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• 10557

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  P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 2
  • Moderators:
  • Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 10568

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    P1.05-011 - Antitumor agent KNG-I-484C causes cell death through inducing cell cycle arrest (ID 1754)

    09:30 - 16:30  |  Author(s): C. Lin
    • Abstract

    Background
    Lung cancer is the leading cause of cancer deaths in the world, and is classified into two major groups, non-small cell lung cancer (NSCLC, ~85%) and small-cell lung cancer (SCLC, ~15%). EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma. However, secondary EGFR mutation may cause drug resistant and cancer relapse. Further investigation and drug development is necessary for lung cancer therapy. KNG-I-484C is an analog of Desmosdumotin B compound, isolated and modified from the roots of Desmos dumosus. Previous studies showed that KNG-I-484C can inhibit cell proliferation of multidrug resistant (MDR) cancer cell line, KB-V, as well as multiple non-MDR cancer cell lines. Therefore, KNG-I-484C may act as a potential antitumor agent to inhibit drug-resistant cancer cells.

    Methods
    KNG-I-484C anti-tumorigenesis activity is estimated in non-small cell lung cancer cell lines by SRB assay and by the soft agar colony formation assay. Flow cytometry is used for cell cycle progression and cell apoptosis evaluation. The centrosomes observation is by the IF staining. The gene expression affected by the compound is by DNA microarray. Nude mice are subcutaneously injected with non-small cell lung cancer cell lines. When the tumor volume reaches about 2 mm[3], KNG-I-484C is administered by intra-peritoneal injection. The body weight of mice will be monitored. Before tumor volume reaches 1 cm[3], the mice will be sacrificed for the measurement of the tumor volume and blood.

    Results
    KNG-I-484C can inhibit cell proliferation and colonies formation in the soft agar in NSCLC cell lines. The compound induces G2/M arrest by flow cytometry and the G2/M markers, cyclin B1 and phospho-histone H3, are upregulated at the early stage. And it then causes cell apoptosis by annexin-V staining assay, and the apoptotic markers, caspase 3 and cleaved PARP increases by the treatment. KNG-I-484C treatment causes abnormal formation of centrosomes in NSCLC cell lines. The microarray results showed that EGR1 (early growth response protein 1) may be one of the target candidate. In the animal model, KNG-I-484C tends to inhibit the tumor growth.

    Conclusion
    KNG-I-484C can inhibit cell proliferation and induce cell apoptosis in lung cancer cell lines by directly inhibiting tubulin polymerization. Additional mechanisms of action may go through the centrosome abnormality. Therefore, KNG-I-484C may serve as a new and potential antitumor agent against NSCLC.

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    P1.05-018 - Inhibition of Non-small-cell Lung Cancer Growth by pH Control Release Nanoparticle Carrying miR-135b Antagomir (ID 2707)

    09:30 - 16:30  |  Author(s): C. Lin
    • Abstract

    Background
    We identified an intronic miRNA, miR-135b, up-regulated in aggressive non-small-cell lung cancer(NSCLC). Ectopically delivering mir-135b enhanced cell invasive and migratory ability in vitro and in vivo; whereas specific inhibition of miR-135b by miR-135b-specific molecular sponge and antagomirs suppressed cancer cell invasion, orthotopic lung tumor growth and metastasis in mouse model. We showed that miR-135b could directly repress the expression of Hippo pathway components. In this study, we design a tunable pH-responsive hydrogels to enhance the bioactivity of chemically modified antisense RNA oligonucleotide and SPION in tumor microenvironment for acidosis-related tumor therapy.

    Methods
    pH-responsive matrix of PEG-imidazole hydrogel releases chemically modified oligonucleotides (antagomir) and positively charged superparamagnetic iron oxide nanoparticles (SPION) were prepared. NOD-SCID mice were subcutaneously injected with CL1-5 cells and control antagomiR or antagomir-135b was intra-tumoural injected for 3 weeks. Body weight was determined. Blood was collected before euthanasia. Total tumor volume, metastatic nodules, and miR-135b expression are measured.

    Results
    By using pH-responsive release of SPION from hydrogels to release antagomiR, we found the hydrogel administered to natural physiology had a rate of slower release at pH6.7 than at pH7.4, which is sufficient to restrain cellular uptake of antagomir and the rate of release in acidic environments can be manipulated via the imidazole content. .In addition, systematic administrated antagomiR-135b through I.V. injection inhibited the orthotopic lung tumor growth and decreased the volume of lung metastases. Both results trigger us to examine the possibility of in vivo placing the antagomiR-containing hydrogels by the side of tumor, to evaluate the effect of localized releasing antagomiR on tumor growth.

    Conclusion
    Our results support that inhibition of miR-135b by pH control release nanoparticle may be promising to develop a new therapeutic strategy for NSCLC.