Table of Contents
Recommendation Letter from the Thesis Advisor
Thesis/Dissertation Oral Defense Committee Certification
Acknowledgments iii
Chinese Abstract iv
English Abstract v
Chapter 1 Background 1
1.1 Lung cancer 1
1.2 Synergistic effect between Modern and Chinese herbal
Medicine 2
Chapter 2 Chinese herb medicine (YQ1) potentiated anti-tumor immune activity combined with chemotherapy, benefiting the survival of patients with non-small cell lung cancer 4
2.1 Introduction 4
2.2 Materials and Methods 10
2.2.1 Chinese herbal extracts 10
2.2.2 Cell culture 12
2.2.3 Clinical Trial 14
2.2.3.1 Patients 14
2.2.3.1.1Ethics Statements 14
2.2.3.1.2 Histology and Nomenclature of Lung Cancer 15
2.2.3.1.3 Subject Recruitment 15
2.2.3.2 Treatment 17
2.2.3.3 Clinical Evaluation 18
2.2.3.4 Treatment Allocation and Regimens 18
2.2.3.5 Outcome Assessment 19
2.2.3.6 Clinical study flowchart 20
2.3 Preliminary Results 21
2.3.1 Systematic profiling of drug combination using L1000 gene expression profiling 21
2.3.2 YQ1 and AM reduce the percentage of lung CSCs, but not lung cancer cells 25
2.3.3 YQ1 and AM can stimulate immune response and have
anti-inflammatory effect 32
2.3.4 Western Blot Analysis as means of large-scale screening
elucidates potential pathway of YQ1: Synergistic treatment of cisplatin and YQ1 may attenuate cancer-proliferation through inhibiting the EGFR/ID1 Cascade in NSCLC 33
2.3.5 YQ1-mediated antitumor effects in NOD/SCID mice tumor xenograft models 37
2.3.6 Clinical Study of YQ1 on Advanced NSCLC Patients 38
2.3.6.1 Efficacy of YQ1 on NSCLC patients with 1st line
platinum-based chemotherapy 40
2.4 Discussion 44
Chapter 3 Antrodia cinnamomea Alleviates Cisplatin-Induced Hepatotoxicity and Enhances Chemo-Sensitivity of Line-1 Lung Carcinoma Xenografted in BALB/cByJ Mice 46
3.1 Introduction 46
3.2 Materials and Methods 48
3.2.1 Cells and cell culture 48
3.2.2 Preparation of A. cinnamomea extract 49
3.2.3 Cell viability assay 50
3.2.4 Nitric oxide assay 50
3.2.5 Ferrous ion chelating activity 51
3.2.6 DPPH radicals scavenging assay 51
3.2.7 Superoxide anion scavenging activity 52
3.2.8 Mice and tumor model 53
3.2.9 Blood sample preparation and analyses 54
3.2.10 Histopathological analysis 54
3.2.11 RNA extraction and real-time PCR 54
3.2.12 Statistical analysis 56
3.3 Results 56
3.3.1 A cinnamomea protects hepatic cells, inhibits lung carcinoma cells and alleviates oxidative stress 56
3.3.2 A cinnamomea in combination with cisplatin inhibits growth of line-1 lung carcinoma cells inoculated into mice 61
3.3.3 A cinnamomea attenuates cisplatin-induced liver damage and inflammation in mice 63
.3.4 Discussion 69
Chapter 4 Prophylactic Administration of Fucoidan Represses Cancer Metastasis by Inhibiting Vascular Endothelial Growth Factor (VEGF) and Matrix Metalloproteinases (MMPs) in Lewis Tumor-Bearing Mice 72
4.1 Introduction 72
4.2 Materials and Methods 74
4.2.1 Cells and cell culture 74
4.2.2 Preparation of fucoidan extract 74
4.2.3 Ethical approval and animals 75
4.2.4 Experimental design 75
4.2.5 Blood sample analysis 76
4.2.6 Flow Cytometry 76
4.2.7 Lewis lung carcinoma cells metastasis models 76
4.2.8 Western blot analysis 77
4.2.9 Histopathological analysis 78
4.2.10 Immunofluorescence assay 78
4.2.11 Cell viability assay 78
4.2.12 Cell migration and invasion assays 79
4.2.13 Gelatin zymography 80
4.2.14 Statistical analysis 81
4.3 Results 81
4.3.1 Fucoidan mitigates cachectic symptoms in LLC- inoculated C57BL/6 mice 81
4.3.2 Fucoidan inhibits lung metastatic colonization of LLC
cells in C57BL/6 mice 84
4.3.3 Fucoidan restrains LLCs metastasis by suppressing expression of VEGF and MMPs 86
4.3.4 Fucoidan has a cytotoxic effect on the LLC cell line 90
4.3.5 Fucoidan prevents metastasis of lung adenocarcinoma cells
93
4.3.6 Effects of fucoidan on expression and activity of MMPs 96
4.4 Discussion 98
Chapter 5 Conclusions 101
References 106


List of figures
Figure 2.1 The connectivity map (CMap) concept 7
Figure 2.2 Trichostatin A as a positive control of the L1000 platform 9
Figure 2.3A Randomized-controlled trial protocol 20
Figure 2.3B clinical follow up 20
Figure 2.3.1 The bar charts show the number of up/down-regulated genes in each sample 22
Figure 2.3.2 Synergistic expression patterns of YQ1 combined with Gemcitabine or Cisplatin 23
Figure 2.3.3 Rankings of mapped drug signatures from LINCS database between YQ1 and YQ1+Gemcitabine 24
Figure 2.3.4. YQ1 and AM have no cytotoxicity against lung cancer cell lines 26
Figure 2.3.5 YQ1 and AM do not have synergistic effect with cisplatin in the cytotoxicity 28
Figure 2.3.6 Astragalus water extracts potentiate the cytotoxicity of cisplatin on lung cancer A549 cells 28
Figure 2.3.7 YQ1 and AM reduce cancer stem cell survival 31
Figure 2.3.8 Both AM and YQ1 can stimulate immune response 33
Figure 2.3.9 ID protein family inhibits basic helix-loop-helix (bHLH) transcription factors from DNA binding 35
Figure 2.3.10 p-EGFR and ID1 are down regulated when treated with YQ1 combined with cisplatin 36
Figure 2.3.11 Regulation of ID protein expression by oncogenes and tumor-suppressor genes 37
Figure 2.3.12 In vivo examination of the inhibitory effect on lung tumorigenesis mediated by YQ1 treatment 38
Figure 2.3.13 Clinical study of YQ1 on advanced NSCLC patients 43
Figure 3.1 Effects of A. cinnamomea on cell viability in cisplatin- treated human hepatic HepG2 and mouse line-1 lung carcinoma cells 58
Figure 3.2 Antioxidation activity of A. cinnamomea 59
Figure 3.3 Inhibition of A. cinnamomea on NO production in LPS-stimulated RAW264.7 macrophages 61
Figure 3.4 A. cinnamomea and cisplatin synergistically inhibit tumor growth in the line-1 xenografted mouse model 64
Figure 3.5 Effects of A. cinnamomea on cisplatin-induced body weight and liver weight loss in the line-1 xenografted mouse model 65
Figure 3.6 A. cinnamomea decreases cisplatin-induced inflammation and cell apoptosis in liver 68
Figure 4.1 Effects of fucoidan on body weight and lung mass in the LLC xenografted mouse model 82
Figure 4.2 Fucoidan reduces growth of lung tumor in mice 86
Figure 4.3 Expression of metastatic proteins in sera of tumor bearing mice treated with fucoidan 88
Figure 4.4 Expression of metastatic proteins in lung tissues of tumor bearing mice treated with fucoidan 90
Figure 4.5 Effects of fucoidan on cell viability in African green monkey kidney Vero and mouse Lewis lung carcinoma cells 92
Figure 4.6 Suppression of migration and invasion of lung adenocarcinoma cells by fucoidan 95
Figure 4.7 Enzymatic activities of MMP-2 and MMP-9 in the LLC cell lines treated with fucoidan 97
Figure 5.1 Different faces of inflammation and its role in tumorigenesis
…………………………………………………………..102
Figure 5.2 Inflammatory networking in cancer……………………..103
Figure 5.3 Summary of mechanisms for the involvment of inflammation in cancer development…………………………………..103



List of tables
Table 2.1 Cell lines will be used in this study 13
Table 2.2 Chinese herbal medicine tested in YQ1 study 13
Table 2.3 Connectivity between drug combinations of YQ1 and shRNA profiles of AURKA and FGFR2 23
Table 2.4 YQ1 and AM do not induce autophagy in lung cancer cells 26
Table 2.5 YQ1 and AM do not significantly affect cell cycle and apoptosis status in lung cancer cells 26
Table 2.6 AM and YQ1 reduce the percentage of non–small cell lung cancer stem-like cells 31
Table 2.7 Patient characteristics 39
Table 3.1 Effect of A. cinnamomea on cisplatin-induced
hepatotoxicity 67
Table 4.1. Effects of fucoidan on hematological and spleen immunological parameters in the LLC xenografted mouse model 83

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