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

Ashley R. Rowson-Hodel, Anastasia L. Berg, Jessica H. Wald, Jason Hatakeyama, Kacey VanderVorst, Daniel A. Curiel, Leonardo J. Leon, Colleen A Sweeney, Kermit L Carraway

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Anticancer chemotherapeutics often rely on induction of apoptosis in rapidly dividing cells. While these treatment strategies are generally effective in debulking the primary tumor, post-therapeutic recurrence and metastasis are pervasive concerns with potentially devastating consequences. We demonstrate that the amiloride derivative 5-(N,N-hexamethylene) amiloride (HMA) harbors cytotoxic properties particularly attractive for a novel class of therapeutic agent. HMA is potently and specifically cytotoxic toward breast cancer cells, with remarkable selectivity for transformed cells relative to non-transformed or primary cells. Nonetheless, HMA is similarly cytotoxic to breast cancer cells irrespective of their molecular profile, proliferative status, or species of origin, suggesting that it engages a cell death mechanism common to all breast tumor subtypes. We observed that HMA induces a novel form of caspase- and autophagy-independent programmed necrosis relying on the orchestration of mitochondrial and lysosomal pro-death mechanisms, where its cytotoxicity was attenuated with ROS-scavengers or lysosomal cathepsin inhibition. Overall, our findings suggest HMA may efficiently target the heterogeneous populations of cancer cells known to reside within a single breast tumor by induction of a ROS- and lysosome-mediated form of programmed necrosis.

Original languageEnglish (US)
Pages (from-to)62-72
Number of pages11
JournalCancer Letters
Volume375
Issue number1
DOIs
StatePublished - May 28 2016

Keywords

  • Apoptosis
  • Breast cancer
  • Cancer therapeutics
  • Cytotoxicity
  • Necrosis

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Hexamethylene amiloride engages a novel reactive oxygen species- and lysosome-dependent programmed necrotic mechanism to selectively target breast cancer cells'. Together they form a unique fingerprint.

Cite this