Therapy-Resistant Cancer Stem Cells Have Differing Sensitivity to Photon versus Proton Beam Radiation Xiaochun Zhang, MD, Steven H. Lin, MD, PhD, Bingliang.

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Therapy-Resistant Cancer Stem Cells Have Differing Sensitivity to Photon versus Proton Beam Radiation Xiaochun Zhang, MD, Steven H. Lin, MD, PhD, Bingliang Fang, MD, PhD, Michael Gillin, PhD, Radhe Mohan, PhD, Joe Y. Chang, MD, PhD Journal of Thoracic Oncology Volume 8, Issue 12, Pages 1484-1491 (December 2013) DOI: 10.1097/JTO.0b013e3182a5fdcb Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Protons have greater cell-killing effects than photons in treatment-resistant NSCLC cell lines but not in normal cells. H460, H460/CR, A549, A549/CR, and NHBE cell lines were irradiated at the indicated doses (0, 1, 2, 4, and 8 Gy) at the same CGE (RBE = 1.1). Cell viability was determined by the sulforhodamine B assay on the fourth day after irradiation. Each experiment was done in quadruplicate and repeated at least twice. Values are means ± SD. *p < 0.05 versus protons at the same dose, as determined using paired two-sided Student’s t test. CR, chemotherapy resistant; NHBE–, normal human bronchial epithelial; NSCLC, non–small-cell lung cancer; CGE, cobalt gray equivalent; RBE, biological effectiveness. Journal of Thoracic Oncology 2013 8, 1484-1491DOI: (10.1097/JTO.0b013e3182a5fdcb) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Protons better target CSC-like cells in treatment-resistant NSCLC compared with photons. Clonogenic survival assay of H460, H460/CR, H460/CR/SP, H460/CR/NSP, A549, A549/CR, A549/CR/SP, and A549/CR/NSP cells on the 14th day after irradiation up to 8 Gy at the same CGE (RBE = 1.1). Values are means (95% CI) of triplicate assay results as determined using paired two-sided Student’s t test. *p < 0.05 versus proton therapy at the same dose. CR, chemotherapy resistant; NSCLC, non–small-cell lung cancer; CGE, cobalt gray equivalent; RBE, biological effectiveness; SP, side population; NSP, nonside population; CSC, cancer stem cell; CI, confidence interval. Journal of Thoracic Oncology 2013 8, 1484-1491DOI: (10.1097/JTO.0b013e3182a5fdcb) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Compared with photons, protons induce a higher level of apoptosis and a greater reduction in cell migration and invasion in a dose-dependent manner in CSC-like NSCLC cells. A, Percentage of apoptotic cells as determined with TUNEL assay by flow cytometry in H460, H460/CR, H460/CR/SP, H460/CR/NSP cells 48 hours after irradiation (0, 0.5, 1, 2, 4 Gy) at the same CGE (RBE = 1.1). Migration (B) and invasiveness (C) of the same cell lines 48 hours after irradiation (0, 0.5, 1, 2, 4 Gy) with the same doses at the same CGE (RBE = 1.1) by 96-well cell migration and invasion assay (fluorometric format). Values are means (95% CI) of three independent experiments. *p < 0.05 versus protons at the same dose, as determined using paired two-sided Student’s t test. CR, chemotherapy resistant; RFU, relative fluorescence unit; NSCLC, non–small-cell lung cancer; CGE, cobalt gray equivalent; RBE, biological effectiveness; SP, side population; NSP, nonside population; CSC, cancer stem cell; CI, confidence interval; TUNEL, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick end-labeling. Journal of Thoracic Oncology 2013 8, 1484-1491DOI: (10.1097/JTO.0b013e3182a5fdcb) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Protons induce higher ROS levels than photons do in CSC-like NSCLC cells. A, Representative histograms of intracellular ROS level in H460, H460/CR, H460/CR/SP, H460/CR/NSP, and NHBE cells. B, Representative histograms of ROS generation at 48 hours after irradiation at 4 Gy. C, Corresponding quantitative comparison of ROS generation. D, Quantitative comparison of ROS generation in H460 and H460/CR/SP cells for up to 9 days after irradiation at 4 Gy. Values are means (95% CIs). All experiments were performed at least three times. *p < 0.05 versus proton at the same dose, as determined using paired two-sided Student’s t test. CR, chemotherapy resistant; NHBE, normal human bronchial epithelial; NSCLC, non–small-cell lung cancer; ROS, reactive oxygen species; SP, side population; NSP, nonside population; CSC, cancer stem cell; CI, confidence interval. Journal of Thoracic Oncology 2013 8, 1484-1491DOI: (10.1097/JTO.0b013e3182a5fdcb) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 Protons cause a greater reduction than photons of sphere formation of CSC-like cells and CSC marker expression in CSC-like NSCLC cells. A, Phase-contrast microscopy images of tumor spheres of H460/CR/SP cells after irradiation at 4 Gy under stem cell–selective conditions for 2 weeks. B, Corresponding quantitative comparison of number of tumor spheres. C, Expression of CSC markers CAR and β-catenin in H460/CR/SP cells. D, The percentage of SP cells in H460/CR/SP cells as measured by flow cytometry 96 hours after irradiation. Values are means (95% CIs). All experiments were performed at least three times. *p < 0.05 versus protons at the same dose, as determined using paired two-sided Student’s t test. CR, chemotherapy resistant; SP, side population; CSC, cancer stem cell; CI, confidence interval; NSCLC, non–small-cell lung cancer; CAR, coxsackievirus and adenovirus receptor. Journal of Thoracic Oncology 2013 8, 1484-1491DOI: (10.1097/JTO.0b013e3182a5fdcb) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions