title: Functional inhibition of acid sphingomyelinase by Fluphenazine triggers hypoxia-specific tumor cell death.
abstract: Owing to lagging or insufficient neo-angiogenesis, hypoxia is a feature of most solid tumors. Hypoxic tumor regions contribute to resistance against antiproliferative chemotherapeutics, radiotherapy and immunotherapy. Targeting cells in hypoxic tumor areas is therefore an important strategy for cancer treatment. Most approaches for targeting hypoxic cells focus on the inhibition of hypoxia adaption pathways but only a limited number of compounds with the potential to specifically target hypoxic tumor regions have been identified. By using tumor spheroids in hypoxic conditions as screening system, we identified a set of compounds, including the phenothiazine antipsychotic Fluphenazine, as hits with novel mode of action. Fluphenazine functionally inhibits acid sphingomyelinase and causes cellular sphingomyelin accumulation, which induces cancer cell death specifically in hypoxic tumor spheroids. Moreover, we found that functional inhibition of acid sphingomyelinase leads to overactivation of hypoxia stress-response pathways and that hypoxia-specific cell death is mediated by the stress-responsive transcription factor ATF4. Taken together, the here presented data suggest a novel, yet unexplored mechanism in which induction of sphingolipid stress leads to the overactivation of hypoxia stress-response pathways and thereby promotes their pro-apoptotic tumor-suppressor functions to specifically kill cells in hypoxic tumor areas.
authors.affiliation: Drug Discovery, Bayer AG, Berlin 13353, Germany.|Department of Bioanalytics, Institute for Biotechnology, Technical University of Berlin, Berlin, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Klutzny
authors.affiliation: Drug Discovery, Bayer AG, Berlin 13353, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Lesche
authors.affiliation: Drug Discovery, Bayer AG, Berlin 13353, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Keck
authors.affiliation: Drug Discovery, Bayer AG, Berlin 13353, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kaulfuss
authors.affiliation: Drug Discovery, Bayer AG, Berlin 13353, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlicker
authors.affiliation: Drug Discovery, Bayer AG, Berlin 13353, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Christian
authors.affiliation: Drug Discovery, Bayer AG, Berlin 13353, Germany.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Sperl
authors.affiliation: Drug Discovery, Bayer AG, Berlin 13353, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Neuhaus
authors.affiliation: Drug Discovery, Bayer AG, Berlin 13353, Germany.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Mowat
authors.affiliation: Drug Discovery, Bayer AG, Berlin 13353, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Steckel
authors.affiliation: Drug Discovery, Bayer AG, Berlin 13353, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Riefke
authors.affiliation: Drug Discovery, Bayer AG, Berlin 13353, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Prechtl
authors.affiliation: Drug Discovery, Bayer AG, Berlin 13353, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Parczyk
authors.affiliation: Drug Discovery, Bayer AG, Berlin 13353, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Steigemann
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005476:Fluphenazine / Q000494:pharmacology*; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: C497109:ATF4 protein, human; D009363:Neoplasm Proteins; D051701:Activating Transcription Factor 4; D013108:Sphingomyelin Phosphodiesterase; D005476:Fluphenazine