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Melatonin acts synergistically with pazopanib against renal cell carcinoma cells through p38 mitogen-activated protein kinase-mediated mitochondrial and autophagic apoptosis
BACKGROUND: Mounting evidence indicates that melatonin has possible activity against different tumors. Pazopanib is an anticancer drug used to treat renal cell carcinoma (RCC). This study tested the anticancer activity of melatonin combined with pazopanib on RCC cells and explored the underlying mec...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Korean Society of Nephrology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407642/ https://www.ncbi.nlm.nih.gov/pubmed/37165617 http://dx.doi.org/10.23876/j.krcp.22.114 |
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author | Lai, Chien-Pin Chen, Yong-Syuan Ying, Tsung-Ho Kao, Cheng-Yen Chiou, Hui-Ling Kao, Shao-Hsuan Hsieh, Yi-Hsien |
author_facet | Lai, Chien-Pin Chen, Yong-Syuan Ying, Tsung-Ho Kao, Cheng-Yen Chiou, Hui-Ling Kao, Shao-Hsuan Hsieh, Yi-Hsien |
author_sort | Lai, Chien-Pin |
collection | PubMed |
description | BACKGROUND: Mounting evidence indicates that melatonin has possible activity against different tumors. Pazopanib is an anticancer drug used to treat renal cell carcinoma (RCC). This study tested the anticancer activity of melatonin combined with pazopanib on RCC cells and explored the underlying mechanistic pathways of its action. METHODS: The 786-O and A-498 human RCC cell lines were used as cell models. Cell viability and tumorigenesis were detected with the MTT and colony formation assays, respectively. Apoptosis and autophagy were assessed using TUNEL, annexin V/propidium iodide, and acridine orange staining with flow cytometry. The expression of cellular signaling proteins was investigated with western blotting. The in vivo growth of tumors derived from RCC cells was evaluated using a xenograft mouse model. RESULTS: Together, melatonin and pazopanib reduced cell viability and colony formation and promoted the apoptosis of RCC cells. Furthermore, the combination of melatonin and pazopanib triggered more mitochondrial, caspase-mediated, and LC3-II-mediated autophagic apoptosis than melatonin or pazopanib alone. The combination also induced higher activation of the p38 mitogen-activated protein kinase (p38MAPK) in the promotion of autophagy and apoptosis by RCC cells than melatonin or pazopanib alone. Finally, tumor xenograft experiments confirmed that melatonin and pazopanib cooperatively inhibited RCC growth in vivo and predicted a possible interaction between melatonin/pazopanib and LC3-II. CONCLUSION: The combination of melatonin and pazopanib inhibits the growth of RCC cells by inducing p38MAPK-mediated mitochondrial and autophagic apoptosis. Therefore, melatonin might be a potential adjuvant that could act synergistically with pazopanib for RCC treatment. |
format | Online Article Text |
id | pubmed-10407642 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | The Korean Society of Nephrology |
record_format | MEDLINE/PubMed |
spelling | pubmed-104076422023-08-09 Melatonin acts synergistically with pazopanib against renal cell carcinoma cells through p38 mitogen-activated protein kinase-mediated mitochondrial and autophagic apoptosis Lai, Chien-Pin Chen, Yong-Syuan Ying, Tsung-Ho Kao, Cheng-Yen Chiou, Hui-Ling Kao, Shao-Hsuan Hsieh, Yi-Hsien Kidney Res Clin Pract Original Article BACKGROUND: Mounting evidence indicates that melatonin has possible activity against different tumors. Pazopanib is an anticancer drug used to treat renal cell carcinoma (RCC). This study tested the anticancer activity of melatonin combined with pazopanib on RCC cells and explored the underlying mechanistic pathways of its action. METHODS: The 786-O and A-498 human RCC cell lines were used as cell models. Cell viability and tumorigenesis were detected with the MTT and colony formation assays, respectively. Apoptosis and autophagy were assessed using TUNEL, annexin V/propidium iodide, and acridine orange staining with flow cytometry. The expression of cellular signaling proteins was investigated with western blotting. The in vivo growth of tumors derived from RCC cells was evaluated using a xenograft mouse model. RESULTS: Together, melatonin and pazopanib reduced cell viability and colony formation and promoted the apoptosis of RCC cells. Furthermore, the combination of melatonin and pazopanib triggered more mitochondrial, caspase-mediated, and LC3-II-mediated autophagic apoptosis than melatonin or pazopanib alone. The combination also induced higher activation of the p38 mitogen-activated protein kinase (p38MAPK) in the promotion of autophagy and apoptosis by RCC cells than melatonin or pazopanib alone. Finally, tumor xenograft experiments confirmed that melatonin and pazopanib cooperatively inhibited RCC growth in vivo and predicted a possible interaction between melatonin/pazopanib and LC3-II. CONCLUSION: The combination of melatonin and pazopanib inhibits the growth of RCC cells by inducing p38MAPK-mediated mitochondrial and autophagic apoptosis. Therefore, melatonin might be a potential adjuvant that could act synergistically with pazopanib for RCC treatment. The Korean Society of Nephrology 2023-07 2023-05-04 /pmc/articles/PMC10407642/ /pubmed/37165617 http://dx.doi.org/10.23876/j.krcp.22.114 Text en Copyright © 2023 The Korean Society of Nephrology https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial and No Derivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ) which permits unrestricted non-commercial use, distribution of the material without any modifications, and reproduction in any medium, provided the original works properly cited. |
spellingShingle | Original Article Lai, Chien-Pin Chen, Yong-Syuan Ying, Tsung-Ho Kao, Cheng-Yen Chiou, Hui-Ling Kao, Shao-Hsuan Hsieh, Yi-Hsien Melatonin acts synergistically with pazopanib against renal cell carcinoma cells through p38 mitogen-activated protein kinase-mediated mitochondrial and autophagic apoptosis |
title | Melatonin acts synergistically with pazopanib against renal cell carcinoma cells through p38 mitogen-activated protein kinase-mediated mitochondrial and autophagic apoptosis |
title_full | Melatonin acts synergistically with pazopanib against renal cell carcinoma cells through p38 mitogen-activated protein kinase-mediated mitochondrial and autophagic apoptosis |
title_fullStr | Melatonin acts synergistically with pazopanib against renal cell carcinoma cells through p38 mitogen-activated protein kinase-mediated mitochondrial and autophagic apoptosis |
title_full_unstemmed | Melatonin acts synergistically with pazopanib against renal cell carcinoma cells through p38 mitogen-activated protein kinase-mediated mitochondrial and autophagic apoptosis |
title_short | Melatonin acts synergistically with pazopanib against renal cell carcinoma cells through p38 mitogen-activated protein kinase-mediated mitochondrial and autophagic apoptosis |
title_sort | melatonin acts synergistically with pazopanib against renal cell carcinoma cells through p38 mitogen-activated protein kinase-mediated mitochondrial and autophagic apoptosis |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407642/ https://www.ncbi.nlm.nih.gov/pubmed/37165617 http://dx.doi.org/10.23876/j.krcp.22.114 |
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