Journal
AGING-US
Volume 13, Issue 14, Pages 18223-18237Publisher
IMPACT JOURNALS LLC
Keywords
autophagy; DNA damage; histone deacetylase inhibitor; radiation; rapamycin
Categories
Funding
- National Natural Science Foundation of China [81560379, 81460292, 81660315]
- Natural Science Foundation of Jiangxi Province [20181BAB205046, 20202BAB216031]
- Technology Supporting Program of Jiangxi Province [2015BBG70236]
- Key Project of Education Department of Jiangxi Province [GJJ170012]
- Guiding Science and Technology Project of Ganzhou [GZ2018ZSF306]
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The combination treatment of RAPA and SAHA significantly enhances the inhibitory effect of radiotherapy on NSCLC, primarily by modulating the expression of DNA damage proteins and increasing radiotherapy sensitivity. This combined therapy also effectively inhibits tumor growth in the A549 xenograft model.
Radiotherapy plays an essential role in the treatment of non-small-cell lung cancer (NSCLC). However, cancer cells' resistance to ionizing radiation (IR) is the primary reason for radiotherapy failure leading to tumor relapse and metastasis. DNA double-strand breaks (DSB) repair after IR is the primary mechanism of radiotherapy resistance. In this study, we investigated the effects of autophagy-inducing agent, Rapamycin (RAPA), combined with the histone deacetylase inhibitor (HDACi), Suberoylanilide Hydroxamic Acid (SAHA), on the radiosensitivity of A549 and SK-MES-1 cells, and examined the combination effects on DNA damage repair, and determined the level of autophagy and acetylation in A549 cells. We also investigated the combination treatment effect on the growth of A549 xenografts after radiotherapy, and the level of DNA damage, autophagy, and acetylation. Our results showed that RAPA combined with SAHA significantly increased the inhibitory effect of radiotherapy compared with the single treatment group. The combined treatment increased the expression of DNA damage protein gamma-H2AX and decreased DNA damage repair protein expression. RAPA combined with SAHA was induced mainly by regulating acetylation levels and autophagy. The effect of combined treatment to increase radiotherapy sensitivity will be weakened by inhibiting the level of autophagy. Besides, the combined treatment also showed a significantly inhibited tumor growth in the A549 xenograft model. In conclusion, these results identify a potential therapeutic strategy of RAPA combined with SAHA as a radiosensitizer to decreased DSB repair and enhanced DNA damage by inducing acetylation levels and autophagy for NSCLC.
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