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Inhibition of Ceramide Metabolism Sensitizes Human Leukemia Cells to Inhibition of BCL2-Like Proteins
The identification of novel combinations of effective cancer drugs is required for the successful treatment of cancer patients for a number of reasons. First, many “cancer specific” therapeutics display detrimental patient side-effects and second, there are almost no examples of single agent therape...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546986/ https://www.ncbi.nlm.nih.gov/pubmed/23342165 http://dx.doi.org/10.1371/journal.pone.0054525 |
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author | Casson, Lavona Howell, Lauren Mathews, Lesley A. Ferrer, Marc Southall, Noel Guha, Rajarshi Keller, Jonathan M. Thomas, Craig Siskind, Leah J. Beverly, Levi J. |
author_facet | Casson, Lavona Howell, Lauren Mathews, Lesley A. Ferrer, Marc Southall, Noel Guha, Rajarshi Keller, Jonathan M. Thomas, Craig Siskind, Leah J. Beverly, Levi J. |
author_sort | Casson, Lavona |
collection | PubMed |
description | The identification of novel combinations of effective cancer drugs is required for the successful treatment of cancer patients for a number of reasons. First, many “cancer specific” therapeutics display detrimental patient side-effects and second, there are almost no examples of single agent therapeutics that lead to cures. One strategy to decrease both the effective dose of individual drugs and the potential for therapeutic resistance is to combine drugs that regulate independent pathways that converge on cell death. BCL2-like family members are key proteins that regulate apoptosis. We conducted a screen to identify drugs that could be combined with an inhibitor of anti-apoptotic BCL2-like proteins, ABT-263, to kill human leukemia cells lines. We found that the combination of D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) hydrochloride, an inhibitor of glucosylceramide synthase, potently synergized with ABT-263 in the killing of multiple human leukemia cell lines. Treatment of cells with PDMP and ABT-263 led to dramatic elevation of two pro-apoptotic sphingolipids, namely ceramide and sphingosine. Furthermore, treatment of cells with the sphingosine kinase inhibitor, SKi-II, also dramatically synergized with ABT-263 to kill leukemia cells and similarly increased ceramides and sphingosine. Data suggest that synergism with ABT-263 requires accumulation of ceramides and sphingosine, as AMP-deoxynojirimycin, (an inhibitor of the glycosphingolipid pathway) did not elevate ceramides or sphingosine and importantly did not sensitize cells to ABT-263 treatment. Taken together, our data suggest that combining inhibitors of anti-apoptotic BCL2-like proteins with drugs that alter the balance of bioactive sphingolipids will be a powerful combination for the treatment of human cancers. |
format | Online Article Text |
id | pubmed-3546986 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-35469862013-01-22 Inhibition of Ceramide Metabolism Sensitizes Human Leukemia Cells to Inhibition of BCL2-Like Proteins Casson, Lavona Howell, Lauren Mathews, Lesley A. Ferrer, Marc Southall, Noel Guha, Rajarshi Keller, Jonathan M. Thomas, Craig Siskind, Leah J. Beverly, Levi J. PLoS One Research Article The identification of novel combinations of effective cancer drugs is required for the successful treatment of cancer patients for a number of reasons. First, many “cancer specific” therapeutics display detrimental patient side-effects and second, there are almost no examples of single agent therapeutics that lead to cures. One strategy to decrease both the effective dose of individual drugs and the potential for therapeutic resistance is to combine drugs that regulate independent pathways that converge on cell death. BCL2-like family members are key proteins that regulate apoptosis. We conducted a screen to identify drugs that could be combined with an inhibitor of anti-apoptotic BCL2-like proteins, ABT-263, to kill human leukemia cells lines. We found that the combination of D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) hydrochloride, an inhibitor of glucosylceramide synthase, potently synergized with ABT-263 in the killing of multiple human leukemia cell lines. Treatment of cells with PDMP and ABT-263 led to dramatic elevation of two pro-apoptotic sphingolipids, namely ceramide and sphingosine. Furthermore, treatment of cells with the sphingosine kinase inhibitor, SKi-II, also dramatically synergized with ABT-263 to kill leukemia cells and similarly increased ceramides and sphingosine. Data suggest that synergism with ABT-263 requires accumulation of ceramides and sphingosine, as AMP-deoxynojirimycin, (an inhibitor of the glycosphingolipid pathway) did not elevate ceramides or sphingosine and importantly did not sensitize cells to ABT-263 treatment. Taken together, our data suggest that combining inhibitors of anti-apoptotic BCL2-like proteins with drugs that alter the balance of bioactive sphingolipids will be a powerful combination for the treatment of human cancers. Public Library of Science 2013-01-16 /pmc/articles/PMC3546986/ /pubmed/23342165 http://dx.doi.org/10.1371/journal.pone.0054525 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article Casson, Lavona Howell, Lauren Mathews, Lesley A. Ferrer, Marc Southall, Noel Guha, Rajarshi Keller, Jonathan M. Thomas, Craig Siskind, Leah J. Beverly, Levi J. Inhibition of Ceramide Metabolism Sensitizes Human Leukemia Cells to Inhibition of BCL2-Like Proteins |
title | Inhibition of Ceramide Metabolism Sensitizes Human Leukemia Cells to Inhibition of BCL2-Like Proteins |
title_full | Inhibition of Ceramide Metabolism Sensitizes Human Leukemia Cells to Inhibition of BCL2-Like Proteins |
title_fullStr | Inhibition of Ceramide Metabolism Sensitizes Human Leukemia Cells to Inhibition of BCL2-Like Proteins |
title_full_unstemmed | Inhibition of Ceramide Metabolism Sensitizes Human Leukemia Cells to Inhibition of BCL2-Like Proteins |
title_short | Inhibition of Ceramide Metabolism Sensitizes Human Leukemia Cells to Inhibition of BCL2-Like Proteins |
title_sort | inhibition of ceramide metabolism sensitizes human leukemia cells to inhibition of bcl2-like proteins |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546986/ https://www.ncbi.nlm.nih.gov/pubmed/23342165 http://dx.doi.org/10.1371/journal.pone.0054525 |
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