Hexamethylene amiloride engages a novel reactive oxygen species- and lysosome-dependent programmed necrotic mechanism to selectively target breast cancer cells

Highlights • Hexamethylene amiloride (HMA) selectively kills breast cancer cells relative to non-transformed cells. • HMA is cytotoxic to breast cancer cells irrespective of their proliferative state. • HMA cytotoxicity in breast cancer cells is independent of their molecular marker status (ER/PR, H...

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Bibliographic Details
Published in:Cancer letters 2016-05, Vol.375 (1), p.62-72
Main Authors: Rowson-Hodel, Ashley R, Berg, Anastasia L, Wald, Jessica H, Hatakeyama, Jason, VanderVorst, Kacey, Curiel, Daniel A, Leon, Leonardo J, Sweeney, Colleen, Carraway, Kermit L
Format: Article
Language:English
Subjects:
Adenosine triphosphatase
Amiloride - analogs & derivatives
Amiloride - pharmacology
Antibiotics
Antineoplastic Agents - pharmacology
Apoptosis
Autophagy
Breast cancer
Breast Neoplasms - drug therapy
Cancer therapeutics
Cell cycle
Cell Line, Tumor
Cell Survival
Cisplatin - pharmacology
Cytotoxicity
Doxorubicin - pharmacology
Drug Screening Assays, Antitumor
Female
Gangrene
Growth factors
Hematology, Oncology and Palliative Medicine
Humans
Kinases
Lysosomes - enzymology
Necrosis
Potassium
Reactive Oxygen Species
Taxoids - pharmacology
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Summary:Highlights • Hexamethylene amiloride (HMA) selectively kills breast cancer cells relative to non-transformed cells. • HMA is cytotoxic to breast cancer cells irrespective of their proliferative state. • HMA cytotoxicity in breast cancer cells is independent of their molecular marker status (ER/PR, HER2, triple negative). • HMA induces a novel form of programmed necrosis dependent upon the activation of lysosomal cathepsins and reactive oxygen species. • Taken together, our data supports HMA as a novel cancer therapeutic with the potential to deplete slowly-proliferating and/or apoptosis resistant cells that are often refractory to conventional chemotherapeutics.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2016.02.042