Esomeprazole enhances the effect of ionizing radiation to improve tumor control

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

Proton pump inhibitors display anti‐tumour potential in glioma

“…Hypoxic tumour cells continue to exist after radiation and transform into a more invasive phenotype 19 . PPIs such as esomeprazole could generate more ROS persistently to make up for the deficiency of oxidative stress caused by limited radiation 285 . The inhibitory effect of many chemotherapeutic drugs depends on the oxygen partial pressure of the TME.…”

“…It has been proved that treatment of the cancer cells with the PPIs resulted in order of magnitude reduction in the half‐maximal inhibitory concentration (IC 50 ) values 301 . Esomeprazole enhances radiosensitivity in radiation‐resistant squamous cell carcinoma of the head and neck 285 . PPIs could also increase chemotherapeutic drug uptake by the tumour cells 302 .…”

“… 19 PPIs such as esomeprazole could generate more ROS persistently to make up for the deficiency of oxidative stress caused by limited radiation. 285 The inhibitory effect of many chemotherapeutic drugs depends on the oxygen partial pressure of the TME. In general, the sensitivity of chemotherapy was the strongest at the peak of oxygen partial pressure.…”

“… 301 Esomeprazole enhances radiosensitivity in radiation‐resistant squamous cell carcinoma of the head and neck. 285 PPIs could also increase chemotherapeutic drug uptake by the tumour cells. 302 PPIs, as the small molecules, could pass through BBB and BTB (Table 1 ).…”