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 Journal Article

Authors: Paoluzzi, L.; Gonen, M.; Gardner, J. R.; Mastrella, J.; Yang, D.; Holmlund, J.; Sorensen, M.; Leopold, L.; Manova, K.; Marcucci, G.; Heaney, M. L.; O'Connor, O. A.
Article 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 intrinsic 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-XL. 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 IC50 for AT-101 is between 1 and 10 μM 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 (Δψm) 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. © 2008 by The American Society of Hematology.
Keywords: cancer chemotherapy; controlled study; treatment response; unclassified drug; doxorubicin; drug dose comparison; drug efficacy; drug potentiation; drug safety; nonhuman; drug targeting; rituximab; drug megadose; flow cytometry; antineoplastic agent; mass spectrometry; animal cell; mouse; animal; animals; mice; protein bcl 2; apoptosis; bortezomib; mantle cell lymphoma; multiple cycle treatment; multiple myeloma; confocal microscopy; microscopy, confocal; etoposide; antineoplastic combined chemotherapy protocols; animal experiment; animal model; mitochondrial membrane potential; antineoplastic agents, phytogenic; cyclophosphamide; antineoplastic activity; in vitro study; drug effect; drug screening; xenograft model antitumor assays; cell line, tumor; monoclonal antibody; disease model; b cell lymphoma; blotting, western; lymphoma, b-cell; antibodies, monoclonal; add on therapy; lymphoma cell; tumor cell line; western blotting; drug derivative; single drug dose; large cell lymphoma; drug blood level; high performance liquid chromatography; drug cytotoxicity; disease models, animal; drug dose increase; biomimetics; bh3 interacting domain death agonist protein; proto-oncogene proteins c-bcl-2; membrane potential, mitochondrial; scid mouse; isosorbide; carfilzomib; protein bid; dose time effect relation; bh3 protein; 4 hydroxycyclophosphamide; gossypol derivative; gossypol; gossypol acetic acid
Journal Title: Blood
Volume: 111
Issue: 11
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2008-06-01
Start Page: 5350
End Page: 5358
Language: English
DOI: 10.1182/blood-2007-12-129833
PUBMED: 18292288
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 50" - "Export Date: 17 November 2011" - "CODEN: BLOOA" - "Source: Scopus"
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MSK Authors
  1. Mark L Heaney
    89 Heaney
  2. Mithat Gonen
    701 Gonen
  3. Jeffrey Gardner
    33 Gardner