臺灣博碩士論文加值系統

藥物開發是一件花錢又費時的工作。過去二十年，由美國FDA認可的藥物平均不到30個，但是新藥開發所需經費卻與日俱增。為了縮短開發時程，我們以老藥新用的模式，搭配生物資訊技術，進行上市藥物新適應症的探索。
Connectivity Map (CMap) 是一個以基因圖譜為基礎的藥物篩選平台，利用疾病基因標記與藥物基因圖譜，探索疾病與藥物間的關係，並藉由統計方法推論潛力治療藥物。此研究中，我們藉由不同的基因標記選取方法進行肺腺癌潛力藥物預測，並以生物實驗驗證。從CMap的藥物基因圖譜中，比較有效藥物與肺腺癌病人間的基因標記，共找到89個逆轉基因。此外，由於眾多證據顯示癌幹細胞與腫瘤發生、復發及抗藥性有密不可分的關係，因此我們以胚胎幹細胞及癌幹細胞基因標記進行藥物探索，成功找到可扭轉幹細胞基因標記的潛力藥物trifluoperazine。經實驗證實，trifluoperazine可有效抑制腫瘤生長並克服癌幹細胞之抗藥性。
此外，我們設計一個以基因演算法為基礎的合併用藥篩選平台。此研究以藥物作用標的為基礎，計算藥物、疾病間基因表現的變化，提供一個系統化藥物組合評估策略。我們以人類三陰性乳癌為藥物篩選標的，藉由篩選找到一組最佳的藥物組合，並以文獻探討此藥物組合的可行性。未來，將進行生物實驗驗證，並以實驗結果調整參數，提升系統預測準確率。
最後，由於中草藥開發在華人地區已成為重要的研究方向。但目前中草藥缺乏系統化科學驗證與作用機轉評估，因此在品質驗證上存在相當大的挑戰。我們嘗試以基因圖譜探討中草藥品質的穩定性，並以中草藥基因標記進行生物反應途徑分析。分析黃耆萃取物（血寶）生物反應途徑，有近八成與免疫相關。另外，我們還發現血寶可提昇化療的敏感性，增進化療療效。

Drug development is an expensive and time-consuming process. Over the past two decades, the expense of drug development grows annually, but new drugs approved by FDA each year remain at less than 30. In order to reduce development time, we adopted the drug-repurposing strategy in combination with bioinformatics to discover new indications for old drugs.
Connectivity Map (CMap) is a gene expression based in silico drug screening platform. Using disease signatures and drug expression profiles, CMap determines connections between disease and drug and predicts potential drugs by statistical methods. In this study, we employed several gene signatures to discover potential drugs for lung adenocarcinoma patients. In addition, we have validated the anticancer effects in lung cancer cells. By comparing the signature of effective drugs with those of lung adenocarcinoma patients, 89 differentially expressed genes were identified that produced a reverse signature. Furthermore, several lines of evidence show that cancer stem cells (CSCs) are associated with tumor initiation, disease relapse, and drug resistance. Therefore, we explored anti-cancer stem cell drugs by using embryonic stem cells (ESCs) and CSCs signature. We have identified trifluoperazine as an anti-lung CSC agent to inhibit tumor growth and overcome chemotherapy resistance.
Moreover, we designed a drug combination prediction system using genetic algorithm. Based on the interaction of drug targets, we provided a systematic evaluation strategy for combinatorial drug therapy. We used the triple-negative breast cancer (TNBC) as our target disease for the prediction of possible drug combinations and discuss the effectiveness of the results by literature review. In the future, we will use experimental results to improve the prediction accuracy.
Finally, Chinese herbal medicine (CHM) has become an important research field in the Ethnic Chinese community. Due to the lack of systematic scientific evidence and evaluation mechanism, there is a considerable challenge for performing quality assurance on CHM. We investigated quality consistency of CHM by using gene expression profiles and pathway analysis. Pathway analysis of PG2 shows that approximately 82% of the affected pathways are immune-related pathways. In addition, we discovered that PG2 enhances doxorubicin sensitivity in leukemia cancer cells.

