the unrelated programmed necrotic mechanism, exhibit efficacy toward cancer stem cell populations that are resistant to currently employed therapeutics. We found that the therapy-resistant stem-like subpopulation of cells from a variety of breast cancer models are as sensitive to CADs as the bulk population. Our observations imply that the incorporation of cationic amphiphilic anticancer agents into existing therapeutic regimens could ultimately improve breast cancer patient outcomes by minimizing tumor recurrence and metastatic outgrowth. ABSTRACT: The resistance of cancer cell subpopulations, including cancer stem cell (CSC) populations, to apoptosis-inducing chemotherapeutic agents is a key barrier to improved outcomes for cancer patients. The cationic amphiphilic drug hexamethylene amiloride (HMA) has been previously demonstrated to efficiently kill bulk breast cancer cells independent of tumor subtype or species but acts poorly toward non-transformed cells derived from multiple tissues. Here, we demonstrate that HMA is similarly cytotoxic toward breast CSC-related subpopulations that are resistant to conventional chemotherapeutic agents, but poorly cytotoxic toward normal mammary stem cells. HMA inhibits the sphere-forming capacity of FACS-sorted human and mouse mammary CSC-related cells in vitro, specifically kills tumor but not normal mammary organoids ex vivo, and inhibits metastatic outgrowth in vivo, consistent with CSC suppression. Moreover, HMA inhibits viability and sphere formation by lung, colon, pancreatic, brain, liver, prostate, and bladder tumor cell lines, suggesting that its effects may be applicable to multiple malignancies. Our observations expose a key vulnerability intrinsic to cancer stem cells and point to novel strategies for the exploitation of cationic amphiphilic drugs in cancer treatment.
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spelling pubmed-88698142022-02-25 The Cationic Amphiphilic Drug Hexamethylene Amiloride Eradicates Bulk Breast Cancer Cells and Therapy-Resistant Subpopulations with Similar Efficiencies Berg, Anastasia L. Rowson-Hodel, Ashley Hu, Michelle Keeling, Michael Wu, Hao VanderVorst, Kacey Chen, Jenny J. Hatakeyama, Jason Jilek, Joseph Dreyer, Courtney A. Wheeler, Madelyn R. Yu, Ai-Ming Li, Yuanpei Carraway, Kermit L. Cancers (Basel) Article SIMPLE SUMMARY: A limitation to successful therapeutic outcomes for breast and other cancer patients is the ability of small subsets of tumor cells to resist the apoptotic cell death provoked by currently employed therapeutic agents. These therapy-resistant cancer stem cell populations can then seed recurrent tumors and metastatic lesions, compromising the efficacy of the treatment regimen. The aim of our study was to assess the hypothesis that cationic amphiphilic drugs (CADs), which induce tumor cell death via the unrelated programmed necrotic mechanism, exhibit efficacy toward cancer stem cell populations that are resistant to currently employed therapeutics. We found that the therapy-resistant stem-like subpopulation of cells from a variety of breast cancer models are as sensitive to CADs as the bulk population. Our observations imply that the incorporation of cationic amphiphilic anticancer agents into existing therapeutic regimens could ultimately improve breast cancer patient outcomes by minimizing tumor recurrence and metastatic outgrowth. ABSTRACT: The resistance of cancer cell subpopulations, including cancer stem cell (CSC) populations, to apoptosis-inducing chemotherapeutic agents is a key barrier to improved outcomes for cancer patients. The cationic amphiphilic drug hexamethylene amiloride (HMA) has been previously demonstrated to efficiently kill bulk breast cancer cells independent of tumor subtype or species but acts poorly toward non-transformed cells derived from multiple tissues. Here, we demonstrate that HMA is similarly cytotoxic toward breast CSC-related subpopulations that are resistant to conventional chemotherapeutic agents, but poorly cytotoxic toward normal mammary stem cells. HMA inhibits the sphere-forming capacity of FACS-sorted human and mouse mammary CSC-related cells in vitro, specifically kills tumor but not normal mammary organoids ex vivo, and inhibits metastatic outgrowth in vivo, consistent with CSC suppression. Moreover, HMA inhibits viability and sphere formation by lung, colon, pancreatic, brain, liver, prostate, and bladder tumor cell lines, suggesting that its effects may be applicable to multiple malignancies. Our observations expose a key vulnerability intrinsic to cancer stem cells and point to novel strategies for the exploitation of cationic amphiphilic drugs in cancer treatment. MDPI 2022-02-14 /pmc/articles/PMC8869814/ /pubmed/35205696 http://dx.doi.org/10.3390/cancers14040949 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
Berg, Anastasia L.
Rowson-Hodel, Ashley
Hu, Michelle
Keeling, Michael
Wu, Hao
VanderVorst, Kacey
Chen, Jenny J.
Hatakeyama, Jason
Jilek, Joseph
Dreyer, Courtney A.
Wheeler, Madelyn R.
Yu, Ai-Ming
Li, Yuanpei
Carraway, Kermit L.
The Cationic Amphiphilic Drug Hexamethylene Amiloride Eradicates Bulk Breast Cancer Cells and Therapy-Resistant Subpopulations with Similar Efficiencies
title The Cationic Amphiphilic Drug Hexamethylene Amiloride Eradicates Bulk Breast Cancer Cells and Therapy-Resistant Subpopulations with Similar Efficiencies
title_full The Cationic Amphiphilic Drug Hexamethylene Amiloride Eradicates Bulk Breast Cancer Cells and Therapy-Resistant Subpopulations with Similar Efficiencies
title_fullStr The Cationic Amphiphilic Drug Hexamethylene Amiloride Eradicates Bulk Breast Cancer Cells and Therapy-Resistant Subpopulations with Similar Efficiencies
title_full_unstemmed The Cationic Amphiphilic Drug Hexamethylene Amiloride Eradicates Bulk Breast Cancer Cells and Therapy-Resistant Subpopulations with Similar Efficiencies
title_short The Cationic Amphiphilic Drug Hexamethylene Amiloride Eradicates Bulk Breast Cancer Cells and Therapy-Resistant Subpopulations with Similar Efficiencies
title_sort cationic amphiphilic drug hexamethylene amiloride eradicates bulk breast cancer cells and therapy-resistant subpopulations with similar efficiencies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8869814/
https://www.ncbi.nlm.nih.gov/pubmed/35205696
http://dx.doi.org/10.3390/cancers14040949
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