Objective: To investigate the radiosensitizing effect of cyclin D-cyclin dependent kinase (CDK) 4/6 inhibitor palbociclib on esophageal squamous cell carcinoma (ESCC) and its underlying mechanisms.
Methods: The effect of palbociclib on ESCC cell radiosensitivity was detected by cell counting kit-8 (CCK-8) and clonogenic assay. γH2AX immunofluorescent staining was used to assess the repair of DNA damage induced by radiation. The expression of DNA repair proteins were examined by western blotting. Subsequently, immunoblotting and autophagy inhibitors were used to evaluate the underlying mechanisms of palbociclib triggered radiosensitization. Finally, the xenografts of ESCC were established to study the radiosensitizing effect of palbociclib in vivo.
Results: Palbociclib combined with irradiation significantly inhibited the cell viability of ESCC in vitro. The expression level of γH2AX showed that radiation induced DNA damage repair was inhibited by palbociclib treatment. Palbociclib also suppressed the expression of RAD51 and phosphorylated DNA-dependent protein kinase catalytic subunit (p-DNA-PKcs) after irradiation. Mechanically, palbociclib enhanced the radiosensitization of ESCC by activating autophagy via suppression of mammalian target of rapamycin (mTOR). Inhibition of autophagy using chloroquine could partially reverse the radiation enhancing effect of palbociclib. Lastly, the xenografted tumor experiment confirmed the radiosensitizing effect of palbociclib in ESCC in vivo.
Conclusion: Our results showed that palbociclib improved the radiosensitivity of ESCC in vivo and in vitro, and thus it may be a promising radiosensitization agent for the treatment of ESCC.
Keywords: CDK4/6 inhibitor; autophagy; esophageal squamous cell carcinoma; radiosensitization.
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