中文摘要 iii
Abstract iv
Contents vi
List of Figures x
List of Tables xi
Chapter 1 Introduction 1
1.1 Cancer 1
1.2 Drug Discovery and Drug Development 2
1.3 Drug Repurposing 4
1.4 Combinatorial Drug Therapy 5
1.5 Gene Expression Profiling 6
1.6 Connectivity Map (CMap) 7
1.6.1 Related works 10
1.7 Manuscript Plan 16
Chapter 2 Drug discovery for lung adenocarcinoma 18
2.1 Introduction 18
2.2 Materials and Methods 19
2.2.1 Collection of lung adenocarcinoma samples 19
2.2.2 Microarray analysis 21
2.2.3 Connectivity Map analysis 23
2.2.4 Gene expression profiling for 9 functional categories of drugs 24
2.2.5 MTT™ assay and clonogenic assay 25
2.3 Results 26
2.3.1 Identification of 363 potential drugs for NSCLC via the CMap 26
2.3.2 Validation of 62 potential drugs via PubMed and biochemical assays 28
2.3.3 Matrix visualization using Generalized Association Plot 37
2.3.4 Pathway analysis of reversed signatures 42
2.4 Discussion 49
Chapter 3 Drug Discovery of Anti-Cancer Stem Cell and Drug Resistance Inhibitor for Lung Cancer 57
3.1 Introduction 57
3.2 Materials and Methods 59
3.2.1 Collection of stem cell-based data 59
3.2.2 Connectivity Map analysis 60
3.2.3 MTT™, clonogenic assay, and side population analysis 61
3.3 Results 62
3.3.1 In silico drug screening reveals that phenothiazines might reverse ESC gene expression 62
3.4 Discussion 71
Chapter 4 Combinatorial drug discovery for triple-negative breast cancer with genetic algorithm 73
4.1 Introduction 73
4.2 Method 75
4.2.1 Triple-negative breast cancer microarray datasets 75
4.2.2 Microarray analysis 76
4.2.3 Collection of drug target information 80
4.2.4 Drug target expansion using human PPI for KEGG DRUG and DrugBank 81
4.2.5 Calculate the score for each drug 82
4.2.6 Score normalization for Drug Bank, and KEGG DRUG 83
4.2.7 Genetic algorithm for drug combination 86
4.2.8 Producing the next generation 87
4.3 Results 87
4.3.1 Identification of single drug score for KEGG and DrugBank 87
4.3.2 Four drug combinations analysis of TNBC 88
4.4 Discussion 90
Chapter 5 Gene expression profiling and pathway network analysis predicts novel function of PG2 92
5.1 Introduction 92
5.2 Materials and Methods 95
5.2.1 Microarray sample preparation 95
5.2.2 Trypan blue exclusion assay and evaluation of drug interactions 96
5.2.3 Statistics analysis 97
5.2.4 Cliques analysis in a Protein-Protein Interaction network 97
5.2.5 Pathway and chemical-protein interaction analysis 100
5.2.6 Connectivity Map analysis 100
5.3 Results 101
5.3.1 Scatter-plot matrix and correlation map with hierarchical clustering analysis for quality consistency 101
5.3.2 Identification of PG2 gene signature 103
5.3.3 Construction of the PG2 PPI network to reveal enriched signature 106
5.3.4 PG2-enriched signature is associated with immune-associated pathway 108
5.3.5 Combined treatment of Doxorubicin and PG2 113
5.3.6 Search for potential small molecules which mimic PG2 mechanism 117
5.4 Discussion 120
Chapter 6 Conclusion 123
6.1 Summary 123
6.2 Future work 125
Bibliography 127

[1]P. Blay, I. Santamaria, A. S. Pitiot, et al., "Mutational analysis of BRCA1 and BRCA2 in hereditary breast and ovarian cancer families from Asturias (Northern Spain)," BMC Cancer, vol. 13, p. 243, 2013.
[2]R. A. Kleinerman, R. E. Tarone, D. H. Abramson, et al., "Hereditary retinoblastoma and risk of lung cancer," J Natl Cancer Inst, vol. 92, pp. 2037-9, Dec 20 2000.
