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Actinomycin V Induces Apoptosis Associated with Mitochondrial and PI3K/AKT Pathways in Human CRC Cells

Actinomycin (Act) V, an analogue of Act D, presented stronger antitumor activity and less hepatorenal toxicity than Act D in our previous studies, which is worthy of further investigation. We hereby report that Act V induces apoptosis via mitochondrial and PI3K/AKT pathways in colorectal cancer (CRC...

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Autores principales: Jiang, Shiqing, Zhang, E, Ruan, Hang, Ma, Jiahui, Zhao, Xingming, Zhu, Yaoyao, Xie, Xiaoyu, Han, Ningning, Li, Jianjiang, Zhang, Hao, Xie, Weidong, Li, Xia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618951/
https://www.ncbi.nlm.nih.gov/pubmed/34822470
http://dx.doi.org/10.3390/md19110599
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author Jiang, Shiqing
Zhang, E
Ruan, Hang
Ma, Jiahui
Zhao, Xingming
Zhu, Yaoyao
Xie, Xiaoyu
Han, Ningning
Li, Jianjiang
Zhang, Hao
Xie, Weidong
Li, Xia
author_facet Jiang, Shiqing
Zhang, E
Ruan, Hang
Ma, Jiahui
Zhao, Xingming
Zhu, Yaoyao
Xie, Xiaoyu
Han, Ningning
Li, Jianjiang
Zhang, Hao
Xie, Weidong
Li, Xia
author_sort Jiang, Shiqing
collection PubMed
description Actinomycin (Act) V, an analogue of Act D, presented stronger antitumor activity and less hepatorenal toxicity than Act D in our previous studies, which is worthy of further investigation. We hereby report that Act V induces apoptosis via mitochondrial and PI3K/AKT pathways in colorectal cancer (CRC) cells. Act V-induced apoptosis was characterized by mitochondrial dysfunction, with loss of mitochondria membrane potential (MMP) and cytochrome c release, which then activated cleaved caspase-9, cleaved caspase-3, and cleaved PARP, revealing that it was related to the mitochondrial pathway, and the apoptotic trendency can be reversed by caspase inhibitor Z-VAD-FMK. Furthermore, we proved that Act V significantly inhibited PI3K/AKT signalling in HCT-116 cells using cell experiments in vitro, and it also presented a potential targeted PI3Kα inhibition using computer docking models. Further elucidation revealed that it exhibited a 28-fold greater potency than the PI3K inhibitor LY294002 on PI3K inhibition efficacy. Taken together, Act V, as a superior potential replacement of Act D, is a potential candidate for inhibiting the PI3K/AKT pathway and is worthy of more pre-clinical studies in the therapy of CRC.
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spelling pubmed-86189512021-11-27 Actinomycin V Induces Apoptosis Associated with Mitochondrial and PI3K/AKT Pathways in Human CRC Cells Jiang, Shiqing Zhang, E Ruan, Hang Ma, Jiahui Zhao, Xingming Zhu, Yaoyao Xie, Xiaoyu Han, Ningning Li, Jianjiang Zhang, Hao Xie, Weidong Li, Xia Mar Drugs Article Actinomycin (Act) V, an analogue of Act D, presented stronger antitumor activity and less hepatorenal toxicity than Act D in our previous studies, which is worthy of further investigation. We hereby report that Act V induces apoptosis via mitochondrial and PI3K/AKT pathways in colorectal cancer (CRC) cells. Act V-induced apoptosis was characterized by mitochondrial dysfunction, with loss of mitochondria membrane potential (MMP) and cytochrome c release, which then activated cleaved caspase-9, cleaved caspase-3, and cleaved PARP, revealing that it was related to the mitochondrial pathway, and the apoptotic trendency can be reversed by caspase inhibitor Z-VAD-FMK. Furthermore, we proved that Act V significantly inhibited PI3K/AKT signalling in HCT-116 cells using cell experiments in vitro, and it also presented a potential targeted PI3Kα inhibition using computer docking models. Further elucidation revealed that it exhibited a 28-fold greater potency than the PI3K inhibitor LY294002 on PI3K inhibition efficacy. Taken together, Act V, as a superior potential replacement of Act D, is a potential candidate for inhibiting the PI3K/AKT pathway and is worthy of more pre-clinical studies in the therapy of CRC. MDPI 2021-10-22 /pmc/articles/PMC8618951/ /pubmed/34822470 http://dx.doi.org/10.3390/md19110599 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jiang, Shiqing
Zhang, E
Ruan, Hang
Ma, Jiahui
Zhao, Xingming
Zhu, Yaoyao
Xie, Xiaoyu
Han, Ningning
Li, Jianjiang
Zhang, Hao
Xie, Weidong
Li, Xia
Actinomycin V Induces Apoptosis Associated with Mitochondrial and PI3K/AKT Pathways in Human CRC Cells
title Actinomycin V Induces Apoptosis Associated with Mitochondrial and PI3K/AKT Pathways in Human CRC Cells
title_full Actinomycin V Induces Apoptosis Associated with Mitochondrial and PI3K/AKT Pathways in Human CRC Cells
title_fullStr Actinomycin V Induces Apoptosis Associated with Mitochondrial and PI3K/AKT Pathways in Human CRC Cells
title_full_unstemmed Actinomycin V Induces Apoptosis Associated with Mitochondrial and PI3K/AKT Pathways in Human CRC Cells
title_short Actinomycin V Induces Apoptosis Associated with Mitochondrial and PI3K/AKT Pathways in Human CRC Cells
title_sort actinomycin v induces apoptosis associated with mitochondrial and pi3k/akt pathways in human crc cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618951/
https://www.ncbi.nlm.nih.gov/pubmed/34822470
http://dx.doi.org/10.3390/md19110599
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