Author of

• 11454

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  P2.01 - Poster Session 2 - Cancer Biology (ID 145)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11460

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    P2.01-006 - Novel small compounds targeting cancer stem cells of non-small cell lung cancer (ID 3176)

    09:30 - 09:30  |  Author(s): Y. Liu
    • Abstract

    Background
    Platinum-based combination chemotherapy is the first-line treatment for advanced non-small cell lung cancer, but tumor recurrence occurs in most of patients who have received this treatment. Recent evidences suggested existence of CD133+ cancer stem cells is the cause of drug resistance and tumor recurrence. However, there is no efficient way to eliminate CD133+ cancer stem cells. Accordingly, the goal of this study is to identify novel compounds that targeting CD133+ CSCs of non-small cell lung cancer.

    Methods
    A hCD133 promoter-driven GFP reporter construct was used to identify CD133+ cells. CD133+ cells were FACS sorted from H460 cell line. The stemness and drug resistance of CD133+ cells were characterized according to their sphere formation, differentiation, gene expression, and chemo-response. IC~50~ of each novel compound was determined using MTT assay.

    Results
    CD133+ lung cancer cells identified by a human CD133 promoter- driven GFP reporter exhibited drug resistance and expressed stem-cell characteristics. Treatment of lung cancer cells with cisplatin was sufficient to result in enrichment of CD133+ cells, to induce DNA damage responses, to up-regulate levels of ABCG2 and ABCB1 which therefore increased resistance to doxorubicin and paclitaxel. We further found that cisplatin-induced enrichment of CD133+ cells was mediated by activation of notch signaling as judge by increased levels of NICD. Pre-treatment of cells with g-secretase inhibitor, DAPT, remarkably reduced cisplatin-induced enrichment of CD133+ cells and increased the sensitivity to doxorubicin and paclitaxol. Ectopic expression of NICD reversed the function of DAPT on drug sensitivity. The similar effect was also observed in tumor-engraft experiments as cisplatin treatment significantly increased the number of CD133+ cells in tumor-engraft in nude mice. In contrast, intra-tumor injection of DAPT together cisplatin was able to significant decrease the number of CD133+ cells in the tumor-engraft of mice. To identify novel compounds that may target CSC and cancer cells, we tested the cytotoxic effect 30 synthesized small compounds. Among of these compounds, 4 compounds, NCKU-44, NCKU-291, NCKU487 and NCKU-570, effectively killed both CD133+ CSCs and parental cancer cells. Three compounds, NCKU-46, NCKU-mo and NCKU-ts, specifically targeted to CD133+ CSCs.

    Conclusion
    In our study, we developed a drug-screening platform of CD133+ CSC of non-small cell lung cancer. At least 7 novel compounds were identified as potential CSC-targeting agents, which could be used in the future pre-clinical trials.