Abstract
Elevated expression of anti-apoptotic Bcl-2 family proteins have been linked to a poor survival rate of patients with Follicular Lymphoma (FL). This prompted us to evaluate a very potent non-peptidic Small-Molecule Inhibitor (SMI) targeting Bcl-2 family proteins, Apogossypolone (ApoG2) using follicular small cleaved cell lymphoma cell line (WSU-FSCCL) and cell isolated from lymphoma patients. ApoG2 inhibited the growth of WSU-FSCCL significantly with a 50% growth inhibition of cells (IC50) of 109 nM and decreased cell number of fresh lymphoma cells. ApoG2 activated caspases-9, -3, and -8, and the cleavage of Poly (ADP-ribose) polymerase (PARP) and Apoptosis Inducing Factor (AIF). In the WSU-FSCCL-SCID xenograft model, ApoG2 showed a significant anti-lymphoma effect, with %ILS of 84% in the intravenous and 63% in intraperitoneal treated mice. These studies suggest that ApoG2 can be an effective therapeutic agent against FL.
Highlights
Follicular Lymphoma (FL) is fifth leading diagnosed cancer estimated with over 63,000 new patients in 2007 within the United States
Phase III trials of Rituximab shows improved progression free survival in relapsed/resistant FL and enhanced remission induction when used with CHOP [6], with these improvements in the treatment, to date there is not a cure except for a limited number of patients who present with localized disease
We evaluated the effect of ApoG2 on growth of malignant lymphoid cells in vitro, its ability to induce apoptosis as well as its anti-lymphoma activity in vivo using a SCID mouse xenograft model of FSCCL
Summary
Follicular Lymphoma (FL) is fifth leading diagnosed cancer estimated with over 63,000 new patients in 2007 within the United States. The natural history of FL has not changed over the last 3 decades with median survival ranging from 7–10 years; the disease is considered incurable using various anti-cancer agents [1,2,3]. Current treatment strategies are aimed at producing remissions, preserving vital organ function and enhancing patients' quality of life [4]. Phase II trials of CHOP followed by Tositumomab/Iodine I-131 demonstrated progression free survival of 67% of patients [5]. Phase III trials of Rituximab shows improved progression free survival in relapsed/resistant FL and enhanced remission induction when used with CHOP [6], with these improvements in the treatment, to date there is not a cure except for a limited number of patients who present with localized disease. Developing targeted therapy to proteins such as Bcl-2 that prevent death of lymphoma cells is advantageous
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