The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak.
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma resistant to conventional chemotherapy. The 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 patients with MCL by releasing Bak from Mcl-1 and Bcl-X(L) 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.
Pérez-Galán
Patricia
P
Hematopathology Unit, Department of Pathology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain.
Roué
Gaël
G
Villamor
Neus
N
Campo
Elias
E
Colomer
Dolors
D
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018716:Molecular Mimicry; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; C474007:Bax protein (53-86); D001897:Boronic Acids; D007211:Indoles; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; C498702:PMAIP1 protein, human; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D011758:Pyrroles; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D000069286:Bortezomib; C520962:obatoclax