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BZD9L1 sirtuin inhibitor as a potential adjuvant for sensitization of colorectal cancer cells to 5-fluorouracil
BACKGROUND: This study aims to investigate the combination effect of a novel sirtuin inhibitor (BZD9L1) with 5-fluorouracil (5-FU) and to determine its molecular mechanism of action in colorectal cancer (CRC). METHODS: BZD9L1 and 5-FU either as single treatment or in combination were tested against...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767736/ https://www.ncbi.nlm.nih.gov/pubmed/31632470 http://dx.doi.org/10.1177/1758835919878977 |
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author | Tan, Yi Jer Lee, Yeuan Ting Petersen, Sven H. Kaur, Gurjeet Kono, Koji Tan, Soo Choon Majid, Amin M. S. Abdul Oon, Chern Ein |
author_facet | Tan, Yi Jer Lee, Yeuan Ting Petersen, Sven H. Kaur, Gurjeet Kono, Koji Tan, Soo Choon Majid, Amin M. S. Abdul Oon, Chern Ein |
author_sort | Tan, Yi Jer |
collection | PubMed |
description | BACKGROUND: This study aims to investigate the combination effect of a novel sirtuin inhibitor (BZD9L1) with 5-fluorouracil (5-FU) and to determine its molecular mechanism of action in colorectal cancer (CRC). METHODS: BZD9L1 and 5-FU either as single treatment or in combination were tested against CRC cells to evaluate synergism in cytotoxicity, senescence and formation of micronucleus, cell cycle and apoptosis, as well as the regulation of related molecular players. The effects of combined treatments at different doses on stress and apoptosis, migration, invasion and cell death mechanism were evaluated through two-dimensional and three-dimensional cultures. In vivo studies include investigation on the combination effects of BZD9L1 and 5-FU on colorectal tumour xenograft growth and an evaluation of tumour proliferation and apoptosis using immunohistochemistry. RESULTS: Combination treatments exerted synergistic reduction on cell viability on HCT 116 cells but not on HT-29 cells. Combined treatments reduced survival, induced cell cycle arrest, apoptosis, senescence and micronucleation in HCT 116 cells through modulation of multiple responsible molecular players and apoptosis pathways, with no effect in epithelial mesenchymal transition (EMT). Combination treatments regulated SIRT1 and SIRT2 protein expression levels differently and changed SIRT2 protein localization. Combined treatment reduced growth, migration, invasion and viability of HCT 116 spheroids through apoptosis, when compared with the single treatment. In addition, combined treatment was found to reduce tumour growth in vivo through reduction of tumour proliferation and necrosis compared with the vehicle control group. This highlights the potential therapeutic effects of BZD9L1 and 5-FU towards CRC. CONCLUSION: This study may pave the way for use of BZD9L1 as an adjuvant to 5-FU in improving the therapeutic efficacy for the treatment of colorectal cancer. |
format | Online Article Text |
id | pubmed-6767736 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-67677362019-10-18 BZD9L1 sirtuin inhibitor as a potential adjuvant for sensitization of colorectal cancer cells to 5-fluorouracil Tan, Yi Jer Lee, Yeuan Ting Petersen, Sven H. Kaur, Gurjeet Kono, Koji Tan, Soo Choon Majid, Amin M. S. Abdul Oon, Chern Ein Ther Adv Med Oncol Original Research BACKGROUND: This study aims to investigate the combination effect of a novel sirtuin inhibitor (BZD9L1) with 5-fluorouracil (5-FU) and to determine its molecular mechanism of action in colorectal cancer (CRC). METHODS: BZD9L1 and 5-FU either as single treatment or in combination were tested against CRC cells to evaluate synergism in cytotoxicity, senescence and formation of micronucleus, cell cycle and apoptosis, as well as the regulation of related molecular players. The effects of combined treatments at different doses on stress and apoptosis, migration, invasion and cell death mechanism were evaluated through two-dimensional and three-dimensional cultures. In vivo studies include investigation on the combination effects of BZD9L1 and 5-FU on colorectal tumour xenograft growth and an evaluation of tumour proliferation and apoptosis using immunohistochemistry. RESULTS: Combination treatments exerted synergistic reduction on cell viability on HCT 116 cells but not on HT-29 cells. Combined treatments reduced survival, induced cell cycle arrest, apoptosis, senescence and micronucleation in HCT 116 cells through modulation of multiple responsible molecular players and apoptosis pathways, with no effect in epithelial mesenchymal transition (EMT). Combination treatments regulated SIRT1 and SIRT2 protein expression levels differently and changed SIRT2 protein localization. Combined treatment reduced growth, migration, invasion and viability of HCT 116 spheroids through apoptosis, when compared with the single treatment. In addition, combined treatment was found to reduce tumour growth in vivo through reduction of tumour proliferation and necrosis compared with the vehicle control group. This highlights the potential therapeutic effects of BZD9L1 and 5-FU towards CRC. CONCLUSION: This study may pave the way for use of BZD9L1 as an adjuvant to 5-FU in improving the therapeutic efficacy for the treatment of colorectal cancer. SAGE Publications 2019-09-27 /pmc/articles/PMC6767736/ /pubmed/31632470 http://dx.doi.org/10.1177/1758835919878977 Text en © The Author(s), 2019 http://www.creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Original Research Tan, Yi Jer Lee, Yeuan Ting Petersen, Sven H. Kaur, Gurjeet Kono, Koji Tan, Soo Choon Majid, Amin M. S. Abdul Oon, Chern Ein BZD9L1 sirtuin inhibitor as a potential adjuvant for sensitization of colorectal cancer cells to 5-fluorouracil |
title | BZD9L1 sirtuin inhibitor as a potential adjuvant for sensitization of
colorectal cancer cells to 5-fluorouracil |
title_full | BZD9L1 sirtuin inhibitor as a potential adjuvant for sensitization of
colorectal cancer cells to 5-fluorouracil |
title_fullStr | BZD9L1 sirtuin inhibitor as a potential adjuvant for sensitization of
colorectal cancer cells to 5-fluorouracil |
title_full_unstemmed | BZD9L1 sirtuin inhibitor as a potential adjuvant for sensitization of
colorectal cancer cells to 5-fluorouracil |
title_short | BZD9L1 sirtuin inhibitor as a potential adjuvant for sensitization of
colorectal cancer cells to 5-fluorouracil |
title_sort | bzd9l1 sirtuin inhibitor as a potential adjuvant for sensitization of
colorectal cancer cells to 5-fluorouracil |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767736/ https://www.ncbi.nlm.nih.gov/pubmed/31632470 http://dx.doi.org/10.1177/1758835919878977 |
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