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The Biological Assessment of Shikonin and β,β-dimethylacrylshikonin Using a Cellular Myxofibrosarcoma Tumor Heterogeneity Model
Myxofibrosarcoma (MFS) is a subtype of soft tissue sarcoma of connective tissue, which is characterized by large intra-tumor heterogeneity. Therapy includes surgical resection. Additional chemotherapy is of limited effect. In this study, we demonstrated the potent anticancer activity of shikonin der...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10650664/ https://www.ncbi.nlm.nih.gov/pubmed/37958891 http://dx.doi.org/10.3390/ijms242115910 |
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author | Lohberger, Birgit Kaltenegger, Heike Eck, Nicole Glänzer, Dietmar Leithner, Andreas Kretschmer, Nadine |
author_facet | Lohberger, Birgit Kaltenegger, Heike Eck, Nicole Glänzer, Dietmar Leithner, Andreas Kretschmer, Nadine |
author_sort | Lohberger, Birgit |
collection | PubMed |
description | Myxofibrosarcoma (MFS) is a subtype of soft tissue sarcoma of connective tissue, which is characterized by large intra-tumor heterogeneity. Therapy includes surgical resection. Additional chemotherapy is of limited effect. In this study, we demonstrated the potent anticancer activity of shikonin derivatives in our MFS cellular model of tumor heterogeneity for developing a new therapeutic approach. The impact of shikonin and β,β-dimethylacrylshikonin (DMAS) on viability, apoptotic induction, MAPK phosphorylation, and DNA damage response were analyzed by means of two human MFS cell lines, MUG-Myx2a and MUG-Myx2b, derived from a singular tumor tissue specimen. MFS cells showed a dose-dependent inhibition of cell viability and a significant induction of apoptosis. Treatment with shikonin derivatives caused an inhibition of pSTAT3 and an increase in pAKT, pERK, pJNK, and pp38. DMAS and shikonin inhibited the activation of the two master upstream regulators of the DNA damage response, ATR and ATM. MUG-Myx2b, which contains an additional PTEN mutation, was more sensitive in some targets. These data demonstrate the significant antitumorigenic effect of shikonin derivatives in MFS and highlight the importance of intra-tumor heterogeneity in treatment planning. |
format | Online Article Text |
id | pubmed-10650664 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-106506642023-11-02 The Biological Assessment of Shikonin and β,β-dimethylacrylshikonin Using a Cellular Myxofibrosarcoma Tumor Heterogeneity Model Lohberger, Birgit Kaltenegger, Heike Eck, Nicole Glänzer, Dietmar Leithner, Andreas Kretschmer, Nadine Int J Mol Sci Article Myxofibrosarcoma (MFS) is a subtype of soft tissue sarcoma of connective tissue, which is characterized by large intra-tumor heterogeneity. Therapy includes surgical resection. Additional chemotherapy is of limited effect. In this study, we demonstrated the potent anticancer activity of shikonin derivatives in our MFS cellular model of tumor heterogeneity for developing a new therapeutic approach. The impact of shikonin and β,β-dimethylacrylshikonin (DMAS) on viability, apoptotic induction, MAPK phosphorylation, and DNA damage response were analyzed by means of two human MFS cell lines, MUG-Myx2a and MUG-Myx2b, derived from a singular tumor tissue specimen. MFS cells showed a dose-dependent inhibition of cell viability and a significant induction of apoptosis. Treatment with shikonin derivatives caused an inhibition of pSTAT3 and an increase in pAKT, pERK, pJNK, and pp38. DMAS and shikonin inhibited the activation of the two master upstream regulators of the DNA damage response, ATR and ATM. MUG-Myx2b, which contains an additional PTEN mutation, was more sensitive in some targets. These data demonstrate the significant antitumorigenic effect of shikonin derivatives in MFS and highlight the importance of intra-tumor heterogeneity in treatment planning. MDPI 2023-11-02 /pmc/articles/PMC10650664/ /pubmed/37958891 http://dx.doi.org/10.3390/ijms242115910 Text en © 2023 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 Lohberger, Birgit Kaltenegger, Heike Eck, Nicole Glänzer, Dietmar Leithner, Andreas Kretschmer, Nadine The Biological Assessment of Shikonin and β,β-dimethylacrylshikonin Using a Cellular Myxofibrosarcoma Tumor Heterogeneity Model |
title | The Biological Assessment of Shikonin and β,β-dimethylacrylshikonin Using a Cellular Myxofibrosarcoma Tumor Heterogeneity Model |
title_full | The Biological Assessment of Shikonin and β,β-dimethylacrylshikonin Using a Cellular Myxofibrosarcoma Tumor Heterogeneity Model |
title_fullStr | The Biological Assessment of Shikonin and β,β-dimethylacrylshikonin Using a Cellular Myxofibrosarcoma Tumor Heterogeneity Model |
title_full_unstemmed | The Biological Assessment of Shikonin and β,β-dimethylacrylshikonin Using a Cellular Myxofibrosarcoma Tumor Heterogeneity Model |
title_short | The Biological Assessment of Shikonin and β,β-dimethylacrylshikonin Using a Cellular Myxofibrosarcoma Tumor Heterogeneity Model |
title_sort | biological assessment of shikonin and β,β-dimethylacrylshikonin using a cellular myxofibrosarcoma tumor heterogeneity model |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10650664/ https://www.ncbi.nlm.nih.gov/pubmed/37958891 http://dx.doi.org/10.3390/ijms242115910 |
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