Targeting DNA-dependent protein kinase sensitizes hepatocellular carcinoma cells to proton beam irradiation through apoptosis induction

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.

Checkpoint Kinase 1 (CHK1) Inhibition Enhances the Sensitivity of Triple-Negative Breast Cancer Cells to Proton Irradiation via Rad51 Downregulation

“…Proton therapy biologically shows a 10% higher effectiveness than conventional photon therapy, and the current use of proton therapy largely relies on its physical superiority, such as the Bragg peak [28]. Accumulating evidence suggests that there is a difference in the biological efficacy between proton and photon therapies [13,15,16,18,29,30]. In the form of a particle beam, protons cause more DNA damage than photons, as photons lack mass.…”

“…In breast cancer, this unique energy deposit profile can reduce heart and lung exposure to radiation, thereby potentially decreasing risk of cardiac toxicity and pneumonitis [12]. In radiobiology, the understanding of the advantages of proton beams over photon beams is still limited, although genetic alterations could modify the biological effectiveness of protons relative to that of photons in the lung, head and neck, liver, and breast cancer cells [13][14][15][16]. Proton beams induce more complex DNA damage, resulting in more prolonged DNA-damage repair and cell-cycle arrest than that observed in response to X-ray irradiation [17].…”

Harnessing the targeting potential of differential radiobiological effects of photon versus particle radiation for cancer treatment

“…Even though both types of IR are considered low‐LET radiation, the complexity of DNA damage caused by protons and photons may differ (Fontana et al, 2015). Proton irradiation of hepatocellular carcinoma (HCC) cells has shown a continuous activation of DNA damage repair proteins over time, reflecting the formation of more complex DSBs by protons, when compared with X‐rays (Choi et al, 2019). Collectively, these observations suggest that the higher the LET, the denser the ionisation events, resulting in a more complex induction of DNA damage.…”

Therapeutic Potential of (−)-Agelamide D, a Diterpene Alkaloid from the Marine Sponge Agelas sp., as a Natural Radiosensitizer in Hepatocellular Carcinoma Models

“…Human HCC Hep3B, Huh7, PLC/PRF-5, and SNU449 cells were purchased from the Korean Cell Line Bank (Seoul National University, Seoul, Korea, 2016) and cultured as previously described [ 43 ]. All cell lines were tested annually for Mycoplasma contamination and were authenticated through short tandem repeat (STR) profiling.…”