CDK4/6 inhibitor enhances the radiosensitization of esophageal squamous cell carcinoma (ESCC) by activating autophagy signaling via the suppression of mTOR.

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.

Response to immune complex vaccine in chronic hepatitis B patients is associated with lower baseline level of serum IgG galactosylation.

The composition of glycan in immunoglobulin G (IgG) has shown to affect various diseases and can be regulated by drugs and preventive vaccination. A hepatitis B surface antigen (HBsAg)-hepatitis B immunoglobulin (HBIG) immune complex (YIC) therapeutic vaccine for chronic hepatitis B (CHB) patients has undergone clinical trials. To explore for markers of CHB, which could be associated with responsiveness to YIC therapeutic vaccine, serum IgG glycosylation in CHB patients was analyzed.Kinetic changes of serum galactosylated IgG in 53 hepatitis Be antigen (HBeAg)-positive CHB patients treated with YIC were monitored by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) analysis. Whole blood cytokines were assayed by cytokine binding assay kits. All samples were back assayed before treatment, during therapy and follow-up for 6 months from a previous completed clinical trial.During YIC treatment, 26 patients with lower IgG galactosylation level at baseline [galactosylation level (Gal-ratio) = -0.29, 0.18 (mean, SD)] showed sustained increase of serum galactosylated IgG, and responded to YIC treatment by HBeAg seroconversion. While those who did not respond to YIC treatment [Gal-ratio = -0.40, 0.15 (mean, SD)] failed to show similar changes. Furthermore, this kinetic increase of galactosylated IgG correlated with marked up-regulated IL-2 level, confirming that effective cellular immune responses have participated in responsiveness.For HBeAg-positive CHB patients lower serum IgG galactosylation level may serve as an indicator for selecting a suitable subpopulation of candidates for YIC therapeutic vaccination.

Thalidomide (THD) alleviates radiation induced lung fibrosis (RILF) via down-regulation of TGF-ß/Smad3 signaling pathway in an Nrf2-dependent manner.

Radiation-induced lung fibrosis (RILF) is a complication of radiotherapy in thoracic cancer patients. Thalidomide (THD) has a therapeutic effect on fibrotic and inflammatory disorders. The purpose of the current study was to investigate the therapeutic effect of THD on RILF in mice and better understand the underlying regulatory mechanisms of the therapeutic effect. We found that THD mitigated the fibrosis caused by irradiation in mice. The action of THD on RILF was related to the elevation of low levels reactive oxygen species (ROS), which inhibited the transforming growth factor­ß (TGF­ß)/Smad3 signaling pathway through activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Analysis of the therapeutic effect of THD using Nrf2-/- mouse model confirmed the role of Nrf2 in vivo. In addition, no radioprotective effect of THD on thoracic cancer cell lines was observed. In conclusion, these data showed that THD attenuated RILF in mice, which was mediated by Nrf2-dependent down-regulation of the TGF-ß/Smad3 pathway, suggesting THD as a potential novel agent for RILF prevention.