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C. Xie



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    P2.05 - Poster Session with Presenters Present (ID 463)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Radiotherapy
    • Presentations: 1
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      P2.05-001 - α7-nAchR Agonist GTS-21 Reduces Radiation-Induced Lung Injury by Inhibiting HMGB1/TLR-4/NF-κB Pathway (ID 4828)

      14:30 - 14:30  |  Author(s): C. Xie

      • Abstract

      Background:
      The cholinergic anti-inflammatory signaling pathway allows the autonomic nervous system to modulate immunologic stimuli and inflammatory processes. α7 nicotinic acetylcholine receptor (α7-nAChR) is a major component in this pathway. GTS-21, a selective α7 nicotinic acetylcholine receptor agonist, has been demonstrated as a promising treatment for inflammation. So, the aim of this study is to determine whether treatment GTS-21 can mitigate the radiation induced lung injury.

      Methods:
      C57BL/6 mice were randomly divided into three groups: a control group, a 12 Gy thoracic irradiation group, a 12 Gy thoracic irradiation group treated with 4mg/kg GTS-21 immediately after irradiation. Each of group were sacrificed at 1,3,7,14,21d and 3m, 6m post-irradiation, and the sections were respectively stained with hematoxylin and eosin (HE) and Masson’s trichrome to assess the degree of inflammation and fibrosis. Serum concentrations of TNF-α, IL-1β and IL-6 were quantitatively measured by Cytometric Bead Array (CBA) kit. Real-time PCR and Western blot were used to detect the mRNA and protein levels of HMGB1, TLR-4, NF-κB, MyD88 and TGF-β in lung tissue from GTS-21 group and irradiation control group at different time after radiation.

      Results:
      The result from HE and Masson staining showed that GTS-21 could dramatically reduce radiation-induced lung inflammation and following mitigate lung fibrosis. Then, we found that radiation-induced TNF-α, IL-1β and IL-6 in serum were also inhibited by GTS-21. Comparing to the control group, the mRNA levels of HMGB1,TLR-4 and NF-κB were decreased at the early time of radiation pneumonitis, and the most significant difference was observed at 21d post-irradiation(P<0.05). the mRNA levels of TGF-β was decrease in GTS-21group at 3m and 6m post -irradiation when compared to control (P<0.05). However, there did not have any different on MyD88 between GTS-21and control groups. The result from western blot showed that the protein levels of HMGB1, TLR-4 and NF-κB in GTS-21 group were also significantly decreased at 21d after radiation. After 3m and 6m from radiation, the protein level of TGF-β was decreased dramatically at GTS-21 group.

      Conclusion:
      GTS-21 can reduce radiation pneumonitis and fibrosis by inhibiting HMGB1/TLR-4/NF-κB pathway which subsequently decrease TGF-β expression.

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    P3.02c - Poster Session with Presenters Present (ID 472)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02c-004 - SBI0206965, a Novel Inhibitor of Ulk1, Suppresses Non-Small Cell Lung Cancer Cell Growth via Modulating Both Autophagy and Apoptosis Pathways (ID 5124)

      14:30 - 14:30  |  Author(s): C. Xie

      • Abstract

      Background:
      Autophagy is a catabolic process that regulates the lysosomal turnover of damaged proteins and organelles in order to maintain cellular homeostasis. Dysregulation of autophagy is often observed in lung cancer. Kinase inhibitors have proved successful in the clinic. The fact that uncoordinated (Unc) 51-like kinase (Ulk1) is the only conserved serine/threonine kinase in the autophagy cascade makes it a very attractive target for therapeutic development. Up-regulation of Ulk1 has been shown to promote cell survival of several cancer cell lines. Moreover, overexpression of Ulk1 has been shown to be negatively correlated with the prognosis of several types of human cancer. However, the role of Ulk1 in NSCLC is largely unknown.

      Methods:
      We evaluated Ulk1 expression levels in human normal lung epithelial cell line BEAS-2B and five NSCLC cell lines, A549, H460, H1299, H292 and HCC827. We analyzed the correlation between Ulk1 expression levels and the prognosis of NSCLC patients. We evaluated the effect of SBI0206965 alone or in combination with cisplatin on cell proliferation, apoptosis and autophagy in two human NSCLC cell lines, A549 and H460. Cell proliferation of untreated or drug-treated cells was measured by CCK8 assay. Percentage of apoptotic cells was measured using PE-conjugated Annexin V with a flow cytometer. Autophagy was determined by conversion of LC3I to LC3II and p62 degradation using Western blot.

      Results:
      Ulk1 is overexpressed in NSCLC cell lines and negatively correlated with the prognosis of NSCLC patients. The inhibition of Ulk1 by a selective inhibitor, SBI0206965, blocks the proliferation of NSCLC cells and induces apoptosis. SBI0206965 treatment augments the efficacy of cisplatin to kill NSCLC cells by inhibiting cisplatin induced cell protective autophagy. SBI0206965 can also destabilize Bcl2/Bclxl to promote cisplatin induced apoptosis in NSCLC cell lines.

      Conclusion:
      Our results suggest that the inhibition of Ulk1 may be a promising strategy for the treatment of NSCLC. SBI0206965 may be a promising agent for the treatment of NSCLC by modulating autophagy and apoptosis pathways. Furthermore, the combination of SBI0206965 with classical chemotherapy agents represents a promising therapeutic strategy that warrants further clinical evaluation in NSCLC.