Researchers from the Baylor College of Medicine say they have discovered a new use for proton pump inhibitors (PPIs) as sensitizers of cancer cells to radiation therapy to improve tumor control. PPIs, which reduce stomach acid, are used to treat gastroesophageal reflux disease, peptic ulcer disease, and Zollinger–Ellison syndrome.
The Baylor team published their findings (“Esomeprazole enhances the effect of ionizing radiation to improve tumor control”) in Oncotarget.
“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,” write the investigators.
“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.”
Large small-molecule library screened
The researchers screened a library of 130,000 small molecules to search for compounds that inhibit an enzyme overexpressed in cancer cells that are considered aggressive, highly vascularized, and radioresistant.
“We were surprised to find the entire class of PPIs, such as esomeprazole and lansoprazole, directly target this enzyme,” said Yohannes Ghebre, PhD, senior author of the study, associate professor of radiation biology at Baylor and member of the Dan L Duncan Comprehensive Cancer Center. “Subsequent studies demonstrated that PPIs sensitize cancer cells to ionizing radiation, depending on the dose. This is a previously unrecognized yet important effect.”
This research demonstrates the efficacy of PPIs in radiosensitizing cancer cells isolated from various tissue sites, including head and neck, breast and the lungs, using cancer cell colony formation assay in vitro and in animal models, according to Ghebre. The team aims to launch clinical studies to evaluate the efficacy of PPIs as radiosensitizers in cancer patients soon.
“A significant fraction of head and neck cancer patients present with aggressive disease that demonstrates an incomplete response to radiation, resulting in rapid recurrence and cancer associated death,” said Vlad Sandulache, MD, PhD, co-author of the study, assistant professor of otolaryngology/head and neck surgery at Baylor and member of the Dan L Duncan Comprehensive Cancer Center. “As a result, it is critically important to identify drugs that can be used to sensitize tumors to radiation. Repurposing existing, FDA-approved drugs is an excellent strategy since it largely eliminates the potential for severe unanticipated toxicities.”
“Given the major contribution of radioresistance to cancer treatment failure and lifelong complications associated with the clinical use of high radiation dose, novel therapeutic agents that can selectively sensitize tumor cells to the effects of radiation to enhance tumor kill are required,” noted Andrew Sikora, MD, PhD, study author, former faculty member in the department of otolaryngology/head and neck surgery at Baylor and current professor and director of research in the department of head and neck surgery at the University of Texas MD Anderson Cancer Center.
“However, currently available radiosensitizers, such as chemotherapeutic agents, are non-selective and are often associated with significant side effects including ototoxicity, immune suppression, hair loss, as well as hematological and cardiovascular complications.”