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Open Access 01-07-2009 | Original Article

Apoptosis of t(14;18)-positive lymphoma cells by a Bcl-2 interacting small molecule

Authors: David R. Abbott, Robert T. Abbott, Stephen D. Jenson, G. Chris Fillmore, Kojo S. J. Elenitoba-Johnson, Megan S. Lim

Published in: Journal of Hematopathology | Issue 2/2009

Abstract

Overexpression of Bcl-2 protein occurs via both t(14;18)-dependent and independent mechanisms and contributes to the survival and chemoresistance of non-Hodgkin lymphomas. HA14–1 is a nonpeptidic organic small molecule, which has been shown to inhibit the interaction of Bcl-2 with Bax, thereby interfering with the antiapoptotic function of Bcl-2. In this study, we sought to determine the in vitro efficacy of HA14–1 as a therapeutic agent for non-Hodgkin lymphomas expressing Bcl-2. Assessment of cell viability demonstrated that HA14–1 induced a dose- (IC₅₀ = 10 μM) and time-dependent growth inhibition of a cell line (SudHL-4) derived from a t(14;18)-positive, Bcl-2-positive, non-Hodgkin lymphoma. HA14–1 effectively induced apoptosis via a caspase 3-mediated pathway but did not affect either the p38 MAPK or p44/42 MAPK pathways. Western blot analyses of Bcl-2 family proteins and other cell cycle-associated proteins were performed to determine the molecular sequelae of HA14–1-induced apoptosis. The results show down-regulation of Mcl-1 but up-regulation of p27^kip1, Bad, Bcl-xL, and Bcl-2 proteins, without change in Bax levels during HA14–1-mediated apoptosis. Our findings further elucidate the cellular mechanisms accompanying Bcl-2 inhibition and demonstrate the potential of Bcl-2 inhibitors as therapeutic agents for the treatment of non-Hodgkin lymphomas.

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Title: Apoptosis of t(14;18)-positive lymphoma cells by a Bcl-2 interacting small molecule
Authors: David R. Abbott
Robert T. Abbott
Stephen D. Jenson
G. Chris Fillmore
Kojo S. J. Elenitoba-Johnson
Megan S. Lim
Publication date: 01-07-2009
Publisher: Springer-Verlag
Published in: Journal of Hematopathology / Issue 2/2009
Print ISSN: 1868-9256
Electronic ISSN: 1865-5785
DOI: https://doi.org/10.1007/s12308-009-0028-x

At a glance: The STEP trials

Springer Medicine

Apoptosis of t(14;18)-positive lymphoma cells by a Bcl-2 interacting small molecule

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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