title: Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma.
abstract: Overexpression of antiapoptotic members of the Bcl-2 family are observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying antiapoptotic function can potentially overcome this in-trinsic and acquired drug resistance. AT-101 is a BH3 mimetic known to be a potent inhibitor of antiapoptotic Bcl-2 family members including Bcl-2, Bcl-X(L), and Mcl-1. In vitro, AT-101 exhibits concentration- and time-dependent cytotoxicity against lymphoma and multiple myeloma cell lines, enhancing the activity of cytotoxic agents. The IC(50) for AT-101 is between 1 and 10 microM for a diverse panel of B-cell lymphomas. AT-101 was synergistic with carfilzomib (C), etoposide (E), doxorubicin (D), and 4-hydroxycyclophosphamide (4-HC) in mantle cell lymphoma (MCL) lines. In a transformed large B-cell lymphoma line (RL), AT-101 was synergistic when sequentially combined with 4-HC, but not when both drugs were added simultaneously. AT-101 also induced potent mitochondrial membrane depolarization (Delta Psi m) and apoptosis when combined with carfilzomib, but not with bortezomib in MCL. In severe combined immunodeficient (SCID) beige mouse models of drug-resistant B-cell lymphoma, 35 mg/kg per day of AT-101 was safe and efficacious. The addition of AT-101 to cyclophosphamide (Cy) and rituximab (R) in a schedule-dependent manner enhanced the efficacy of the conventional therapy.
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Paoluzzi
authors.forename: Mithat
authors.initials: M
authors.lastname: Gonen
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Gardner
authors.forename: Jill
authors.initials: J
authors.lastname: Mastrella
authors.forename: Dajun
authors.initials: D
authors.lastname: Yang
authors.forename: Jon
authors.initials: J
authors.lastname: Holmlund
authors.forename: Mel
authors.initials: M
authors.lastname: Sorensen
authors.forename: Lance
authors.initials: L
authors.lastname: Leopold
authors.forename: Katia
authors.initials: K
authors.lastname: Manova
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Mark L
authors.initials: ML
authors.lastname: Heaney
authors.forename: Owen A
authors.initials: OA
authors.lastname: O'Connor
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein; D032701:Biomimetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006072:Gossypol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D018613:Microscopy, Confocal; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects*; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000972:Antineoplastic Agents, Phytogenic; D051023:BH3 Interacting Domain Death Agonist Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D000069283:Rituximab; D003520:Cyclophosphamide; D006072:Gossypol; C028178:gossypol acetic acid