title: A Small Molecule that Induces Intrinsic Pathway Apoptosis with Unparalleled Speed.
abstract: Apoptosis is generally believed to be a process that requires several hours, in contrast to non-programmed forms of cell death that can occur in minutes. Our findings challenge the time-consuming nature of apoptosis as we describe the discovery and characterization of a small molecule, named Raptinal, which initiates intrinsic pathway caspase-dependent apoptosis within minutes in multiple cell lines. Comparison to a mechanistically diverse panel of apoptotic stimuli reveals that Raptinal-induced apoptosis proceeds with unparalleled speed. The rapid phenotype enabled identification of the critical roles of mitochondrial voltage-dependent anion channel function, mitochondrial membrane potential/coupled respiration, and mitochondrial complex I, III, and IV function for apoptosis induction. Use of Raptinal in whole organisms demonstrates its utility for studying apoptosis in vivo for a variety of applications. Overall, rapid inducers of apoptosis are powerful tools that will be used in a variety of settings to generate further insight into the apoptotic machinery.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Palchaudhuri
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lambrecht
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Botham
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Partlow
authors.affiliation: Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Tjakko J
authors.initials: TJ
authors.lastname: van Ham
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Karson S
authors.initials: KS
authors.lastname: Putt
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Laurie T
authors.initials: LT
authors.lastname: Nguyen
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Seok-Ho
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Randall T
authors.initials: RT
authors.lastname: Peterson
authors.affiliation: Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Fan
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Electronic address: hergenro@illinois.edu.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hergenrother
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003185:Complement C8 / Q000172:deficiency / Q000235:genetics; D003517:Cyclopentanes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D004625:Embryo, Nonmammalian / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000172:deficiency / Q000235:genetics; D005449:Fluorenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D006207:Half-Life; D006801:Humans; D019169:Jurkat Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015027:Zebrafish
chemical_list: D003185:Complement C8; D003517:Cyclopentanes; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D005449:Fluorenes; D034741:RNA, Small Interfering; C000611311:raptinal; D053148:Caspase 3