Abstract
PurposeHigh-intensity focused ultrasound (HIFU/FUS) has expanded as a noninvasive quantifiable option for hyperthermia (HT). HT in a temperature range of 40–47 °C (thermal dose CEM43 ≥ 25) could work as a sensitizer to radiation therapy (RT). Here, we attempted to understand the tumor radiosensitization effect at the cellular level after a combination treatment of FUS+RT.MethodsAn in vitro FUS system was developed to induce HT at frequencies of 1.147 and 1.467 MHz. Human head and neck cancer (FaDU), glioblastoma (T98G), and prostate cancer (PC-3) cells were exposed to FUS in ultrasound-penetrable 96-well plates followed by single-dose X‑ray irradiation (10 Gy). Radiosensitizing effects of FUS were investigated by cell metabolic activity (WST‑1 assay), apoptosis (annexin V assay, sub-G1 assay), cell cycle phases (propidium iodide staining), and DNA double-strand breaks (γH2A.X assay).ResultsThe FUS intensities of 213 (1.147 MHz) and 225 W/cm2 (1.467 MHz) induced HT for 30 min at mean temperatures of 45.20 ± 2.29 °C (CEM43 = 436 ± 88) and 45.59 ± 1.65 °C (CEM43 = 447 ± 79), respectively. FUS improves the effect of RT significantly by reducing metabolic activity in T98G cells 48 h (RT: 96.47 ± 8.29%; FUS+RT: 79.38 ± 14.93%; p = 0.012) and in PC-3 cells 72 h (54.20 ± 10.85%; 41.01 ± 11.17%; p = 0.016) after therapy, but not in FaDu cells. Mechanistically, FUS+RT leads to increased apoptosis and enhancement of DNA double-strand breaks compared to RT alone in T98G and PC-3 cells.ConclusionOur in vitro findings demonstrate that FUS has good potential to sensitize glioblastoma and prostate cancer cells to RT by mainly enhancing DNA damage.
Highlights
High-intensity focused ultrasound (HIFU) or focused ultrasound (FUS) plays an increasing role in medical applications because of thermal and mechanical effects on cells, biological molecules, and tissue, expanding the traditional application of ultrasound in diagnostic imaging to therapeutic applications [1, 2]
Human head and neck cancer (FaDU), glioblastoma (T98G), and prostate cancer (PC-3) cells were exposed to FUS in ultrasound-penetrable 96-well plates followed by single-dose X-ray irradiation (10 Gy)
Our in vitro findings demonstrate that FUS has good potential to sensitize glioblastoma and prostate cancer cells to radiation therapy (RT) by mainly enhancing DNA damage
Summary
High-intensity focused ultrasound (HIFU) or focused ultrasound (FUS) plays an increasing role in medical applications because of thermal and mechanical effects on cells, biological molecules, and tissue, expanding the traditional application of ultrasound in diagnostic imaging to therapeutic applications [1, 2]. Surgery, image-guided ablation, local radiation therapy (RT), and systemic chemotherapeutics are the four clinical treatment modalities, but all are accompanied by significant adverse effects [13, 14]. As examples of highly aggressive cancer entities, head and neck tumors, glioblastoma, and metastatic prostate cancer subtypes require novel and more effective treatment regimens, and were thereby chosen in our study
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