[3]A. K. Rustgi, "The genetics of hereditary colon cancer," Genes Dev, vol. 21, pp. 2525-38, Oct 15 2007.
[4]C. a. B. Adams, Van V., "Spending on New Drug Development," Available at SSRN, 2008.
[5]K. I. Kaitin and J. A. DiMasi, "Pharmaceutical innovation in the 21st century: new drug approvals in the first decade, 2000-2009," Clin Pharmacol Ther, vol. 89, pp. 183-8, Feb 2011.
[6]C. R. Chong and D. J. Sullivan, Jr., "New uses for old drugs," Nature, vol. 448, pp. 645-6, Aug 9 2007.
[7]T. T. Ashburn and K. B. Thor, "Drug repositioning: identifying and developing new uses for existing drugs," Nat Rev Drug Discov, vol. 3, pp. 673-83, Aug 2004.
[8]M. Colleoni, S. Li, R. D. Gelber, et al., "Timing of CMF chemotherapy in combination with tamoxifen in postmenopausal women with breast cancer: role of endocrine responsiveness of the tumor," Ann Oncol, vol. 16, pp. 716-25, May 2005.
[9]B. Al-Lazikani, U. Banerji, and P. Workman, "Combinatorial drug therapy for cancer in the post-genomic era," Nat Biotechnol, vol. 30, pp. 679-92, Jul 2012.
[10]J. Maertzdorf, M. Ota, D. Repsilber, et al., "Functional correlations of pathogenesis-driven gene expression signatures in tuberculosis," PloS one, vol. 6, p. e26938, 2011.
[11]S. R. Hegde, P. Manimaran, and S. C. Mande, "Dynamic changes in protein functional linkage networks revealed by integration with gene expression data," PLoS computational biology, vol. 4, p. e1000237, Nov 2008.
[12]J. L. DeRisi, V. R. Iyer, and P. O. Brown, "Exploring the metabolic and genetic control of gene expression on a genomic scale," Science, vol. 278, pp. 680-6, Oct 24 1997.
[13]J. Lamb, S. Ramaswamy, H. L. Ford, et al., "A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer," Cell, vol. 114, pp. 323-34, Aug 8 2003.
[14]T. R. Golub, D. K. Slonim, P. Tamayo, et al., "Molecular classification of cancer: class discovery and class prediction by gene expression monitoring," Science, vol. 286, pp. 531-7, Oct 15 1999.
[15]C. M. Perou, T. Sorlie, M. B. Eisen, et al., "Molecular portraits of human breast tumours," Nature, vol. 406, pp. 747-52, Aug 17 2000.
[16]S. L. Pomeroy, P. Tamayo, M. Gaasenbeek, et al., "Prediction of central nervous system embryonal tumour outcome based on gene expression," Nature, vol. 415, pp. 436-42, Jan 24 2002.
[17]L. J. van ''t Veer, H. Dai, M. J. van de Vijver, et al., "Gene expression profiling predicts clinical outcome of breast cancer," Nature, vol. 415, pp. 530-6, Jan 31 2002.
[18]T. R. Hughes, M. J. Marton, A. R. Jones, et al., "Functional discovery via a compendium of expression profiles," Cell, vol. 102, pp. 109-26, Jul 7 2000.
[19]B. Ganter, S. Tugendreich, C. I. Pearson, et al., "Development of a large-scale chemogenomics database to improve drug candidate selection and to understand mechanisms of chemical toxicity and action," Journal of biotechnology, vol. 119, pp. 219-44, Sep 29 2005.
[20]R. Garcia-Escudero and J. M. Paramio, "Gene expression profiling as a tool for basic analysis and clinical application of human cancer," Molecular carcinogenesis, vol. 47, pp. 573-9, Aug 2008.
[21]W. E. Evans and R. K. Guy, "Gene expression as a drug discovery tool," Nature genetics, vol. 36, pp. 214-5, Mar 2004.
[22]J. Lamb, "The Connectivity Map: a new tool for biomedical research," Nature reviews. Cancer, vol. 7, pp. 54-60, Jan 2007.
