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The over-expression of survivin enhances the chemotherapeutic efficacy of YM155 in human hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. The inability of chemotherapeutic drugs to selectively target HCC tumor cells because of their predominant resistant phenotype to most conventional anticancer agents bestows a major obstacle for the clinic...

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Autores principales: Xia, Hongping, Chen, Jianxiang, Shi, Ming, Deivasigamani, Amudha, P.J. Ooi, London Lucien, Hui, Kam M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467416/
https://www.ncbi.nlm.nih.gov/pubmed/25714025
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author Xia, Hongping
Chen, Jianxiang
Shi, Ming
Deivasigamani, Amudha
P.J. Ooi, London Lucien
Hui, Kam M.
author_facet Xia, Hongping
Chen, Jianxiang
Shi, Ming
Deivasigamani, Amudha
P.J. Ooi, London Lucien
Hui, Kam M.
author_sort Xia, Hongping
collection PubMed
description Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. The inability of chemotherapeutic drugs to selectively target HCC tumor cells because of their predominant resistant phenotype to most conventional anticancer agents bestows a major obstacle for the clinical management of HCC. In this report, we have examined and demonstrated the remarkable heterogeneity of expression of survivin and its phosphorylated active form (p-survivin) in HCC patients' tissues and cell lines. Furthermore, the expression of survivin and p-survivin in HCC cell lines was found to be associated with response to the small-molecule survivin suppressant YM155. Therefore, in the HCC cell lines that express elevated level of survivin and p-survivin, YM155 efficiently inhibited their proliferation, induced cell cycle arrest and apoptosis resulting in DNA damage through the dysregulation of cell-cycle checkpoint-related regulatory genes. Importantly, YM155 yielded significantly better therapeutic effect than sorafenib when tested in an orthotopic mouse model using patient-derived HCC xenografts with elevated survivin and p-survivin expression. Our results clearly demonstrated that the level of survivin and p-survivin expression could serve as molecular predictive biomarkers to select potential YM155-responsive patients, in a move towards delivering precision medicine for HCC patients.
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spelling pubmed-44674162015-06-22 The over-expression of survivin enhances the chemotherapeutic efficacy of YM155 in human hepatocellular carcinoma Xia, Hongping Chen, Jianxiang Shi, Ming Deivasigamani, Amudha P.J. Ooi, London Lucien Hui, Kam M. Oncotarget Research Paper Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. The inability of chemotherapeutic drugs to selectively target HCC tumor cells because of their predominant resistant phenotype to most conventional anticancer agents bestows a major obstacle for the clinical management of HCC. In this report, we have examined and demonstrated the remarkable heterogeneity of expression of survivin and its phosphorylated active form (p-survivin) in HCC patients' tissues and cell lines. Furthermore, the expression of survivin and p-survivin in HCC cell lines was found to be associated with response to the small-molecule survivin suppressant YM155. Therefore, in the HCC cell lines that express elevated level of survivin and p-survivin, YM155 efficiently inhibited their proliferation, induced cell cycle arrest and apoptosis resulting in DNA damage through the dysregulation of cell-cycle checkpoint-related regulatory genes. Importantly, YM155 yielded significantly better therapeutic effect than sorafenib when tested in an orthotopic mouse model using patient-derived HCC xenografts with elevated survivin and p-survivin expression. Our results clearly demonstrated that the level of survivin and p-survivin expression could serve as molecular predictive biomarkers to select potential YM155-responsive patients, in a move towards delivering precision medicine for HCC patients. Impact Journals LLC 2015-01-21 /pmc/articles/PMC4467416/ /pubmed/25714025 Text en Copyright: © 2015 Xia 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
Xia, Hongping
Chen, Jianxiang
Shi, Ming
Deivasigamani, Amudha
P.J. Ooi, London Lucien
Hui, Kam M.
The over-expression of survivin enhances the chemotherapeutic efficacy of YM155 in human hepatocellular carcinoma
title The over-expression of survivin enhances the chemotherapeutic efficacy of YM155 in human hepatocellular carcinoma
title_full The over-expression of survivin enhances the chemotherapeutic efficacy of YM155 in human hepatocellular carcinoma
title_fullStr The over-expression of survivin enhances the chemotherapeutic efficacy of YM155 in human hepatocellular carcinoma
title_full_unstemmed The over-expression of survivin enhances the chemotherapeutic efficacy of YM155 in human hepatocellular carcinoma
title_short The over-expression of survivin enhances the chemotherapeutic efficacy of YM155 in human hepatocellular carcinoma
title_sort over-expression of survivin enhances the chemotherapeutic efficacy of ym155 in human hepatocellular carcinoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467416/
https://www.ncbi.nlm.nih.gov/pubmed/25714025
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