Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Anastasia L Berg
,
Ashley Rowson-Hodel
ORCID logo ,
Michelle Hu
ORCID logo ,
Michael Keeling
,
Hao Wu
,
Kacey VanderVorst
,
Jenny J Chen
,
Jason Hatakeyama
,
Joseph Jilek
,
Courtney A Dreyer
,
Madelyn R Wheeler
,
Ai-Ming Yu
ORCID logo ,
Yuanpei Li
,
Kermit L Carraway
* ORCID logo
Version 1 : Received: 31 December 2021 / Approved: 6 January 2022 / Online: 6 January 2022 (11:51:28 CET)

A peer-reviewed article of this Preprint also exists.

Berg, A.L.; Rowson-Hodel, A.; Hu, M.; Keeling, M.; Wu, H.; VanderVorst, K.; Chen, J.J.; Hatakeyama, J.; Jilek, J.; Dreyer, C.A.; Wheeler, M.R.; Yu, A.-M.; Li, Y.; Carraway, K.L., III. The Cationic Amphiphilic Drug Hexamethylene Amiloride Eradicates Bulk Breast Cancer Cells and Therapy-Resistant Subpopulations with Similar Efficiencies. Cancers 2022, 14, 949. Berg, A.L.; Rowson-Hodel, A.; Hu, M.; Keeling, M.; Wu, H.; VanderVorst, K.; Chen, J.J.; Hatakeyama, J.; Jilek, J.; Dreyer, C.A.; Wheeler, M.R.; Yu, A.-M.; Li, Y.; Carraway, K.L., III. The Cationic Amphiphilic Drug Hexamethylene Amiloride Eradicates Bulk Breast Cancer Cells and Therapy-Resistant Subpopulations with Similar Efficiencies. Cancers 2022, 14, 949.

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. Mechanistically, HMA elicits the permeabilization of the limiting lysosomal membrane, a hallmark feature of the lysosome-dependent cell death pathway. 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.

Keywords

breast cancer; cancer stem cell; therapy resistance; cationic amphiphilic drug; lysosome-dependent cell death

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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