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.
Blood 2008 Feb 21; In press
Paoluzzi L L, Gonen M M, Gardner J JR, Mastrella J J, Yang D D, Holmlund J J, Sorensen M M, Leopold L L, Manova K K, Marcucci G G, Heaney M ML, O' Connor O OA
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY.
Over-expression of anti-apoptotic members of the Bcl-2 family are observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying anti-apoptotic function can potentially overcome this intrinsic and acquired drug resistance. AT-101 is a BH3 mimetic known to be a potent inhibitor of anti-apoptotic 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 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 (DeltaPsim) and apoptosis when combined with carfilzomib, but not with bortezomib in MCL. In SCID beige mouse models of drug resistant B-cell lymphoma, 35 mg/kg/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.
Keywords: Bcl-2 BH3 AT-101 lymphoma cyclophosphamide rituximab