A Small Molecule that Induces Intrinsic Pathway Apoptosis with Unparalleled Speed
Rahul Palchaudhuri,
Michael J. Lambrecht,
Rachel C. Botham,
Kathryn C. Partlow,
Tjakko J. van Ham,
Karson S. Putt,
Laurie T. Nguyen,
Seok-Ho Kim,
Randall T. Peterson,
Timothy M. Fan,
Paul J. Hergenrother
Affiliations
Rahul Palchaudhuri
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Michael J. Lambrecht
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Rachel C. Botham
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Kathryn C. Partlow
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Tjakko J. van Ham
Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Karson S. Putt
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Laurie T. Nguyen
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Seok-Ho Kim
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Randall T. Peterson
Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Timothy M. Fan
Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA
Paul J. Hergenrother
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
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.
