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The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro

A major challenge in current cancer therapy is still the treatment of metastatic melanomas of the skin. BH3 mimetics represent a novel group of substances inducing apoptosis. In this study, we investigated the cytotoxic effect of (±) gossypol (GP), a natural compound from cotton seed, on A375 melano...

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Autores principales: Haasler, Lisa, Kondadi, Arun Kumar, Tsigaras, Thanos, von Montfort, Claudia, Graf, Peter, Stahl, Wilhelm, Brenneisen, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032633/
https://www.ncbi.nlm.nih.gov/pubmed/33523262
http://dx.doi.org/10.1007/s00204-021-02987-4
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author Haasler, Lisa
Kondadi, Arun Kumar
Tsigaras, Thanos
von Montfort, Claudia
Graf, Peter
Stahl, Wilhelm
Brenneisen, Peter
author_facet Haasler, Lisa
Kondadi, Arun Kumar
Tsigaras, Thanos
von Montfort, Claudia
Graf, Peter
Stahl, Wilhelm
Brenneisen, Peter
author_sort Haasler, Lisa
collection PubMed
description A major challenge in current cancer therapy is still the treatment of metastatic melanomas of the skin. BH3 mimetics represent a novel group of substances inducing apoptosis. In this study, we investigated the cytotoxic effect of (±) gossypol (GP), a natural compound from cotton seed, on A375 melanoma cells and the underlying biochemical mechanisms. To prevent undesired side effects due to toxicity on normal (healthy) cells, concentrations only toxic for tumor cells have been elaborated. Viability assays were performed to determine the cytotoxicity of GP in A375 melanoma and normal (healthy) cells. For the majority of experiments, a concentration of 2.5 µM GP was used resulting in a ROS-independent but caspase-dependent cell death of A375 melanoma cells. At this level, GP was non-toxic for normal human epidermal melanocytes. GP has a very short half-life, however, it was demonstrated that only the “parent” compound and not decomposition products are responsible for the cytotoxic effect in A375 melanoma cells. GP significantly decreased mitochondrial membrane potential accompanied by a Drp1-dependent loss of mitochondrial integrity (fragmentation) in tumor cells. Taken together, GP induced a ROS-independent intrinsic apoptosis leading to the conclusion that within a specific concentration range, GP may work as effective anticancer drug without harmful side effects. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00204-021-02987-4.
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spelling pubmed-80326332021-04-27 The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro Haasler, Lisa Kondadi, Arun Kumar Tsigaras, Thanos von Montfort, Claudia Graf, Peter Stahl, Wilhelm Brenneisen, Peter Arch Toxicol Molecular Toxicology A major challenge in current cancer therapy is still the treatment of metastatic melanomas of the skin. BH3 mimetics represent a novel group of substances inducing apoptosis. In this study, we investigated the cytotoxic effect of (±) gossypol (GP), a natural compound from cotton seed, on A375 melanoma cells and the underlying biochemical mechanisms. To prevent undesired side effects due to toxicity on normal (healthy) cells, concentrations only toxic for tumor cells have been elaborated. Viability assays were performed to determine the cytotoxicity of GP in A375 melanoma and normal (healthy) cells. For the majority of experiments, a concentration of 2.5 µM GP was used resulting in a ROS-independent but caspase-dependent cell death of A375 melanoma cells. At this level, GP was non-toxic for normal human epidermal melanocytes. GP has a very short half-life, however, it was demonstrated that only the “parent” compound and not decomposition products are responsible for the cytotoxic effect in A375 melanoma cells. GP significantly decreased mitochondrial membrane potential accompanied by a Drp1-dependent loss of mitochondrial integrity (fragmentation) in tumor cells. Taken together, GP induced a ROS-independent intrinsic apoptosis leading to the conclusion that within a specific concentration range, GP may work as effective anticancer drug without harmful side effects. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00204-021-02987-4. Springer Berlin Heidelberg 2021-02-01 2021 /pmc/articles/PMC8032633/ /pubmed/33523262 http://dx.doi.org/10.1007/s00204-021-02987-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Molecular Toxicology
Haasler, Lisa
Kondadi, Arun Kumar
Tsigaras, Thanos
von Montfort, Claudia
Graf, Peter
Stahl, Wilhelm
Brenneisen, Peter
The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro
title The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro
title_full The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro
title_fullStr The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro
title_full_unstemmed The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro
title_short The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro
title_sort bh3 mimetic (±) gossypol induces ros-independent apoptosis and mitochondrial dysfunction in human a375 melanoma cells in vitro
topic Molecular Toxicology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032633/
https://www.ncbi.nlm.nih.gov/pubmed/33523262
http://dx.doi.org/10.1007/s00204-021-02987-4
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