[23]J. Lamb, E. D. Crawford, D. Peck, et al., "The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease," Science, vol. 313, pp. 1929-35, Sep 29 2006.
[24]D. W. M. Hollander, "Nonparametric Statistical Methods," pp. 178-185, Wiley, New York, ed. 2, 1999.
[25]A. Subramanian, P. Tamayo, V. K. Mootha, et al., "Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles," Proceedings of the National Academy of Sciences of the United States of America, vol. 102, pp. 15545-50, Oct 25 2005.
[26]D. C. Hassane, M. L. Guzman, C. Corbett, et al., "Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data," Blood, vol. 111, pp. 5654-62, Jun 15 2008.
[27]J. M. Rosenbluth, D. J. Mays, M. F. Pino, L. J. Tang, and J. A. Pietenpol, "A gene signature-based approach identifies mTOR as a regulator of p73," Molecular and cellular biology, vol. 28, pp. 5951-64, Oct 2008.
[28]S. R. Setlur, K. D. Mertz, Y. Hoshida, et al., "Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer," Journal of the National Cancer Institute, vol. 100, pp. 815-25, Jun 4 2008.
[29]S. Claerhout, J. Y. Lim, W. Choi, et al., "Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer," PloS one, vol. 6, p. e24662, 2011.
[30]G. Wang, Y. Ye, X. Yang, et al., "Expression-based in silico screening of candidate therapeutic compounds for lung adenocarcinoma," PloS one, vol. 6, p. e14573, 2011.
[31]F. M. Siu, D. L. Ma, Y. W. Cheung, et al., "Proteomic and transcriptomic study on the action of a cytotoxic saponin (Polyphyllin D): induction of endoplasmic reticulum stress and mitochondria-mediated apoptotic pathways," Proteomics, vol. 8, pp. 3105-17, Aug 2008.
[32]H. Ebi, S. Tomida, T. Takeuchi, et al., "Relationship of deregulated signaling converging onto mTOR with prognosis and classification of lung adenocarcinoma shown by two independent in silico analyses," Cancer research, vol. 69, pp. 4027-35, May 1 2009.
[33]T. Sanda, X. Li, A. Gutierrez, et al., "Interconnecting molecular pathways in the pathogenesis and drug sensitivity of T-cell acute lymphoblastic leukemia," Blood, vol. 115, pp. 1735-45, Mar 4 2010.
[34]E. Vilar, B. Mukherjee, R. Kuick, et al., "Gene expression patterns in mismatch repair-deficient colorectal cancers highlight the potential therapeutic role of inhibitors of the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway," Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 15, pp. 2829-39, Apr 15 2009.
[35]T. Krech, M. Thiede, E. Hilgenberg, R. Schafer, and K. Jurchott, "Characterization of AKT independent effects of the synthetic AKT inhibitors SH-5 and SH-6 using an integrated approach combining transcriptomic profiling and signaling pathway perturbations," BMC cancer, vol. 10, p. 287, 2010.
[36]C. Braconi, F. Meng, E. Swenson, et al., "Candidate therapeutic agents for hepatocellular cancer can be identified from phenotype-associated gene expression signatures," Cancer, vol. 115, pp. 3738-48, Aug 15 2009.
[37]K. De Preter, S. De Brouwer, T. Van Maerken, et al., "Meta-mining of neuroblastoma and neuroblast gene expression profiles reveals candidate therapeutic compounds," Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 15, pp. 3690-6, Jun 1 2009.
[38]J. Gheeya, P. Johansson, Q. R. Chen, et al., "Expression profiling identifies epoxy anthraquinone derivative as a DNA topoisomerase inhibitor," Cancer letters, vol. 293, pp. 124-31, Jul 1 2010.
[39]M. Zimmer, J. Lamb, B. L. Ebert, et al., "The connectivity map links iron regulatory protein-1-mediated inhibition of hypoxia-inducible factor-2a translation to the anti-inflammatory 15-deoxy-delta12,14-prostaglandin J2," Cancer research, vol. 70, pp. 3071-9, Apr 15 2010.
