Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10901347 | Cancer Letters | 2016 | 11 Pages |
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
HMADAPIRPMIDCFH-DAV-ATPaseERKmTORNACLC3PARPPKBmTORC1FBSDMEMuPARNHEEGFPI3KtBHPMLKLzVADfmk4′,6-diamidino-2-phenylindoleDMSOENaCDulbecco's modified Eagle's mediummTOR complex 1ROSAIFtert-Butyl hydrogen peroxideApoptosisCancer therapeuticsDimethyl sulfoxideRIPKlight chain 3Breast cancerfetal bovine serumCytotoxicityapoptosis-inducing factorepidermal growth factorphosphatidylinositol-3 kinaselactate dehydrogenaseLDHRoswell Park Memorial Institute mediumNecrosisN-acetyl cysteineMechanistic target of rapamycinSodium hydrogen exchangerprotein kinase BPropidium iodidepoly (ADP-ribose) polymeraseepithelial sodium channelextracellular regulated kinaseReactive oxygen speciesUrokinase receptor
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Authors
Ashley R. Rowson-Hodel, Anastasia L. Berg, Jessica H. Wald, Jason Hatakeyama, Kacey VanderVorst, Daniel A. Curiel, Leonardo J. Leon, Colleen Sweeney, Kermit L. III,