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

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 inter...

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Autores principales: Abbott, David R., Abbott, Robert T., Jenson, Stephen D., Fillmore, G. Chris, Elenitoba-Johnson, Kojo S. J., Lim, Megan S.
Formato: Texto
Lenguaje:English
Publicado: Springer-Verlag 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725288/
https://www.ncbi.nlm.nih.gov/pubmed/19669197
http://dx.doi.org/10.1007/s12308-009-0028-x
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author Abbott, David R.
Abbott, Robert T.
Jenson, Stephen D.
Fillmore, G. Chris
Elenitoba-Johnson, Kojo S. J.
Lim, Megan S.
author_facet Abbott, David R.
Abbott, Robert T.
Jenson, Stephen D.
Fillmore, G. Chris
Elenitoba-Johnson, Kojo S. J.
Lim, Megan S.
author_sort Abbott, David R.
collection PubMed
description 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- (IC(50) = 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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spelling pubmed-27252882009-08-13 Apoptosis of t(14;18)-positive lymphoma cells by a Bcl-2 interacting small molecule Abbott, David R. Abbott, Robert T. Jenson, Stephen D. Fillmore, G. Chris Elenitoba-Johnson, Kojo S. J. Lim, Megan S. J Hematop Original Article 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- (IC(50) = 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. Springer-Verlag 2009-02-28 /pmc/articles/PMC2725288/ /pubmed/19669197 http://dx.doi.org/10.1007/s12308-009-0028-x Text en © Springer-Verlag 2009
spellingShingle Original Article
Abbott, David R.
Abbott, Robert T.
Jenson, Stephen D.
Fillmore, G. Chris
Elenitoba-Johnson, Kojo S. J.
Lim, Megan S.
Apoptosis of t(14;18)-positive lymphoma cells by a Bcl-2 interacting small molecule
title Apoptosis of t(14;18)-positive lymphoma cells by a Bcl-2 interacting small molecule
title_full Apoptosis of t(14;18)-positive lymphoma cells by a Bcl-2 interacting small molecule
title_fullStr Apoptosis of t(14;18)-positive lymphoma cells by a Bcl-2 interacting small molecule
title_full_unstemmed Apoptosis of t(14;18)-positive lymphoma cells by a Bcl-2 interacting small molecule
title_short Apoptosis of t(14;18)-positive lymphoma cells by a Bcl-2 interacting small molecule
title_sort apoptosis of t(14;18)-positive lymphoma cells by a bcl-2 interacting small molecule
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725288/
https://www.ncbi.nlm.nih.gov/pubmed/19669197
http://dx.doi.org/10.1007/s12308-009-0028-x
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