Deoxyelephantopin induces ROS-mediated autophagy and apoptosis in human colorectal cancer in vitro and in vivo
Objective: To systematically map the stepwise events leading to deoxyelephantopin-induced cell death of HCT116 human colorectal cancer cells and evaluate the effectiveness of deoxyelephantopin in vivo. Methods: HCT116 cells were treated with deoxyelephantopin at various concentrations and time point...
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Wolters Kluwer Medknow Publications
2020
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ftdoajarticles:oai:doaj.org/article:065a0cb20adf481f9566812dee362f86 2023-05-15T15:11:48+02:00 Deoxyelephantopin induces ROS-mediated autophagy and apoptosis in human colorectal cancer in vitro and in vivo Chim-Kei Chan Kind-Leng Tong Pooi-Fong Wong Habsah Abdul Kadir 2020-01-01T00:00:00Z https://doi.org/10.4103/2221-1691.276318 https://doaj.org/article/065a0cb20adf481f9566812dee362f86 EN eng Wolters Kluwer Medknow Publications http://www.apjtb.org/article.asp?issn=2221-1691;year=2020;volume=10;issue=3;spage=120;epage=135;aulast=Chan https://doaj.org/toc/2588-9222 2588-9222 doi:10.4103/2221-1691.276318 https://doaj.org/article/065a0cb20adf481f9566812dee362f86 Asian Pacific Journal of Tropical Biomedicine, Vol 10, Iss 3, Pp 120-135 (2020) deoxyelephantopin autophagy pi3k mtor colorectal cancer mapk Arctic medicine. Tropical medicine RC955-962 Biology (General) QH301-705.5 article 2020 ftdoajarticles https://doi.org/10.4103/2221-1691.276318 2022-12-31T04:56:54Z Objective: To systematically map the stepwise events leading to deoxyelephantopin-induced cell death of HCT116 human colorectal cancer cells and evaluate the effectiveness of deoxyelephantopin in vivo. Methods: HCT116 cells were treated with deoxyelephantopin at various concentrations and time points. Autophagy was confirmed by the detection of autophagosomes and autophagosomal proteins by electron microscopy and Western blotting assays, respectively, and then validated by siRNA knockdown. In addition, apoptosis was confirmed by the detection of apoptosis-related proteins. The intracellular reactive oxygen species (ROS) level was measured using flow cytometry. The growth inhibitory effect of deoxyelephantopin was further evaluated in vivo using a mouse xenograft model. Results: Deoxyelephantopin firstly elevated ROS production, which then triggered autophagic flux with the accumulation of autophagosomal proteins including LC3A/B, ATG5, and ATG7, followed by the induction of apoptosis via the intrinsic and extrinsic pathways. Pre-treatment with N-acetyl-L-cysteine, a ROS inhibitor, reversed both apoptosis and autophagy. The knockdown of LC3 prevented apoptosis induction which confirmed that deoxyelephantopin induced autophagy-dependent apoptosis in HCT116 cells. Accumulation of ROS also activated apoptosis via the mitogen-activated protein kinases signaling pathway. Furthermore, deoxyelephantopin also inhibited the PI3K/AKT/mTOR pathway, which then released the inhibition of autophagy. In vivo study further showed that deoxyelephantopin significantly suppressed the growth of HCT116 subcutaneous xenograft in nude mice. Conclusions: Our findings revealed that deoxyelephantopin elevates oxidative stress and induces ROS-dependent autophagy followed by apoptosis in HCT116 cells via the concerted modulation of multiple signaling pathways. These findings further support the development of deoxyelephantopin as a therapeutic agent for colorectal cancer. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Asian Pacific Journal of Tropical Biomedicine 10 3 120 |
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Directory of Open Access Journals: DOAJ Articles |
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language |
English |
topic |
deoxyelephantopin autophagy pi3k mtor colorectal cancer mapk Arctic medicine. Tropical medicine RC955-962 Biology (General) QH301-705.5 |
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deoxyelephantopin autophagy pi3k mtor colorectal cancer mapk Arctic medicine. Tropical medicine RC955-962 Biology (General) QH301-705.5 Chim-Kei Chan Kind-Leng Tong Pooi-Fong Wong Habsah Abdul Kadir Deoxyelephantopin induces ROS-mediated autophagy and apoptosis in human colorectal cancer in vitro and in vivo |
