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Mubritinib enhanced the inhibiting function of cisplatin in lung cancer by interfering with mitochondrial function

BACKGROUND: Lung cancer is one of the most lethal cancers worldwide. Cisplatin, a widely used anti‐lung cancer drug, has been limited in clinical application due to its drug resistance. Medicines targeting mitochondrial electron transport chain (ETC) complexes may be effective candidates for cisplat...

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Autores principales: Dong, Jingyao, Zhu, Dongshan, Chen, Mengmeng, Wang, Taiwei, Gao, Yan, Liu, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons Australia, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9108040/
https://www.ncbi.nlm.nih.gov/pubmed/35429141
http://dx.doi.org/10.1111/1759-7714.14425
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author Dong, Jingyao
Zhu, Dongshan
Chen, Mengmeng
Wang, Taiwei
Gao, Yan
Liu, Wei
author_facet Dong, Jingyao
Zhu, Dongshan
Chen, Mengmeng
Wang, Taiwei
Gao, Yan
Liu, Wei
author_sort Dong, Jingyao
collection PubMed
description BACKGROUND: Lung cancer is one of the most lethal cancers worldwide. Cisplatin, a widely used anti‐lung cancer drug, has been limited in clinical application due to its drug resistance. Medicines targeting mitochondrial electron transport chain (ETC) complexes may be effective candidates for cisplatin‐based chemotherapy. METHODS: In this study, the small molecule drug library from Food and Drug Administration FDA was used to screen for medicines targeting ETC. MTT and colony formation assays were used to investigate cell proliferation. Flow cytometry was employed to analyze cell cycle, apoptosis, reactive oxygen species (ROS), and mitochondrial membrane potential. Wound scratch and transwell assays were used to detect migration and invasion abilities. The activities of the ETC complex were tested using kits. Western blot analysis was used to investigate the expressions of related proteins. A mouse xenograft model was constructed to verify the antitumor effect in vivo. RESULTS: The results showed that mubritinib can reduce the activation of the PI3K/mTOR signal pathway, disrupt mitochondrial function, significantly increase ROS levels and induce oxidative stress, and ultimately exert its antitumor effect against non‐small cell lung cancer (NSCLC) both in vivo and in vitro. In addition, the combination of cisplatin and mubritinib can improve the tumor‐suppressive effect of cisplatin. CONCLUSION: Mubritinib can upregulate intracellular ROS concentration and cell apoptosis, inhibit the PI3K signaling pathway and interfere with the function of mitochondria, thus reducing cell proliferation and increasing ROS induced apoptosis by reducing the activation of Nrf2 by PI3K.
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spelling pubmed-91080402022-05-20 Mubritinib enhanced the inhibiting function of cisplatin in lung cancer by interfering with mitochondrial function Dong, Jingyao Zhu, Dongshan Chen, Mengmeng Wang, Taiwei Gao, Yan Liu, Wei Thorac Cancer Original Articles BACKGROUND: Lung cancer is one of the most lethal cancers worldwide. Cisplatin, a widely used anti‐lung cancer drug, has been limited in clinical application due to its drug resistance. Medicines targeting mitochondrial electron transport chain (ETC) complexes may be effective candidates for cisplatin‐based chemotherapy. METHODS: In this study, the small molecule drug library from Food and Drug Administration FDA was used to screen for medicines targeting ETC. MTT and colony formation assays were used to investigate cell proliferation. Flow cytometry was employed to analyze cell cycle, apoptosis, reactive oxygen species (ROS), and mitochondrial membrane potential. Wound scratch and transwell assays were used to detect migration and invasion abilities. The activities of the ETC complex were tested using kits. Western blot analysis was used to investigate the expressions of related proteins. A mouse xenograft model was constructed to verify the antitumor effect in vivo. RESULTS: The results showed that mubritinib can reduce the activation of the PI3K/mTOR signal pathway, disrupt mitochondrial function, significantly increase ROS levels and induce oxidative stress, and ultimately exert its antitumor effect against non‐small cell lung cancer (NSCLC) both in vivo and in vitro. In addition, the combination of cisplatin and mubritinib can improve the tumor‐suppressive effect of cisplatin. CONCLUSION: Mubritinib can upregulate intracellular ROS concentration and cell apoptosis, inhibit the PI3K signaling pathway and interfere with the function of mitochondria, thus reducing cell proliferation and increasing ROS induced apoptosis by reducing the activation of Nrf2 by PI3K. John Wiley & Sons Australia, Ltd 2022-04-16 2022-05 /pmc/articles/PMC9108040/ /pubmed/35429141 http://dx.doi.org/10.1111/1759-7714.14425 Text en © 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Dong, Jingyao
Zhu, Dongshan
Chen, Mengmeng
Wang, Taiwei
Gao, Yan
Liu, Wei
Mubritinib enhanced the inhibiting function of cisplatin in lung cancer by interfering with mitochondrial function
title Mubritinib enhanced the inhibiting function of cisplatin in lung cancer by interfering with mitochondrial function
title_full Mubritinib enhanced the inhibiting function of cisplatin in lung cancer by interfering with mitochondrial function
title_fullStr Mubritinib enhanced the inhibiting function of cisplatin in lung cancer by interfering with mitochondrial function
title_full_unstemmed Mubritinib enhanced the inhibiting function of cisplatin in lung cancer by interfering with mitochondrial function
title_short Mubritinib enhanced the inhibiting function of cisplatin in lung cancer by interfering with mitochondrial function
title_sort mubritinib enhanced the inhibiting function of cisplatin in lung cancer by interfering with mitochondrial function
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9108040/
https://www.ncbi.nlm.nih.gov/pubmed/35429141
http://dx.doi.org/10.1111/1759-7714.14425
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