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Reversing platinum resistance in ovarian cancer multicellular spheroids by targeting Bcl-2

PURPOSE: Peritoneal metastasis is the most common pathway for the spread of ovarian cancer. Ovarian cancer cells in ascites prefer to aggregate into the more chemoresistant multicellular spheroids (MCSs), leading to treatment failure and disease recurrence. We previously established a suspension MCS...

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Autores principales: Yang, Ya’nan, Li, Song, Sun, Yiting, Zhang, Di, Zhao, Zeyi, Liu, Lian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357888/
https://www.ncbi.nlm.nih.gov/pubmed/30774376
http://dx.doi.org/10.2147/OTT.S187015
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author Yang, Ya’nan
Li, Song
Sun, Yiting
Zhang, Di
Zhao, Zeyi
Liu, Lian
author_facet Yang, Ya’nan
Li, Song
Sun, Yiting
Zhang, Di
Zhao, Zeyi
Liu, Lian
author_sort Yang, Ya’nan
collection PubMed
description PURPOSE: Peritoneal metastasis is the most common pathway for the spread of ovarian cancer. Ovarian cancer cells in ascites prefer to aggregate into the more chemoresistant multicellular spheroids (MCSs), leading to treatment failure and disease recurrence. We previously established a suspension MCS model of ovarian cancer cells in vitro and found that the MCS cells acquired drug resistance to cisplatin. In the present study, we aimed to uncover the underlying mechanism of the platinum resistance of MCS and the potential targets to reverse the drug resistance. MATERIALS AND METHODS: MCS models were established for the phenotypic studies, including proliferation, invasion, migration, drug resistance, apoptosis assays, and signaling pathway analysis. The key molecule, Bcl-2, was screened by profile analysis and validated by Western blotting. siRNA was used to verify the anti-cisplatin-induced apoptosis effect of Bcl-2. The Bcl-2 inhibitor, ABT-737, was used for improving the sensitivity of MCS to cisplatin. The 50% inhibitory concentrations (IC50) were measured by viability assays treated with different concentrations of cisplatin. Flow cytometry and Western blotting were used for quantification of drug-induced apoptosis. RESULTS: The ovarian cancer MCS showed a proliferation-stagnant but invasive phenotype when resuspended. When treated with cisplatin, MCS cells showed much higher viability, with significantly fewer apoptotic cells than the adherent cells. Levels of Bcl-2 were upregulated in ovarian cancer ascitic cells and MCS cells. Bcl-2 knockdown by siRNA or blockage by ABT-737 enhanced the cisplatin-induced apoptosis and reduced the 50% inhibitory concentrations of cisplatin for MCS by 58.5% and 88.2%, respectively. CONCLUSION: The upregulated Bcl-2 contributes to cisplatin resistance in our MCS model and targeting it sensitizes the MCS to cisplatin treatment. This provides us a preliminary treatment method for ovarian cancer peritoneal metastasis.
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spelling pubmed-63578882019-02-15 Reversing platinum resistance in ovarian cancer multicellular spheroids by targeting Bcl-2 Yang, Ya’nan Li, Song Sun, Yiting Zhang, Di Zhao, Zeyi Liu, Lian Onco Targets Ther Original Research PURPOSE: Peritoneal metastasis is the most common pathway for the spread of ovarian cancer. Ovarian cancer cells in ascites prefer to aggregate into the more chemoresistant multicellular spheroids (MCSs), leading to treatment failure and disease recurrence. We previously established a suspension MCS model of ovarian cancer cells in vitro and found that the MCS cells acquired drug resistance to cisplatin. In the present study, we aimed to uncover the underlying mechanism of the platinum resistance of MCS and the potential targets to reverse the drug resistance. MATERIALS AND METHODS: MCS models were established for the phenotypic studies, including proliferation, invasion, migration, drug resistance, apoptosis assays, and signaling pathway analysis. The key molecule, Bcl-2, was screened by profile analysis and validated by Western blotting. siRNA was used to verify the anti-cisplatin-induced apoptosis effect of Bcl-2. The Bcl-2 inhibitor, ABT-737, was used for improving the sensitivity of MCS to cisplatin. The 50% inhibitory concentrations (IC50) were measured by viability assays treated with different concentrations of cisplatin. Flow cytometry and Western blotting were used for quantification of drug-induced apoptosis. RESULTS: The ovarian cancer MCS showed a proliferation-stagnant but invasive phenotype when resuspended. When treated with cisplatin, MCS cells showed much higher viability, with significantly fewer apoptotic cells than the adherent cells. Levels of Bcl-2 were upregulated in ovarian cancer ascitic cells and MCS cells. Bcl-2 knockdown by siRNA or blockage by ABT-737 enhanced the cisplatin-induced apoptosis and reduced the 50% inhibitory concentrations of cisplatin for MCS by 58.5% and 88.2%, respectively. CONCLUSION: The upregulated Bcl-2 contributes to cisplatin resistance in our MCS model and targeting it sensitizes the MCS to cisplatin treatment. This provides us a preliminary treatment method for ovarian cancer peritoneal metastasis. Dove Medical Press 2019-01-29 /pmc/articles/PMC6357888/ /pubmed/30774376 http://dx.doi.org/10.2147/OTT.S187015 Text en © 2019 Yang et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Yang, Ya’nan
Li, Song
Sun, Yiting
Zhang, Di
Zhao, Zeyi
Liu, Lian
Reversing platinum resistance in ovarian cancer multicellular spheroids by targeting Bcl-2
title Reversing platinum resistance in ovarian cancer multicellular spheroids by targeting Bcl-2
title_full Reversing platinum resistance in ovarian cancer multicellular spheroids by targeting Bcl-2
title_fullStr Reversing platinum resistance in ovarian cancer multicellular spheroids by targeting Bcl-2
title_full_unstemmed Reversing platinum resistance in ovarian cancer multicellular spheroids by targeting Bcl-2
title_short Reversing platinum resistance in ovarian cancer multicellular spheroids by targeting Bcl-2
title_sort reversing platinum resistance in ovarian cancer multicellular spheroids by targeting bcl-2
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357888/
https://www.ncbi.nlm.nih.gov/pubmed/30774376
http://dx.doi.org/10.2147/OTT.S187015
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