[40]S. C. Pitt, H. Chen, and M. Kunnimalaiyaan, "Phosphatidylinositol 3-kinase-Akt signaling in pulmonary carcinoid cells," Journal of the American College of Surgeons, vol. 209, pp. 82-8, Jul 2009.
[41]S. W. Shin, C. Y. Seo, H. Han, et al., "15d-PGJ2 induces apoptosis by reactive oxygen species-mediated inactivation of Akt in leukemia and colorectal cancer cells and shows in vivo antitumor activity," Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 15, pp. 5414-25, Sep 1 2009.
[42]T. Peng, T. R. Golub, and D. M. Sabatini, "The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation," Molecular and cellular biology, vol. 22, pp. 5575-84, Aug 2002.
[43]A. S. Lader, M. F. Ramoni, B. R. Zetter, I. S. Kohane, and D. J. Kwiatkowski, "Identification of a transcriptional profile associated with in vitro invasion in non-small cell lung cancer cell lines," Cancer biology & therapy, vol. 3, pp. 624-31, Jul 2004.
[44]C. A. Powell, G. Xu, J. Filmus, et al., "Oligonucleotide microarray analysis of lung adenocarcinoma in smokers and nonsmokers identifies GPC3 as a potential lung tumor suppressor," Chest, vol. 121, pp. 6S-7S, Mar 2002.
[45]A. Jemal, R. Siegel, E. Ward, et al., "Cancer statistics, 2008," CA: a cancer journal for clinicians, vol. 58, pp. 71-96, Mar-Apr 2008.
[46]t. E. Y. Department of Health, "Cancer registry annual report in Taiwan area, Department of Health, Executive Yuan, ROC," 2007.
[47]N. Thatcher, A. Chang, P. Parikh, et al., "Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer)," Lancet, vol. 366, pp. 1527-37, Oct 29-Nov 4 2005.
[48]F. A. Shepherd, J. Rodrigues Pereira, T. Ciuleanu, et al., "Erlotinib in previously treated non-small-cell lung cancer," The New England journal of medicine, vol. 353, pp. 123-32, Jul 14 2005.
[49]S. F. Huang, H. P. Liu, L. H. Li, et al., "High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan," Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 10, pp. 8195-203, Dec 15 2004.
[50]H. Shigematsu, L. Lin, T. Takahashi, et al., "Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers," Journal of the National Cancer Institute, vol. 97, pp. 339-46, Mar 2 2005.
[51]L. J. Su, C. W. Chang, Y. C. Wu, et al., "Selection of DDX5 as a novel internal control for Q-RT-PCR from microarray data using a block bootstrap re-sampling scheme," BMC genomics, vol. 8, p. 140, 2007.
[52]A. R. Gibbs and F. B. Thunnissen, "Histological typing of lung and pleural tumours: third edition," Journal of clinical pathology, vol. 54, pp. 498-9, Jul 2001.
[53]C. F. Mountain, "Revisions in the International System for Staging Lung Cancer," Chest, vol. 111, pp. 1710-7, Jun 1997.
[54]M. T. Landi, T. Dracheva, M. Rotunno, et al., "Gene expression signature of cigarette smoking and its role in lung adenocarcinoma development and survival," PloS one, vol. 3, p. e1651, 2008.
[55]V. G. Tusher, R. Tibshirani, and G. Chu, "Significance analysis of microarrays applied to the ionizing radiation response," Proceedings of the National Academy of Sciences of the United States of America, vol. 98, pp. 5116-21, Apr 24 2001.
[56]H. Y. Chen, S. L. Yu, C. H. Chen, et al., "A five-gene signature and clinical outcome in non-small-cell lung cancer," The New England journal of medicine, vol. 356, pp. 11-20, Jan 4 2007.
[57]S. K. Lau, P. C. Boutros, M. Pintilie, et al., "Three-gene prognostic classifier for early-stage non small-cell lung cancer," Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol. 25, pp. 5562-9, Dec 10 2007.
