| Distinct cellular and therapeutic effects of obatoclax in rituximab-sensitive and -resistant lymphomas. | |
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MedLine Citation:
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PMID: 21492126 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Elizabeth A Brem; Karen Thudium; Sapna Khubchandani; Ping-Chiao Tsai; Scott H Olejniczak; Seema Bhat; Wasif Riaz; Jenny Gu; Arshad Iqbal; Ryan Campagna; Joy Knight; Cory Mavis; Paul Hoskin; George Deeb; John F Gibbs; Gerald Fetterly; Myron S Czuczman; Francisco J Hernandez-Ilizaliturri |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-04-15 |
Journal Detail:
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Title: British journal of haematology Volume: 153 ISSN: 1365-2141 ISO Abbreviation: Br. J. Haematol. Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-05-10 Completed Date: 2011-07-08 Revised Date: 2012-04-18 |
Medline Journal Info:
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Nlm Unique ID: 0372544 Medline TA: Br J Haematol Country: England |
Other Details:
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Languages: eng Pagination: 599-611 Citation Subset: IM |
Copyright Information:
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© 2011 Blackwell Publishing Ltd. |
Affiliation:
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Department of Medicine, Roswell Park Cancer Institute,Elm and Carlton Streets, Buffalo, NY 14263, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antibodies, Monoclonal, Murine-Derived
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administration & dosage,
pharmacology Antibody-Dependent Cell Cytotoxicity / drug effects Antineoplastic Combined Chemotherapy Protocols / pharmacology* Apoptosis Regulatory Proteins / biosynthesis Autophagy / drug effects Caspases / physiology Cell Death / drug effects Drug Evaluation, Preclinical / methods Drug Resistance, Neoplasm / drug effects Drug Synergism Humans Lymphoma, B-Cell / metabolism, pathology* Lymphoma, Follicular / metabolism, pathology Lymphoma, Large B-Cell, Diffuse / metabolism, pathology Neoplasm Proteins / biosynthesis Proto-Oncogene Proteins / biosynthesis Proto-Oncogene Proteins c-bcl-2 / biosynthesis Pyrroles / administration & dosage, pharmacology Tumor Cells, Cultured Up-Regulation / drug effects bcl-2 Homologous Antagonist-Killer Protein / analysis bcl-2-Associated X Protein / analysis |
| Grant Support | |
ID/Acronym/Agency:
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CA136907-01A1/CA/NCI NIH HHS; P01-CA103985-02/CA/NCI NIH HHS; R01 CA136907-01A1/CA/NCI NIH HHS; R01 CA136907-04/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Monoclonal, Murine-Derived; 0/Apoptosis Regulatory Proteins; 0/BAK1 protein, human; 0/BAX protein, human; 0/BBC3 protein, human; 0/Neoplasm Proteins; 0/PMAIP1 protein, human; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyrroles; 0/bcl-2 Homologous Antagonist-Killer Protein; 0/bcl-2-Associated X Protein; 0/obatoclax; 0/rituximab; EC 3.4.22.-/Caspases |
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