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Cancer Lett. 2016 May 28;375(1):62-72. doi: 10.1016/j.canlet.2016.02.042. Epub 2016 Mar 2.

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

Author information

1
Department of Biochemistry and Molecular Medicine and University of California Davis Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA.
2
Department of Biochemistry and Molecular Medicine and University of California Davis Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA. Electronic address: klcarraway@ucdavis.edu.

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.

KEYWORDS:

Apoptosis; Breast cancer; Cancer therapeutics; Cytotoxicity; Necrosis

PMID:
26944316
PMCID:
PMC5554595
DOI:
10.1016/j.canlet.2016.02.042
[Indexed for MEDLINE]
Free PMC Article

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