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.
Highlights
Radiation therapy is a standard of care approach in the treatment of cancer patients who are medically inoperable or have surgically unresectable tumors
Emerging studies indicate that proton pump inhibitors (PPIs), a class of Food and Drug Administration (FDA)-approved drug for the treatment of gastroesophageal reflux diseases, have chemosensitizing activity in tumor cells derived from melanoma, colon, breast and ovarian cancers [1,2,3]
The effect of esomeprazole on the growth of the head and neck, breast and lung cancer cells was significantly enhanced by extending the incubation time beyond 24 hours
Summary
Radiation therapy is a standard of care approach in the treatment of cancer patients who are medically inoperable or have surgically unresectable tumors. Many solid tumors are only partially responsive to radiation therapy-based interventions. Combination of radiation with radiosensitizers is able to enhance tumor cell killing. Currently available radiosensitizers, such as cisplatin and other cytotoxic agents, are non-selective and often associated with a plethora of side effects including ototoxicity, infection, hair loss, as well as hematological and cardiovascular complications. There is an opportunity to search and develop safer and effective radiosensitizers. One strategy is to screen among existing drugs including those that are originally approved for non-oncologic indications
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