Palchaudhuri, R., Lambrecht, M.J., Botham, R.C., Partlow, K.C., van Ham, T.J., Putt, K.S., Nguyen, L.T., Kim, S.H., Peterson, R.T., Fan, T.M., Hergenrother, P.J. (2015) A Small Molecule that Induces Intrinsic Pathway Apoptosis with Unparalleled Speed. Cell Reports. 13:2027-36.
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.