4.6 Article

Downregulation of Mcl-1 by Panobinostat Potentiates Proton Beam Therapy in Hepatocellular Carcinoma Cells

期刊

CELLS
卷 10, 期 3, 页码 -

出版社

MDPI
DOI: 10.3390/cells10030554

关键词

proton therapy; hepatocellular carcinoma; panobinostat; Mcl-1

资金

  1. National Research Foundation of Korea (NRF) - Ministry of Education [NRF2018R1D1A1B07042738]
  2. MSIT [NRF-2018R1A2B2002835]

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The study found that the combination of panobinostat and proton irradiation effectively enhanced radiation sensitivity of hepatocellular carcinoma cells, leading to increased apoptotic cell death. Panobinostat increased G2/M arrest and production of reactive oxygen species, exacerbating proton-induced DNA damage, potentially playing a role in HCC treatment.
Epigenetic modulation by histone deacetylase (HDAC) inhibitors is an attractive anti-cancer strategy for diverse hematological and solid cancers. Herein, we explored the relative effectiveness of the pan-HDAC inhibitor panobinostat in combination with proton over X-ray irradiation in HCC cells. Clonogenic survival assays revealed that radiosensitization of Huh7 and Hep3B cells by panobinostat was more evident when combined with protons than X-rays. Panobinostat increased G2/M arrest and production of intracellular reactive oxygen species, which was further enhanced by proton irradiation. Immunofluorescence staining of gamma H2AX showed that panobinostat enhanced proton-induced DNA damage. Panobinostat dose-dependently decreased expression of an anti-apoptotic protein, Mcl-1, concomitant with increasing acetylation of histone H4. The combination of panobinostat with proton irradiation enhanced apoptotic cell death to a greater extent than that with X-ray irradiation. Depletion of Mcl-1 by RNA interference enhanced proton-induced apoptosis and proton radiosensitization, suggesting a potential role of Mcl-1 in determining proton sensitivity. Together, our findings suggest that panobinostat may be a promising combination agent for proton beam therapy in HCC treatment.

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