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Artesunate Impairs Growth in Cisplatin-Resistant Bladder Cancer Cells by Cell Cycle Arrest, Apoptosis and Autophagy Induction

Cisplatin, which induces DNA damage, is standard chemotherapy for advanced bladder cancer (BCa). However, efficacy is limited due to resistance development. Since artesunate (ART), a derivative of artemisinin originating from Traditional Chinese Medicine, has been shown to exhibit anti-tumor activit...

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Autores principales: Zhao, Fuguang, Vakhrusheva, Olesya, Markowitsch, Sascha D., Slade, Kimberly S., Tsaur, Igor, Cinatl, Jindrich, Michaelis, Martin, Efferth, Thomas, Haferkamp, Axel, Juengel, Eva
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763932/
https://www.ncbi.nlm.nih.gov/pubmed/33316936
http://dx.doi.org/10.3390/cells9122643
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author Zhao, Fuguang
Vakhrusheva, Olesya
Markowitsch, Sascha D.
Slade, Kimberly S.
Tsaur, Igor
Cinatl, Jindrich
Michaelis, Martin
Efferth, Thomas
Haferkamp, Axel
Juengel, Eva
author_facet Zhao, Fuguang
Vakhrusheva, Olesya
Markowitsch, Sascha D.
Slade, Kimberly S.
Tsaur, Igor
Cinatl, Jindrich
Michaelis, Martin
Efferth, Thomas
Haferkamp, Axel
Juengel, Eva
author_sort Zhao, Fuguang
collection PubMed
description Cisplatin, which induces DNA damage, is standard chemotherapy for advanced bladder cancer (BCa). However, efficacy is limited due to resistance development. Since artesunate (ART), a derivative of artemisinin originating from Traditional Chinese Medicine, has been shown to exhibit anti-tumor activity, and to inhibit DNA damage repair, the impact of artesunate on cisplatin-resistant BCa was evaluated. Cisplatin-sensitive (parental) and cisplatin-resistant BCa cells, RT4, RT112, T24, and TCCSup, were treated with ART (1–100 µM). Cell growth, proliferation, and cell cycle phases were investigated, as were apoptosis, necrosis, ferroptosis, autophagy, metabolic activity, and protein expression. Exposure to ART induced a time- and dose-dependent significant inhibition of tumor cell growth and proliferation of parental and cisplatin-resistant BCa cells. This inhibition was accompanied by a G0/G1 phase arrest and modulation of cell cycle regulating proteins. ART induced apoptos is by enhancing DNA damage, especially in the resistant cells. ART did not induce ferroptosis, but led to a disturbance of mitochondrial respiration and ATP generation. This impairment correlated with autophagy accompanied by a decrease in LC3B-I and an increase in LC3B-II. Since ART significantly inhibits proliferative and metabolic aspects of cisplatin-sensitive and cisplatin-resistant BCa cells, it may hold potential in treating advanced and therapy-resistant BCa.
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spelling pubmed-77639322020-12-27 Artesunate Impairs Growth in Cisplatin-Resistant Bladder Cancer Cells by Cell Cycle Arrest, Apoptosis and Autophagy Induction Zhao, Fuguang Vakhrusheva, Olesya Markowitsch, Sascha D. Slade, Kimberly S. Tsaur, Igor Cinatl, Jindrich Michaelis, Martin Efferth, Thomas Haferkamp, Axel Juengel, Eva Cells Article Cisplatin, which induces DNA damage, is standard chemotherapy for advanced bladder cancer (BCa). However, efficacy is limited due to resistance development. Since artesunate (ART), a derivative of artemisinin originating from Traditional Chinese Medicine, has been shown to exhibit anti-tumor activity, and to inhibit DNA damage repair, the impact of artesunate on cisplatin-resistant BCa was evaluated. Cisplatin-sensitive (parental) and cisplatin-resistant BCa cells, RT4, RT112, T24, and TCCSup, were treated with ART (1–100 µM). Cell growth, proliferation, and cell cycle phases were investigated, as were apoptosis, necrosis, ferroptosis, autophagy, metabolic activity, and protein expression. Exposure to ART induced a time- and dose-dependent significant inhibition of tumor cell growth and proliferation of parental and cisplatin-resistant BCa cells. This inhibition was accompanied by a G0/G1 phase arrest and modulation of cell cycle regulating proteins. ART induced apoptos is by enhancing DNA damage, especially in the resistant cells. ART did not induce ferroptosis, but led to a disturbance of mitochondrial respiration and ATP generation. This impairment correlated with autophagy accompanied by a decrease in LC3B-I and an increase in LC3B-II. Since ART significantly inhibits proliferative and metabolic aspects of cisplatin-sensitive and cisplatin-resistant BCa cells, it may hold potential in treating advanced and therapy-resistant BCa. MDPI 2020-12-09 /pmc/articles/PMC7763932/ /pubmed/33316936 http://dx.doi.org/10.3390/cells9122643 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhao, Fuguang
Vakhrusheva, Olesya
Markowitsch, Sascha D.
Slade, Kimberly S.
Tsaur, Igor
Cinatl, Jindrich
Michaelis, Martin
Efferth, Thomas
Haferkamp, Axel
Juengel, Eva
Artesunate Impairs Growth in Cisplatin-Resistant Bladder Cancer Cells by Cell Cycle Arrest, Apoptosis and Autophagy Induction
title Artesunate Impairs Growth in Cisplatin-Resistant Bladder Cancer Cells by Cell Cycle Arrest, Apoptosis and Autophagy Induction
title_full Artesunate Impairs Growth in Cisplatin-Resistant Bladder Cancer Cells by Cell Cycle Arrest, Apoptosis and Autophagy Induction
title_fullStr Artesunate Impairs Growth in Cisplatin-Resistant Bladder Cancer Cells by Cell Cycle Arrest, Apoptosis and Autophagy Induction
title_full_unstemmed Artesunate Impairs Growth in Cisplatin-Resistant Bladder Cancer Cells by Cell Cycle Arrest, Apoptosis and Autophagy Induction
title_short Artesunate Impairs Growth in Cisplatin-Resistant Bladder Cancer Cells by Cell Cycle Arrest, Apoptosis and Autophagy Induction
title_sort artesunate impairs growth in cisplatin-resistant bladder cancer cells by cell cycle arrest, apoptosis and autophagy induction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763932/
https://www.ncbi.nlm.nih.gov/pubmed/33316936
http://dx.doi.org/10.3390/cells9122643
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