topic_facet |
deoxyelephantopin autophagy pi3k mtor colorectal cancer mapk Arctic medicine. Tropical medicine RC955-962 Biology (General) QH301-705.5 |
description |
Objective: To systematically map the stepwise events leading to deoxyelephantopin-induced cell death of HCT116 human colorectal cancer cells and evaluate the effectiveness of deoxyelephantopin in vivo. Methods: HCT116 cells were treated with deoxyelephantopin at various concentrations and time points. Autophagy was confirmed by the detection of autophagosomes and autophagosomal proteins by electron microscopy and Western blotting assays, respectively, and then validated by siRNA knockdown. In addition, apoptosis was confirmed by the detection of apoptosis-related proteins. The intracellular reactive oxygen species (ROS) level was measured using flow cytometry. The growth inhibitory effect of deoxyelephantopin was further evaluated in vivo using a mouse xenograft model. Results: Deoxyelephantopin firstly elevated ROS production, which then triggered autophagic flux with the accumulation of autophagosomal proteins including LC3A/B, ATG5, and ATG7, followed by the induction of apoptosis via the intrinsic and extrinsic pathways. Pre-treatment with N-acetyl-L-cysteine, a ROS inhibitor, reversed both apoptosis and autophagy. The knockdown of LC3 prevented apoptosis induction which confirmed that deoxyelephantopin induced autophagy-dependent apoptosis in HCT116 cells. Accumulation of ROS also activated apoptosis via the mitogen-activated protein kinases signaling pathway. Furthermore, deoxyelephantopin also inhibited the PI3K/AKT/mTOR pathway, which then released the inhibition of autophagy. In vivo study further showed that deoxyelephantopin significantly suppressed the growth of HCT116 subcutaneous xenograft in nude mice. Conclusions: Our findings revealed that deoxyelephantopin elevates oxidative stress and induces ROS-dependent autophagy followed by apoptosis in HCT116 cells via the concerted modulation of multiple signaling pathways. These findings further support the development of deoxyelephantopin as a therapeutic agent for colorectal cancer. |
format |
Article in Journal/Newspaper |
author |
Chim-Kei Chan Kind-Leng Tong Pooi-Fong Wong Habsah Abdul Kadir |
author_facet |
Chim-Kei Chan Kind-Leng Tong Pooi-Fong Wong Habsah Abdul Kadir |
author_sort |
Chim-Kei Chan |
title |
Deoxyelephantopin induces ROS-mediated autophagy and apoptosis in human colorectal cancer in vitro and in vivo |
title_short |
Deoxyelephantopin induces ROS-mediated autophagy and apoptosis in human colorectal cancer in vitro and in vivo |
title_full |
Deoxyelephantopin induces ROS-mediated autophagy and apoptosis in human colorectal cancer in vitro and in vivo |
title_fullStr |
Deoxyelephantopin induces ROS-mediated autophagy and apoptosis in human colorectal cancer in vitro and in vivo |
title_full_unstemmed |
Deoxyelephantopin induces ROS-mediated autophagy and apoptosis in human colorectal cancer in vitro and in vivo |
title_sort |
deoxyelephantopin induces ros-mediated autophagy and apoptosis in human colorectal cancer in vitro and in vivo |
publisher |
Wolters Kluwer Medknow Publications |
publishDate |
2020 |
url |
https://doi.org/10.4103/2221-1691.276318 https://doaj.org/article/065a0cb20adf481f9566812dee362f86 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Asian Pacific Journal of Tropical Biomedicine, Vol 10, Iss 3, Pp 120-135 (2020) |
op_relation |
http://www.apjtb.org/article.asp?issn=2221-1691;year=2020;volume=10;issue=3;spage=120;epage=135;aulast=Chan https://doaj.org/toc/2588-9222 2588-9222 doi:10.4103/2221-1691.276318 https://doaj.org/article/065a0cb20adf481f9566812dee362f86 |
op_doi |
https://doi.org/10.4103/2221-1691.276318 |
container_title |
Asian Pacific Journal of Tropical Biomedicine |
container_volume |
10 |
container_issue |
3 |
container_start_page |
120 |
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1766342595964829696 |