Journal article
Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy
Pharmaceuticals (Basel, Switzerland), Vol.14(7), p.682
07/01/2021
DOI: 10.3390/ph14070682
PMCID: PMC8308742
PMID: 34358108
Abstract
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.
Details
- Title: Subtitle
- Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy
- Creators
- Jianling Bi - University of IowaGarima Dixit - University of IowaYuping Zhang - University of IowaEric J. Devor - University of IowaHaley A. Losh - University of IowaAndreea M. Newtson - University of IowaKristen L. Coleman - University of IowaDonna A. Santillan - University of IowaThorsten Maretzky - University of IowaKristina W. Thiel - University of IowaKimberly K. Leslie - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Pharmaceuticals (Basel, Switzerland), Vol.14(7), p.682
- DOI
- 10.3390/ph14070682
- PMID
- 34358108
- PMCID
- PMC8308742
- NLM abbreviation
- Pharmaceuticals (Basel)
- ISSN
- 1424-8247
- eISSN
- 1424-8247
- Publisher
- Mdpi
- Number of pages
- 16
- Grant note
- UL1TR002537 / National Center for Advancing Translational Sciences of the National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) OC190352 / Department of Defense Ovarian Cancer Research Program; United States Department of Defense R01CA099908 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P30CA086862 / National Cancer Institute of the National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) ACS-IRG-15-176-41; ACS-IRG-18-165-43 / American Cancer Society
- Language
- English
- Date published
- 07/01/2021
- Academic Unit
- Biology; Radiation Oncology; Obstetrics and Gynecology; Holden Comprehensive Cancer Center; Internal Medicine
- Record Identifier
- 9984318327002771
Metrics
28 Record Views