[58]M. Skrzypski, E. Jassem, M. Taron, et al., "Three-gene expression signature predicts survival in early-stage squamous cell carcinoma of the lung," Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 14, pp. 4794-9, Aug 1 2008.
[59]C. C. Wu, C. T. Yu, G. C. Chang, J. M. Lai, and S. L. Hsu, "Aurora-A promotes gefitinib resistance via a NF-kappaB signaling pathway in p53 knockdown lung cancer cells," Biochemical and biophysical research communications, vol. 405, pp. 168-72, Feb 11 2011.
[60]Y. R. Chen, Y. N. Fu, C. H. Lin, et al., "Distinctive activation patterns in constitutively active and gefitinib-sensitive EGFR mutants," Oncogene, vol. 25, pp. 1205-15, Feb 23 2006.
[61]C. H. Chen, "Generalized Association Plots for Information Visualization: The applications of the convergence of iteratively formed correlation matrices," Statistica Sinica, vol. 12, pp. 1-23, 2002.
[62]Y. J. Tien, Y. S. Lee, H. M. Wu, and C. H. Chen, "Methods for simultaneously identifying coherent local clusters with smooth global patterns in gene expression profiles," BMC Bioinformatics, vol. 9, p. 155, 2008.
[63]H.-M. Wu, Y.-J. Tien, and C.-h. Chen, "GAP: A graphical environment for matrix visualization and cluster analysis," Comput. Stat. Data Anal., vol. 54, pp. 767-778, 2010.
[64]A. Kamburov, K. Pentchev, H. Galicka, et al., "ConsensusPathDB: toward a more complete picture of cell biology," Nucleic acids research, vol. 39, pp. D712-7, Jan 2011.
[65]Z. Kan, B. S. Jaiswal, J. Stinson, et al., "Diverse somatic mutation patterns and pathway alterations in human cancers," Nature, vol. 466, pp. 869-73, Aug 12 2010.
[66]L. Ding, G. Getz, D. A. Wheeler, et al., "Somatic mutations affect key pathways in lung adenocarcinoma," Nature, vol. 455, pp. 1069-75, Oct 23 2008.
[67]R. Rodriguez and M. Meuth, "Chk1 and p21 cooperate to prevent apoptosis during DNA replication fork stress," Molecular biology of the cell, vol. 17, pp. 402-12, Jan 2006.
[68]A. A. Elbendary, F. D. Cirisano, A. C. Evans, Jr., et al., "Relationship between p21 expression and mutation of the p53 tumor suppressor gene in normal and malignant ovarian epithelial cells," Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 2, pp. 1571-5, Sep 1996.
[69]E. Garner and K. Raj, "Protective mechanisms of p53-p21-pRb proteins against DNA damage-induced cell death," Cell cycle, vol. 7, pp. 277-82, Feb 1 2008.
[70]B. Ferraro, G. Bepler, S. Sharma, A. Cantor, and E. B. Haura, "EGR1 predicts PTEN and survival in patients with non-small-cell lung cancer," Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol. 23, pp. 1921-6, Mar 20 2005.
[71]A. Calogero, A. Arcella, G. De Gregorio, et al., "The early growth response gene EGR-1 behaves as a suppressor gene that is down-regulated independent of ARF/Mdm2 but not p53 alterations in fresh human gliomas," Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 7, pp. 2788-96, Sep 2001.
[72]M. Tarocchi, R. Hannivoort, Y. Hoshida, et al., "Carcinogen-induced hepatic tumors in KLF6+/- mice recapitulate aggressive human hepatocellular carcinoma associated with p53 pathway deregulation," Hepatology, vol. 54, pp. 522-31, Aug 2011.
[73]J. Sangodkar, J. Shi, A. DiFeo, et al., "Functional role of the KLF6 tumour suppressor gene in gastric cancer," European journal of cancer, vol. 45, pp. 666-76, Mar 2009.
[74]G. Narla, K. E. Heath, H. L. Reeves, et al., "KLF6, a candidate tumor suppressor gene mutated in prostate cancer," Science, vol. 294, pp. 2563-6, Dec 21 2001.
