Abstract
Recent studies have highlighted the implications of genetic variations in the relative biological effectiveness (RBE) of proton beam irradiation over conventional X-ray irradiation. Proton beam radiotherapy is a reasonable radiotherapy option for hepatocellular carcinoma (HCC), but the impact of genetic difference on the HCC RBE remains unknown. Here, we determined proton RBE in human HCC cells by exposing them to various doses of either 6-MV X-rays or 230-MeV proton beams. Clonogenic survival assay revealed variable radiosensitivity of human HCC cell lines with survival fraction at 2 Gy ranging from 0.38 to 0.83 and variable proton RBEs with 37% survival fraction ranging from 1.00 to 1.48. HCC cells appeared more sensitive to proton irradiation than X-rays, with more persistent activation of DNA damage repair proteins over time. Depletion of a DNA damage repair gene, DNA-PKcs, by siRNA dramatically increased the sensitivity of HCC cells to proton beams with a decrease in colony survival and an increase in apoptosis. Our findings suggest that there are large variations in proton RBE in HCC cells despite the use of a constant RBE of 1.1 in the clinic and targeting DNA-PKcs in combination with proton beam therapy may be a promising regimen for treating HCC.
Highlights
Radiation therapy is recognized as effective alternative option for treating liver cancers such as hepatocellular carcinoma (HCC) [1,2,3]
Before measuring radiosensitivity in HCC cells, we first determined proton relative biological effectiveness (RBE) in Human salivary gland (HSG) cells, which were used as a refence cell line for RBE comparison at multiple proton therapy facilities in japan, as a biological quality assurance process [29]
A clonogenic survival assay showed that proton irradiation was slightly more effective than X-rays (Fig 1B) and the dose-response curves showed that proton RBE at 10% survival was estimated as 1.16 (Fig 1C)
Summary
Radiation therapy is recognized as effective alternative option for treating liver cancers such as hepatocellular carcinoma (HCC) [1,2,3]. Advanced radiation techniques such as stereotactic body radiotherapy improve clinical outcomes in patients with unresectable primary HCC. Accumulating evidence indicates that charged particle beam therapy such as protons and carbon ions is promising for HCC, as these techniques lead to better tumor control and minimal toxicity in normal tissues due to dosimetric advantages over conventional radiotherapy [4,5,6,7,8,9].
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