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  2. A Small Molecule that Induces Intrinsic Pathway Apoptosis with Unparalleled Speed

A Small Molecule that Induces Intrinsic Pathway Apoptosis with Unparalleled Speed

  • Cell Rep. 2015 Dec 1;13(9):2027-36. doi: 10.1016/j.celrep.2015.10.042.
Rahul Palchaudhuri 1 Michael J Lambrecht 1 Rachel C Botham 1 Kathryn C Partlow 1 Tjakko J van Ham 2 Karson S Putt 3 Laurie T Nguyen 3 Seok-Ho Kim 1 Randall T Peterson 2 Timothy M Fan 4 Paul J Hergenrother 5
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • 2 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.
  • 3 Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • 4 Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA.
  • 5 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Electronic address: hergenro@illinois.edu.
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.

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