Cellular characterization of ultrasound-stimulated microbubble radiation enhancement in a prostate cancer xenograft model.
Tumor radiation resistance poses a major obstacle in achieving an optimal outcome in radiation therapy. In the current study, we characterize a novel therapeutic approach that combines ultrasound-driven microbubbles with radiation to increase treatment responses in a prostate cancer xenograft model in mice. Tumor response to ultrasound-driven microbubbles and radiation was assessed 24 hours after treatment, which consisted of radiation treatments alone (2 Gy or 8 Gy) or ultrasound-stimulated microbubbles only, or a combination of radiation and ultrasound-stimulated microbubbles. Immunohistochemical analysis using in situ end labeling (ISEL) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) revealed increased cell death within tumors exposed to combined treatments compared with untreated tumors or tumors exposed to radiation alone. Several biomarkers were investigated to evaluate cell proliferation (Ki67), blood leakage (factor VIII), angiogenesis (cluster of differentiation molecule CD31), ceramide-formation, angiogenesis signaling [vascular endothelial growth factor (VEGF)], oxygen limitation (prolyl hydroxylase PHD2) and DNA damage/repair (γH2AX). Results demonstrated reduced vascularity due to vascular disruption by ultrasound-stimulated microbubbles, increased ceramide production and increased DNA damage of tumor cells, despite decreased tumor oxygenation with significantly less proliferating cells in the combined treatments. This combined approach could be a feasible option as a novel enhancing approach in radiation therapy.
Physical Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
Azza A
AA
Al-Mahrouki
Sara
S
Iradji
William Tyler
WT
Tran
Gregory J
GJ
Czarnota
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D016923:Cell Death; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002518:Ceramides / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D016513:Mice, SCID; D045423:Microbubbles; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000473:pathology / Q000532:radiotherapy*; D015398:Signal Transduction; D014465:Ultrasonics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D002518:Ceramides; D019394:Ki-67 Antigen; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010100:Oxygen
Angiogenesis; Microbubbles; Proliferation; Radiation; Ultrasound