Abstract
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.
Highlights
Radiotherapy is considered to be an effective conventional therapy for various tumors (Folkman and Camphausen, 2001; Spiegelhalter et al, 2011; Wei et al, 2012)
Using immunohistochemical analyses, the authors evaluated the levels of a range of molecular markers associated with cellular processes that are potentially affected by combined ultrasound-based radiationenhancing therapy
Markers associated with apoptotic signaling, proliferation, vasculature, cell-membrane damage, hypoxia and DNA damage were examined in xenograft models of prostate cancer
Summary
Radiotherapy is considered to be an effective conventional therapy for various tumors (Folkman and Camphausen, 2001; Spiegelhalter et al, 2011; Wei et al, 2012). Radiation resistance is a challenge in many treatments (Wei et al, 2012; Diepart et al, 2012; Garden et al, 1991; Bao et al, 2006) in part owing to factors such as hypoxia, genetic instability, tumor hypervascularity and the presence of tumor stem cells (Diehn et al, 2009). These cellular behaviors contribute to a spectrum of obstacles in cancer therapy. Radiationsensitizing agents are mostly systemic agents that have associated toxicities, limiting their use
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