Apoptosis of t14;18-positive lymphoma cells by a Bcl-2 interacting small moleculeReport as inadecuate




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Journal of Hematopathology

, Volume 2, Issue 2, pp 113–119

First Online: 28 February 2009Received: 11 August 2008Accepted: 12 February 2009

Abstract

Overexpression of Bcl-2 protein occurs via both t14;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 t14;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, 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.

KeywordsFollicular lymphoma Bcl-2 HA14–1 Antiapoptosis Small molecule inhibitor  Download fulltext PDF



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

Source: https://link.springer.com/







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