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Reductive damage induced autophagy inhibition for tumor therapy
Numerous therapeutic anti-tumor strategies have been developed in recent decades. However, their therapeutic efficacy is reduced by the intrinsic protective autophagy of tumors. Autophagy plays a key role in tumorigenesis and tumor treatment, in which the overproduction of reactive oxygen species (R...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Tsinghua University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9684861/ https://www.ncbi.nlm.nih.gov/pubmed/36465522 http://dx.doi.org/10.1007/s12274-022-5139-z |
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author | Wang, Yuqian Huang, Yingjian Fu, Yu Guo, Zhixiong Chen, Da Cao, Fangxian Ye, Qi Duan, Qiqi Liu, Meng Wang, Ning Han, Dan Qu, Chaoyi Tian, Zhimin Qu, Yongquan Zheng, Yan |
author_facet | Wang, Yuqian Huang, Yingjian Fu, Yu Guo, Zhixiong Chen, Da Cao, Fangxian Ye, Qi Duan, Qiqi Liu, Meng Wang, Ning Han, Dan Qu, Chaoyi Tian, Zhimin Qu, Yongquan Zheng, Yan |
author_sort | Wang, Yuqian |
collection | PubMed |
description | Numerous therapeutic anti-tumor strategies have been developed in recent decades. However, their therapeutic efficacy is reduced by the intrinsic protective autophagy of tumors. Autophagy plays a key role in tumorigenesis and tumor treatment, in which the overproduction of reactive oxygen species (ROS) is recognized as the direct cause of protective autophagy. Only a few molecules have been employed as autophagy inhibitors in tumor therapy to reduce protective autophagy. Among them, hydroxychloroquine is the most commonly used autophagy inhibitor in clinics, but it is severely limited by its high therapeutic dose, significant toxicity, poor reversal efficacy, and nonspecific action. Herein, we demonstrate a reductive-damage strategy to enable tumor therapy by the inhibition of protective autophagy via the catalytic scavenging of ROS using porous nanorods of ceria (PN-CeO(2)) nanozymes as autophagy inhibitor. The antineoplastic effects of PN-CeO(2) were mediated by its high reductive activity for intratumoral ROS degradation, thereby inhibiting protective autophagy and activating apoptosis by suppressing the activities of phosphatidylinositide 3-kinase/protein kinase B and p38 mitogen-activated protein kinase pathways in human cutaneous squamous cell carcinoma. Further investigation highlighted PN-CeO(2) as a safe and efficient anti-tumor autophagy inhibitor. Overall, this study presents a reductive-damage strategy as a promising anti-tumor approach that catalytically inhibits autophagy and activates the intrinsic antioxidant pathways of tumor cells and also shows its potential for the therapy of other autophagy-related diseases. [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material (cellular uptake of PN-CeO(2), effects of PN-CeO(2) on several common malignant tumor models, viability of HaCaT cells treated with PN-CeO(2) at different concentrations, time-dependent body-weight curves of SCL-1 tumor-bearing nude mice, the biodistribution of Ce element in main tissues and tumors after injection of PN-CeO(2), measurement of Ce element concentration in urine and feces samples, H&E-stained images of main organs, and measurement of liver and kidney function in mice after different treatment) is available in the online version of this article at 10.1007/s12274-022-5139-z. |
format | Online Article Text |
id | pubmed-9684861 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Tsinghua University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-96848612022-11-28 Reductive damage induced autophagy inhibition for tumor therapy Wang, Yuqian Huang, Yingjian Fu, Yu Guo, Zhixiong Chen, Da Cao, Fangxian Ye, Qi Duan, Qiqi Liu, Meng Wang, Ning Han, Dan Qu, Chaoyi Tian, Zhimin Qu, Yongquan Zheng, Yan Nano Res Research Article Numerous therapeutic anti-tumor strategies have been developed in recent decades. However, their therapeutic efficacy is reduced by the intrinsic protective autophagy of tumors. Autophagy plays a key role in tumorigenesis and tumor treatment, in which the overproduction of reactive oxygen species (ROS) is recognized as the direct cause of protective autophagy. Only a few molecules have been employed as autophagy inhibitors in tumor therapy to reduce protective autophagy. Among them, hydroxychloroquine is the most commonly used autophagy inhibitor in clinics, but it is severely limited by its high therapeutic dose, significant toxicity, poor reversal efficacy, and nonspecific action. Herein, we demonstrate a reductive-damage strategy to enable tumor therapy by the inhibition of protective autophagy via the catalytic scavenging of ROS using porous nanorods of ceria (PN-CeO(2)) nanozymes as autophagy inhibitor. The antineoplastic effects of PN-CeO(2) were mediated by its high reductive activity for intratumoral ROS degradation, thereby inhibiting protective autophagy and activating apoptosis by suppressing the activities of phosphatidylinositide 3-kinase/protein kinase B and p38 mitogen-activated protein kinase pathways in human cutaneous squamous cell carcinoma. Further investigation highlighted PN-CeO(2) as a safe and efficient anti-tumor autophagy inhibitor. Overall, this study presents a reductive-damage strategy as a promising anti-tumor approach that catalytically inhibits autophagy and activates the intrinsic antioxidant pathways of tumor cells and also shows its potential for the therapy of other autophagy-related diseases. [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material (cellular uptake of PN-CeO(2), effects of PN-CeO(2) on several common malignant tumor models, viability of HaCaT cells treated with PN-CeO(2) at different concentrations, time-dependent body-weight curves of SCL-1 tumor-bearing nude mice, the biodistribution of Ce element in main tissues and tumors after injection of PN-CeO(2), measurement of Ce element concentration in urine and feces samples, H&E-stained images of main organs, and measurement of liver and kidney function in mice after different treatment) is available in the online version of this article at 10.1007/s12274-022-5139-z. Tsinghua University Press 2022-11-22 2023 /pmc/articles/PMC9684861/ /pubmed/36465522 http://dx.doi.org/10.1007/s12274-022-5139-z Text en © Tsinghua University Press 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. |
spellingShingle | Research Article Wang, Yuqian Huang, Yingjian Fu, Yu Guo, Zhixiong Chen, Da Cao, Fangxian Ye, Qi Duan, Qiqi Liu, Meng Wang, Ning Han, Dan Qu, Chaoyi Tian, Zhimin Qu, Yongquan Zheng, Yan Reductive damage induced autophagy inhibition for tumor therapy |
title | Reductive damage induced autophagy inhibition for tumor therapy |
title_full | Reductive damage induced autophagy inhibition for tumor therapy |
title_fullStr | Reductive damage induced autophagy inhibition for tumor therapy |
title_full_unstemmed | Reductive damage induced autophagy inhibition for tumor therapy |
title_short | Reductive damage induced autophagy inhibition for tumor therapy |
title_sort | reductive damage induced autophagy inhibition for tumor therapy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9684861/ https://www.ncbi.nlm.nih.gov/pubmed/36465522 http://dx.doi.org/10.1007/s12274-022-5139-z |
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