title: Distinct cellular and therapeutic effects of obatoclax in rituximab-sensitive and -resistant lymphomas.
abstract: Bcl-2 proteins represent a rheostat that controls cellular viability. Obatoclax, a BH3-mimetic, has been designed to specifically target and counteract anti-apoptotic Bcl-2 proteins. We evaluated the biological effects of obatoclax on the anti-tumour activity of rituximab and chemotherapy agents. Obatoclax induced cell death of rituximab/chemotherapy-sensitive (RSCL), -resistant cell lines (RRCL) and primary tumour-cells derived from patients with B-cell lymphomas (N=39). Obatoclax also enhanced the activity of rituximab and had synergistic activity when combined with chemotherapy agents. The ability of Obatoclax to induce PARP cleavage varied between patient samples and was not observed in some RRCL. Inhibition of caspase activity did not affect obatoclax activity, suggesting the existence of caspase-independent death pathways. Autophagy was detected by LC3 conversion and/or electron microscopy in RRCL and in patient-derived tumour cells. Moreover, obatoclax activity was inhibited by Beclin-1 knockdown. In summary, obatoclax is an active Bcl-2 inhibitor that potentiates the activity of chemotherapy agents and, to a lesser degree, rituximab. Defining the molecular events triggered by obatoclax is necessary to further its clinical development and identify potential biomarkers that are predictive of response.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute,Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Brem
authors.forename: Karen
authors.initials: K
authors.lastname: Thudium
authors.forename: Sapna
authors.initials: S
authors.lastname: Khubchandani
authors.forename: Ping-Chiao
authors.initials: PC
authors.lastname: Tsai
authors.forename: Scott H
authors.initials: SH
authors.lastname: Olejniczak
authors.forename: Seema
authors.initials: S
authors.lastname: Bhat
authors.forename: Wasif
authors.initials: W
authors.lastname: Riaz
authors.forename: Jenny
authors.initials: J
authors.lastname: Gu
authors.forename: Arshad
authors.initials: A
authors.lastname: Iqbal
authors.forename: Ryan
authors.initials: R
authors.lastname: Campagna
authors.forename: Joy
authors.initials: J
authors.lastname: Knight
authors.forename: Cory
authors.initials: C
authors.lastname: Mavis
authors.forename: Paul
authors.initials: P
authors.lastname: Hoskin
authors.forename: George
authors.initials: G
authors.lastname: Deeb
authors.forename: John F
authors.initials: JF
authors.lastname: Gibbs
authors.forename: Gerald
authors.initials: G
authors.lastname: Fetterly
authors.forename: Myron S
authors.initials: MS
authors.lastname: Czuczman
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Hernandez-Ilizaliturri
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001343:Autophagy / Q000187:drug effects; D020169:Caspases / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007211:Indoles; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000473:pathology*; D008224:Lymphoma, Follicular / Q000378:metabolism / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D000069283:Rituximab; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000032:analysis; D051028:bcl-2-Associated X Protein / Q000032:analysis
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; C494826:BAX protein, human; C438378:BBC3 protein, human; D007211:Indoles; D009363:Neoplasm Proteins; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D000069283:Rituximab; D020169:Caspases; C520962:obatoclax