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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
| Content Provider | Scilit |
|---|---|
| Author | O'connor, Owen A. Paoluzzi, Luca Gonen, Mithat Gardner, Jeffrey R. Mastrella, Jill Yang, Dajun Holmlund, Jon Sorensen, Mel Leopold, Lance Manova, Katia Marcucci, Guido Heaney, Mark L. |
| Copyright Year | 2008 |
| Description | 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-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. |
| Related Links | http://www.bloodjournal.org/content/111/11/5350.full.pdf |
| Ending Page | 5358 |
| Page Count | 9 |
| Starting Page | 5350 |
| DOI | 10.1182/blood-2007-12-129833 |
| Journal | Blood |
| Issue Number | 11 |
| Volume Number | 111 |
| Language | English |
| Publisher | American Society of Hematology |
| Publisher Date | 2008-06-01 |
| Access Restriction | Open |
| Subject Keyword | Hematology Multiple Myeloma Apoptosis Cytotoxicity Models Drug Resistance Bcl Efficacious Cell Lymphoma Journal: Blood (Vol- 117, Issue- 11) |
| Content Type | Text |
| Resource Type | Article |
