Submitted July 13, 2006
Accepted January 9, 2007
The BH3-mimetic GX15-070 synergizes with Bortezomib in Mantle Cell Lymphoma by enhancing Noxa-mediated activation of Bak
Patricia Perez-Galan, Gael Roue, Neus Villamor, Elias Campo, and Dolors Colomer*
Hematopathology Unit, Dept of Pathology, Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain
* Corresponding author; email: dcolomer{at}clinic.ub.es.
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma resistant to conventional chemotherapy. Bcl-2 pathway is deregulated in these tumors and may represent an interesting target for new therapeutic strategies.The new small molecule pan-Bcl-2 inhibitor GX15-070 mimics BH3-only proteins by binding to multiple antiapoptotic Bcl-2 members. Here we show that GX15-070 induced apoptosis in vitro in MCL cell lines and primary cells from MCL patients, by releasing Bak from Mcl-1 and Bcl-XL, at short incubation times and low micromolar doses. GX15-070 was effective in cells bearing defective DNA damage sensor genes or cell cycle regulators, inducing Bax and Bak conformational changes, mitochondrial depolarization, phosphatidylserine exposure and caspase-3 activation. Furthermore, GX15-070 synergized with bortezomib, sensitizing MCL cells to low doses of this proteasome inhibitor, by neutralizing bortezomib-induced Mcl-1 accumulation and cooperating with Noxa to induce Bak displacement from this protein. These events led to an increased activation of the mitochondrial apoptotic pathway. Importantly, GX15-070 alone or in combination with bortezomib showed no significant cytotoxic effect in peripheral blood mononuclear cells from healthy donors. All these findings suggest that GX15-070 alone or in combination with bortezomib represents a new attractive therapeutic approach for MCL treatment.
