Therapy-resistant cancer stem cells have differing sensitivity to photon versus proton beam radiation

Background: Cancer stem cells (CSCs) play an important role in non-small-cell lung cancer recurrence and metastasis. We sought to determine whether CSC-like cells respond differentially to proton and photon beam therapies. Methods: CSC-enriched cells from paclitaxel-resistant human H460 and A549 cell lines were irradiated with the same relative biological effectiveness dose and analyzed for cell viability, clonogenic survival, apoptosis, cell migration, cell invasiveness, tumor sphere formation, and CSC markers. The intracellular concentration of reactive oxygen species (ROS) was measured before and after irradiation. Results: Compared with photons, protons caused significantly lower cell viability in chemoresistant cells and, in CSC-like cells, significantly lower clonogenic survival, invasiveness, and number of tumor spheres; less migration and CSC markers (coxsackievirus and adenovirus receptor, β-catenin, and side population cells); more apoptosis; and higher ROS level. CSC-like cells contained less than half the ROS levels of parental cancer cells or normal human bronchial epithelial cells. Conclusions: CSC-like cells may be more sensitive to irradiation with protons than photons. The increased sensitivity could be caused by the greater ROS generated by protons. Because chemoresistant CSCs play an important role in tumor recurrence, protons may be more effective than photons in eliminating recurrent or persistent non-small-cell lung cancer.