The Cationic Amphiphilic Drug Hexamethylene Amiloride Eradicates Bulk Breast Cancer Cells and Therapy-Resistant Subpopulations with Similar Efficiencies.
Anastasia L BergAshley Rowson-HodelMichelle HuMichael KeelingHao WuKacey VanderVorstJenny J ChenJason HatakeyamaJoseph JilekCourtney A DreyerMadelyn R WheelerAi-Ming YuYuanpei LiKermit L CarrawayPublished in: Cancers (2022)
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.
Keyphrases
- cancer stem cells
- cell cycle arrest
- breast cancer cells
- induced apoptosis
- stem cells
- endoplasmic reticulum stress
- cell death
- prostate cancer
- oxidative stress
- endothelial cells
- squamous cell carcinoma
- gene expression
- small cell lung cancer
- drug induced
- pi k akt
- type diabetes
- climate change
- white matter
- spinal cord injury
- induced pluripotent stem cells
- benign prostatic hyperplasia
- adipose tissue
- functional connectivity
- genetic diversity
- cell proliferation
- metabolic syndrome
- multiple sclerosis
- glycemic control