Activation of the Proapoptotic Bcl-2 Protein Bax by a Small Molecule Induces Tumor Cell Apoptosis

Abstract

The proapoptotic Bcl-2 protein Bax by itself is sufficient to initiate apoptosis in almost all apoptotic paradigms. Thus, compounds that can facilitate disruptive Bax insertion into mitochondrial membranes have potential as cancer therapeutics. In our study, we have identified small-molecule compounds predicted to associate with the Bax hydrophobic groove by a virtual-screen approach. Among these, one lead compound (compound 106) promotes Bax-dependent but not Bak-dependent apoptosis. Importantly, this compound alters Bax protein stability in vitro and promotes the insertion of Bax into mitochondria, leading to Bax-dependent permeabilization of the mitochondrial outer membrane. Furthermore, as a single agent, compound 106 inhibits the growth of transplanted tumors, probably by inducing apoptosis in tumors. Our study has revealed a compound that activates Bax and induces Bax-dependent apoptosis, which may lead to the development of new therapeutic agents for cancer.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00996-13.

ACKNOWLEDGMENTS

We are grateful to John Eaton for critical reading of the manuscript, to B. Vogelstein and K. Kinzler at Johns Hopkins University for Bax^+/− and Bax^−/− HCT116 cells, to S. Fesik and S. Rosenberg at Abbott Laboratories for providing ABT-737, and to W.-X. Zong for providing untransformed and transformed MEFs.

This work was supported by grants CA106599, CA175003, and RR018733 from the National Institutes of Health (to C.L.), by funding from the University of Louisville Clinical Translational Research Grant, the Kentucky Lung Cancer Research Program, and the James Graham Brown Cancer Center (to C.L.), and by NIH/NCRR 5P20RR018733 (to J.O.T.).

There is no actual, potential, or perceived conflict of interest to disclose.