title: A novel mitochondriotoxic small molecule that selectively inhibits tumor cell growth.
abstract: Tumorigenesis results from events that impinge on a variety of collaborating metabolic pathways. To assess their role in this process, we utilized a cell-based assay to perform a high-throughput, chemical library screen. In so doing, we identified F16, a small molecule that selectively inhibits proliferation of mammary epithelial, neu-overexpressing cells, as well as a variety of mouse mammary tumor and human breast cancer cell lines. F16 belongs to a group of structurally similar molecules with a delocalized positive charge. The compound is accumulated in mitochondria of responsive cells, driven by the membrane potential, and it compromises their functional integrity. Mitochondrial hyperpolarization is a shared feature of many tumor cell lines, explaining the broad action spectrum of this novel delocalized lipophilic cation.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Fantin
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Berardi
authors.forename: Luca
authors.initials: L
authors.lastname: Scorrano
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Korsmeyer
authors.forename: Philip
authors.initials: P
authors.lastname: Leder
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002412:Cations / Q000494:pharmacology / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018734:Genes, erbB-2 / Q000235:genetics*; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007211:Indoles / Q000378:metabolism* / Q000494:pharmacology; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D008564:Membrane Potentials; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D011726:Pyridinium Compounds / Q000378:metabolism* / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D002412:Cations; D006131:Growth Inhibitors; D007211:Indoles; D011726:Pyridinium Compounds; D018719:Erb-b2 Receptor Tyrosine Kinases; C471842:4-(2-(indol-3-yl)vinyl)-1-methylpyridinium