Ym155 Induces Oxidative Stress-Mediated DNA Damage and Cell Cycle Arrest, and Causes Programmed Cell Death in Anaplastic Thyroid Cancer Cells
Anaplastic thyroid cancer (ATC) is one of the most lethal malignancies with a median survival time of about 4 months. Currently, there is no effective treatment, and the development of new therapies is an important and urgent issue for ATC patients. YM155 is a small molecule that was identified as t...
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MDPI AG
2021-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/4/1961 |
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| author | Qinqin Xu Ryan P. Mackay Adam Y. Xiao John A. Copland Paul M. Weinberger |
| author_facet | Qinqin Xu Ryan P. Mackay Adam Y. Xiao John A. Copland Paul M. Weinberger |
| author_sort | Qinqin Xu |
| collection | DOAJ |
| description | Anaplastic thyroid cancer (ATC) is one of the most lethal malignancies with a median survival time of about 4 months. Currently, there is no effective treatment, and the development of new therapies is an important and urgent issue for ATC patients. YM155 is a small molecule that was identified as the top candidate in a high-throughput screen of small molecule inhibitors performed against a panel of ATC cell lines by the National Cancer Institute. However, there were no follow-up studies investigating YM155 in ATC. Here, we determined the effects of YM155 on ATC and human primary benign thyroid cell (PBTC) survival with alamarBlue assay. Our data show that YM155 inhibited proliferation of ATC cell lines while sparing normal thyroid cells, suggesting a high therapeutic window. YM155-induced DNA damage was detected by measuring phosphorylation of γ-H2AX as a marker for DNA double-strand breaks. The formamidopyrimidine-DNA glycosylase (FPG)-modified alkaline comet assay in conjunction with reactive oxygen species (ROS) assay and glutathione (GSH)/glutathione (GSSG) assay suggests that YM155-mediated oxidative stress contributes to DNA damage. In addition, we provide evidence that YM155 causes cell cycle arrest in S phase and in the G2/M transition and causes apoptosis, as seen with flow cytometry. In this study, we show for the first time the multiple effects of YM155 in ATC cells, furthering a potential therapeutic approach for ATC. |
| first_indexed | 2024-03-09T00:49:15Z |
| format | Article |
| id | doaj.art-15f3c11681564e2e93ed1a3813e035f9 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T00:49:15Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-15f3c11681564e2e93ed1a3813e035f92023-12-11T17:18:33ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01224196110.3390/ijms22041961Ym155 Induces Oxidative Stress-Mediated DNA Damage and Cell Cycle Arrest, and Causes Programmed Cell Death in Anaplastic Thyroid Cancer CellsQinqin Xu0Ryan P. Mackay1Adam Y. Xiao2John A. Copland3Paul M. Weinberger4Departments of Otolaryngology, Head & Neck Surgery, LSU Health Shreveport, 1501 Kings Highway, Shreveport, LA 71103, USADepartments of Otolaryngology, Head & Neck Surgery, LSU Health Shreveport, 1501 Kings Highway, Shreveport, LA 71103, USADepartments of Molecular and Cellular Physiology, LSU Health Shreveport, 1501 Kings Highway, Shreveport, LA 71103, USADepartment of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USADepartments of Otolaryngology, Head & Neck Surgery, LSU Health Shreveport, 1501 Kings Highway, Shreveport, LA 71103, USAAnaplastic thyroid cancer (ATC) is one of the most lethal malignancies with a median survival time of about 4 months. Currently, there is no effective treatment, and the development of new therapies is an important and urgent issue for ATC patients. YM155 is a small molecule that was identified as the top candidate in a high-throughput screen of small molecule inhibitors performed against a panel of ATC cell lines by the National Cancer Institute. However, there were no follow-up studies investigating YM155 in ATC. Here, we determined the effects of YM155 on ATC and human primary benign thyroid cell (PBTC) survival with alamarBlue assay. Our data show that YM155 inhibited proliferation of ATC cell lines while sparing normal thyroid cells, suggesting a high therapeutic window. YM155-induced DNA damage was detected by measuring phosphorylation of γ-H2AX as a marker for DNA double-strand breaks. The formamidopyrimidine-DNA glycosylase (FPG)-modified alkaline comet assay in conjunction with reactive oxygen species (ROS) assay and glutathione (GSH)/glutathione (GSSG) assay suggests that YM155-mediated oxidative stress contributes to DNA damage. In addition, we provide evidence that YM155 causes cell cycle arrest in S phase and in the G2/M transition and causes apoptosis, as seen with flow cytometry. In this study, we show for the first time the multiple effects of YM155 in ATC cells, furthering a potential therapeutic approach for ATC.https://www.mdpi.com/1422-0067/22/4/1961anaplastic thyroid cancerYM155DNA damagecell cycle arrestapoptosis |
| spellingShingle | Qinqin Xu Ryan P. Mackay Adam Y. Xiao John A. Copland Paul M. Weinberger Ym155 Induces Oxidative Stress-Mediated DNA Damage and Cell Cycle Arrest, and Causes Programmed Cell Death in Anaplastic Thyroid Cancer Cells International Journal of Molecular Sciences anaplastic thyroid cancer YM155 DNA damage cell cycle arrest apoptosis |
| title | Ym155 Induces Oxidative Stress-Mediated DNA Damage and Cell Cycle Arrest, and Causes Programmed Cell Death in Anaplastic Thyroid Cancer Cells |
| title_full | Ym155 Induces Oxidative Stress-Mediated DNA Damage and Cell Cycle Arrest, and Causes Programmed Cell Death in Anaplastic Thyroid Cancer Cells |
| title_fullStr | Ym155 Induces Oxidative Stress-Mediated DNA Damage and Cell Cycle Arrest, and Causes Programmed Cell Death in Anaplastic Thyroid Cancer Cells |
| title_full_unstemmed | Ym155 Induces Oxidative Stress-Mediated DNA Damage and Cell Cycle Arrest, and Causes Programmed Cell Death in Anaplastic Thyroid Cancer Cells |
| title_short | Ym155 Induces Oxidative Stress-Mediated DNA Damage and Cell Cycle Arrest, and Causes Programmed Cell Death in Anaplastic Thyroid Cancer Cells |
| title_sort | ym155 induces oxidative stress mediated dna damage and cell cycle arrest and causes programmed cell death in anaplastic thyroid cancer cells |
| topic | anaplastic thyroid cancer YM155 DNA damage cell cycle arrest apoptosis |
| url | https://www.mdpi.com/1422-0067/22/4/1961 |
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