title: Hexamethylene amiloride engages a novel reactive oxygen species- and lysosome-dependent programmed necrotic mechanism to selectively target breast cancer cells.
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.
authors.affiliation: Department of Biochemistry and Molecular Medicine and University of California Davis Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA.
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Rowson-Hodel
authors.affiliation: Department of Biochemistry and Molecular Medicine and University of California Davis Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA.
authors.forename: Anastasia L
authors.initials: AL
authors.lastname: Berg
authors.affiliation: Department of Biochemistry and Molecular Medicine and University of California Davis Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA.
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Wald
authors.affiliation: Department of Biochemistry and Molecular Medicine and University of California Davis Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Hatakeyama
authors.affiliation: Department of Biochemistry and Molecular Medicine and University of California Davis Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA.
authors.forename: Kacey
authors.initials: K
authors.lastname: VanderVorst
authors.affiliation: Department of Biochemistry and Molecular Medicine and University of California Davis Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Curiel
authors.affiliation: Department of Biochemistry and Molecular Medicine and University of California Davis Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA.
authors.forename: Leonardo J
authors.initials: LJ
authors.lastname: Leon
authors.affiliation: Department of Biochemistry and Molecular Medicine and University of California Davis Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Sweeney
authors.affiliation: 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.
authors.forename: Kermit L
authors.initials: KL
authors.lastname: Carraway
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D000077143:Docetaxel; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D009336:Necrosis; D017382:Reactive Oxygen Species; D043823:Taxoids / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D043823:Taxoids; C057360:5-(N,N-hexamethylene)amiloride; D000077143:Docetaxel; D000584:Amiloride; D004317:Doxorubicin; D002945:Cisplatin
keywords: Apoptosis; Breast cancer; Cancer therapeutics; Cytotoxicity; Necrosis