Oncotarget

Research Papers:

Esomeprazole enhances the effect of ionizing radiation to improve tumor control

Kassidy A. Hebert, Sergio Jaramillo, Wangjie Yu, Min Wang, Ratna Veeramachaneni, Vlad C. Sandulache, Andrew G. Sikora, Mark D. Bonnen, Ananth V. Annapragada, David Corry, Farrah Kheradmand, Raj K. Pandita, Michelle S. Ludwig, Tej K. Pandita, Shixia Huang, Cristian Coarfa, Sandra L. Grimm, Dimuthu Perera, George Miles and Yohannes T. Ghebre _

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Oncotarget. 2021; 12:1339-1353. https://doi.org/10.18632/oncotarget.28008

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Abstract

Kassidy A. Hebert1,2, Sergio Jaramillo1, Wangjie Yu3, Min Wang1, Ratna Veeramachaneni4, Vlad C. Sandulache3, Andrew G. Sikora4, Mark D. Bonnen1, Ananth V. Annapragada5,6,7, David Corry8, Farrah Kheradmand8,9, Raj K. Pandita10, Michelle S. Ludwig1, Tej K. Pandita10, Shixia Huang11, Cristian Coarfa12, Sandra L. Grimm12, Dimuthu Perera12, George Miles13 and Yohannes T. Ghebre1,7,9

1 Department of Radiation Oncology, Baylor College of Medicine, Houston, Texas 77030, USA

2 Interdepartmental Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas 77030, USA

3 Department of Otolaryngology – Head and Neck Surgery, Baylor College of Medicine, Houston, Texas 77030, USA

4 Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

5 E.B. Singleton Department of Radiology, Texas Children's Hospital and Baylor College of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA

6 Department of Obstetrics and Gynecology, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas 77030, USA

7 Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA

8 Department of Medicine, Section on Pulmonary and Critical Care Medicine, Center for Translational Research on Inflammatory Diseases, Baylor College of Medicine, Houston, Texas 77030, USA

9 Department of Medicine, Section on Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Texas 77030, USA

10 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA

11 Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA

12 Advanced Technology Cores, Multi-Omics Data Analysis Core, Baylor College of Medicine, Houston, Texas 77030, USA

13 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA

Correspondence to:

Yohannes T. Ghebre,email: [email protected]

Keywords: esomeprazole; proton pump inhibitors; ionizing radiation; radiosensitization; tumor control

Abbreviations: FDA: Food and Drug Administration; HNSCC: head and neck squamous cell carcinoma; RPPA: reverse phase protein array; Cdks: cyclin-dependent kinases

Received: April 13, 2021     Accepted: June 11, 2021     Published: July 06, 2021

Copyright: © 2021 Hebert et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

The resistance of cancer cells to radiation-based treatment is a major clinical challenge confounding standard of care in cancer. This problem is particularly notable in many solid tumors where cancer cells are only partially responsive to radiation therapy. Combination of radiation with radiosensitizers is able to enhance tumor cell killing. However, currently available radiosensitizers are associated with significant normal tissue toxicity. Accordingly, there is an unmet need to develop safer and more effective radiosensitizers to improve tumor control. Here, we evaluated the radiosensitizing effect of the FDA-approved drug esomeprazole in normal and radioresistant human head and neck squamous cell carcinoma (HNSCC) cells in vitro, and in a mouse model of HNSCC. For the in vitro studies, we used cancer cell colony formation (clonogenicity) assay to compare cancer cell growth in the absence or presence of esomeprazole. To determine mechanism(s) of action, we assessed cell proliferation and profiled cell cycle regulatory proteins. In addition, we performed reverse phase protein array (RPPA) study to understand the global effect of esomeprazole on over 200 cancer-related proteins. For the in vivo study, we engrafted HNSCC in a mouse model and compared tumor growth in animals treated with radiation, esomeprazole, and combination of radiation with esomeprazole. We found that esomeprazole inhibits tumor growth and dose-dependently enhances the cell killing effect of ionizing radiation in wildtype and p53-mutant radioresistant cancer cells. Mechanistic studies demonstrate that esomeprazole arrests cancer cells in the G1 phase of the cell cycle through upregulation of p21 protein and inhibition of cyclin-dependent kinases (Cdks) type 1 (Cdk1) and type 2 (Cdk2). In vivo data showed greater tumor control in animals treated with combination of radiation and esomeprazole compared to either treatment alone, and that this was associated with inhibition of cell proliferation in vivo. In addition, combination of esomeprazole with radiation significantly impaired repair following radiation-induced DNA damage. Our studies indicate that esomeprazole sensitizes cancer cells to ionizing radiation, and is associated with upregulation of p21 to arrest cells in the G1 phase of the cell cycle. Our findings have significant therapeutic implications for the repurposing of esomeprazole as a radiosensitizer in HNSCC and other solid tumors.


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