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Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR/ABL axis
The abundance of the BCR/ABL protein critically contributes to CML pathogenesis and drug resistance. However, understanding of molecular mechanisms underlying BCR/ABL gene regulation remains incomplete. While BCR/ABL kinase inhibitors have shown unprecedented efficacy in the clinic, most patients re...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095007/ https://www.ncbi.nlm.nih.gov/pubmed/27144331 http://dx.doi.org/10.18632/oncotarget.8871 |
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author | Yang, Xiaojuan Pang, Jiuxia Shen, Na Yan, Fei Wu, Lai-Chu Al-Kali, Aref Litzow, Mark R. Peng, Yong Lee, Robert J. Liu, Shujun |
author_facet | Yang, Xiaojuan Pang, Jiuxia Shen, Na Yan, Fei Wu, Lai-Chu Al-Kali, Aref Litzow, Mark R. Peng, Yong Lee, Robert J. Liu, Shujun |
author_sort | Yang, Xiaojuan |
collection | PubMed |
description | The abundance of the BCR/ABL protein critically contributes to CML pathogenesis and drug resistance. However, understanding of molecular mechanisms underlying BCR/ABL gene regulation remains incomplete. While BCR/ABL kinase inhibitors have shown unprecedented efficacy in the clinic, most patients relapse. In this study, we demonstrated that the Sp1 oncogene functions as a positive regulator for BCR/ABL expression. Inactivation of Sp1 by genetic and pharmacological approaches abrogated BCR/ABL expression, leading to suppression of BCR/ABL kinase signaling and CML cell proliferation. Because of potential adverse side effects of bortezomib (BORT) in imatinib-refractory CML patients, we designed a transferrin (Tf)-targeted liposomal formulation (Tf-L-BORT) for BORT delivery. Cellular uptake assays showed that BORT was efficiently delivered into K562 cells, with the highest efficacy obtained in Tf-targeted group. After administered into mice, L-BORT exhibited slower clearance with less toxicity compared to free BORT. Furthermore, L-BORT exposure significantly blocked BCR/ABL kinase activities and sensitized CML cell lines, tumor cells and doxorubicin (DOX) resistant cells to DOX. This occurred through the more pronounced inhibition of BCR/ABL activity by L-BORT and DOX. Collectively, these findings highlight the therapeutic relevance of disrupting BCR/ABL protein expression and strongly support the utilization of L-BORT alone or in combination with DOX to treat CML patients with overexpressing BCR/ABL. |
format | Online Article Text |
id | pubmed-5095007 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-50950072016-11-22 Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR/ABL axis Yang, Xiaojuan Pang, Jiuxia Shen, Na Yan, Fei Wu, Lai-Chu Al-Kali, Aref Litzow, Mark R. Peng, Yong Lee, Robert J. Liu, Shujun Oncotarget Research Paper The abundance of the BCR/ABL protein critically contributes to CML pathogenesis and drug resistance. However, understanding of molecular mechanisms underlying BCR/ABL gene regulation remains incomplete. While BCR/ABL kinase inhibitors have shown unprecedented efficacy in the clinic, most patients relapse. In this study, we demonstrated that the Sp1 oncogene functions as a positive regulator for BCR/ABL expression. Inactivation of Sp1 by genetic and pharmacological approaches abrogated BCR/ABL expression, leading to suppression of BCR/ABL kinase signaling and CML cell proliferation. Because of potential adverse side effects of bortezomib (BORT) in imatinib-refractory CML patients, we designed a transferrin (Tf)-targeted liposomal formulation (Tf-L-BORT) for BORT delivery. Cellular uptake assays showed that BORT was efficiently delivered into K562 cells, with the highest efficacy obtained in Tf-targeted group. After administered into mice, L-BORT exhibited slower clearance with less toxicity compared to free BORT. Furthermore, L-BORT exposure significantly blocked BCR/ABL kinase activities and sensitized CML cell lines, tumor cells and doxorubicin (DOX) resistant cells to DOX. This occurred through the more pronounced inhibition of BCR/ABL activity by L-BORT and DOX. Collectively, these findings highlight the therapeutic relevance of disrupting BCR/ABL protein expression and strongly support the utilization of L-BORT alone or in combination with DOX to treat CML patients with overexpressing BCR/ABL. Impact Journals LLC 2016-04-20 /pmc/articles/PMC5095007/ /pubmed/27144331 http://dx.doi.org/10.18632/oncotarget.8871 Text en Copyright: © 2016 Yang et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Yang, Xiaojuan Pang, Jiuxia Shen, Na Yan, Fei Wu, Lai-Chu Al-Kali, Aref Litzow, Mark R. Peng, Yong Lee, Robert J. Liu, Shujun Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR/ABL axis |
title | Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR/ABL axis |
title_full | Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR/ABL axis |
title_fullStr | Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR/ABL axis |
title_full_unstemmed | Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR/ABL axis |
title_short | Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR/ABL axis |
title_sort | liposomal bortezomib is active against chronic myeloid leukemia by disrupting the sp1-bcr/abl axis |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095007/ https://www.ncbi.nlm.nih.gov/pubmed/27144331 http://dx.doi.org/10.18632/oncotarget.8871 |
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