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Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy

Angiogenesis plays a crucial role in tumor development and metastasis. Both bevacizumab and cediranib have demonstrated activity as single anti-angiogenic agents in endometrial cancer, though subsequent studies of bevacizumab combined with chemotherapy failed to improve outcomes compared to chemothe...

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Autores principales: Bi, Jianling, Dixit, Garima, Zhang, Yuping, Devor, Eric J., Losh, Haley A., Newtson, Andreea M., Coleman, Kristen L., Santillan, Donna A., Maretzky, Thorsten, Thiel, Kristina W., Leslie, Kimberly K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308742/
https://www.ncbi.nlm.nih.gov/pubmed/34358108
http://dx.doi.org/10.3390/ph14070682
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author Bi, Jianling
Dixit, Garima
Zhang, Yuping
Devor, Eric J.
Losh, Haley A.
Newtson, Andreea M.
Coleman, Kristen L.
Santillan, Donna A.
Maretzky, Thorsten
Thiel, Kristina W.
Leslie, Kimberly K.
author_facet Bi, Jianling
Dixit, Garima
Zhang, Yuping
Devor, Eric J.
Losh, Haley A.
Newtson, Andreea M.
Coleman, Kristen L.
Santillan, Donna A.
Maretzky, Thorsten
Thiel, Kristina W.
Leslie, Kimberly K.
author_sort Bi, Jianling
collection PubMed
description Angiogenesis plays a crucial role in tumor development and metastasis. Both bevacizumab and cediranib have demonstrated activity as single anti-angiogenic agents in endometrial cancer, though subsequent studies of bevacizumab combined with chemotherapy failed to improve outcomes compared to chemotherapy alone. Our objective was to compare the efficacy of cediranib and bevacizumab in endometrial cancer models. The cellular effects of bevacizumab and cediranib were examined in endometrial cancer cell lines using extracellular signal-related kinase (ERK) phosphorylation, ligand shedding, cell viability, and cell cycle progression as readouts. Cellular viability was also tested in eight patient-derived organoid models of endometrial cancer. Finally, we performed a phosphoproteomic array of 875 phosphoproteins to define the signaling changes related to bevacizumab versus cediranib. Cediranib but not bevacizumab blocked ligand-mediated ERK activation in endometrial cancer cells. In both cell lines and patient-derived organoids, neither bevacizumab nor cediranib alone had a notable effect on cell viability. Cediranib but not bevacizumab promoted marked cell death when combined with chemotherapy. Cell cycle analysis demonstrated an accumulation in mitosis after treatment with cediranib + chemotherapy, consistent with the abrogation of the G2/M checkpoint and subsequent mitotic catastrophe. Molecular analysis of key controllers of the G2/M cell cycle checkpoint confirmed its abrogation. Phosphoproteomic analysis revealed that bevacizumab and cediranib had both similar and unique effects on cell signaling that underlie their shared versus individual actions as anti-angiogenic agents. An anti-angiogenic tyrosine kinase inhibitor such as cediranib has the potential to be superior to bevacizumab in combination with chemotherapy.
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spelling pubmed-83087422021-07-25 Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy Bi, Jianling Dixit, Garima Zhang, Yuping Devor, Eric J. Losh, Haley A. Newtson, Andreea M. Coleman, Kristen L. Santillan, Donna A. Maretzky, Thorsten Thiel, Kristina W. Leslie, Kimberly K. Pharmaceuticals (Basel) Article Angiogenesis plays a crucial role in tumor development and metastasis. Both bevacizumab and cediranib have demonstrated activity as single anti-angiogenic agents in endometrial cancer, though subsequent studies of bevacizumab combined with chemotherapy failed to improve outcomes compared to chemotherapy alone. Our objective was to compare the efficacy of cediranib and bevacizumab in endometrial cancer models. The cellular effects of bevacizumab and cediranib were examined in endometrial cancer cell lines using extracellular signal-related kinase (ERK) phosphorylation, ligand shedding, cell viability, and cell cycle progression as readouts. Cellular viability was also tested in eight patient-derived organoid models of endometrial cancer. Finally, we performed a phosphoproteomic array of 875 phosphoproteins to define the signaling changes related to bevacizumab versus cediranib. Cediranib but not bevacizumab blocked ligand-mediated ERK activation in endometrial cancer cells. In both cell lines and patient-derived organoids, neither bevacizumab nor cediranib alone had a notable effect on cell viability. Cediranib but not bevacizumab promoted marked cell death when combined with chemotherapy. Cell cycle analysis demonstrated an accumulation in mitosis after treatment with cediranib + chemotherapy, consistent with the abrogation of the G2/M checkpoint and subsequent mitotic catastrophe. Molecular analysis of key controllers of the G2/M cell cycle checkpoint confirmed its abrogation. Phosphoproteomic analysis revealed that bevacizumab and cediranib had both similar and unique effects on cell signaling that underlie their shared versus individual actions as anti-angiogenic agents. An anti-angiogenic tyrosine kinase inhibitor such as cediranib has the potential to be superior to bevacizumab in combination with chemotherapy. MDPI 2021-07-16 /pmc/articles/PMC8308742/ /pubmed/34358108 http://dx.doi.org/10.3390/ph14070682 Text en © 2021 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
Bi, Jianling
Dixit, Garima
Zhang, Yuping
Devor, Eric J.
Losh, Haley A.
Newtson, Andreea M.
Coleman, Kristen L.
Santillan, Donna A.
Maretzky, Thorsten
Thiel, Kristina W.
Leslie, Kimberly K.
Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy
title Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy
title_full Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy
title_fullStr Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy
title_full_unstemmed Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy
title_short Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy
title_sort advantages of tyrosine kinase anti-angiogenic cediranib over bevacizumab: cell cycle abrogation and synergy with chemotherapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308742/
https://www.ncbi.nlm.nih.gov/pubmed/34358108
http://dx.doi.org/10.3390/ph14070682
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