[75]M. Hartel, G. Narla, M. N. Wente, et al., "Increased alternative splicing of the KLF6 tumour suppressor gene correlates with prognosis and tumour grade in patients with pancreatic cancer," European journal of cancer, vol. 44, pp. 1895-903, Sep 2008.
[76]A. H. Wahab, A. M. Kassem, S. Matter, et al., "Role of KLF6 tumor suppressor gene mutations in the development of colorectal carcinoma in an Egyptian population," Hepato-gastroenterology, vol. 57, pp. 1405-10, Nov-Dec 2010.
[77]T. Ripperger, D. Gadzicki, A. Meindl, and B. Schlegelberger, "Breast cancer susceptibility: current knowledge and implications for genetic counselling," European journal of human genetics : EJHG, vol. 17, pp. 722-31, Jun 2009.
[78]A. C. Antoniou, O. M. Sinilnikova, L. McGuffog, et al., "Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers," Human molecular genetics, vol. 18, pp. 4442-56, Nov 15 2009.
[79]A. C. Antoniou, J. Beesley, L. McGuffog, et al., "Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction," Cancer research, vol. 70, pp. 9742-54, Dec 1 2010.
[80]G. Rehbein, A. Simm, H. S. Hofmann, R. E. Silber, and B. Bartling, "Molecular regulation of S100P in human lung adenocarcinomas," International journal of molecular medicine, vol. 22, pp. 69-77, Jul 2008.
[81]J. H. Rho, M. H. Roehrl, and J. Y. Wang, "Glycoproteomic analysis of human lung adenocarcinomas using glycoarrays and tandem mass spectrometry: differential expression and glycosylation patterns of vimentin and fetuin A isoforms," The protein journal, vol. 28, pp. 148-60, May 2009.
[82]R. Jing, M. Cui, J. Wang, and H. Wang, "Receptor for advanced glycation end products (RAGE) soluble form (sRAGE): a new biomarker for lung cancer," Neoplasma, vol. 57, pp. 55-61, 2010.
[83]M. Maemondo, A. Inoue, K. Kobayashi, et al., "Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR," The New England journal of medicine, vol. 362, pp. 2380-8, Jun 24 2010.
[84]T. S. Mok, Y. L. Wu, S. Thongprasert, et al., "Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma," The New England journal of medicine, vol. 361, pp. 947-57, Sep 3 2009.
[85]G. L. Ceresoli, F. Cappuzzo, V. Gregorc, et al., "Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial," Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, vol. 15, pp. 1042-7, Jul 2004.
[86]J. E. Kim, D. H. Lee, Y. Choi, et al., "Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis," Lung cancer, vol. 65, pp. 351-4, Sep 2009.
[87]C. Wu, Y. L. Li, Z. M. Wang, et al., "Gefitinib as palliative therapy for lung adenocarcinoma metastatic to the brain," Lung cancer, vol. 57, pp. 359-64, Sep 2007.
[88]S. Heon, B. Y. Yeap, G. J. Britt, et al., "Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib," Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 16, pp. 5873-82, Dec 1 2010.
[89]J. H. Schiller, D. Harrington, C. P. Belani, et al., "Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer," The New England journal of medicine, vol. 346, pp. 92-8, Jan 10 2002.
[90]S. Bao, Q. Wu, R. E. McLendon, et al., "Glioma stem cells promote radioresistance by preferential activation of the DNA damage response," Nature, vol. 444, pp. 756-60, Dec 7 2006.
[91]M. Dean, T. Fojo, and S. Bates, "Tumour stem cells and drug resistance," Nat Rev Cancer, vol. 5, pp. 275-84, Apr 2005.
[92]M. Diehn, R. W. Cho, N. A. Lobo, et al., "Association of reactive oxygen species levels and radioresistance in cancer stem cells," Nature, vol. 458, pp. 780-3, Apr 9 2009.
[93]P. B. Gupta, T. T. Onder, G. Jiang, et al., "Identification of selective inhibitors of cancer stem cells by high-throughput screening," Cell, vol. 138, pp. 645-59, Aug 21 2009.
[94]H. Clevers, "The cancer stem cell: premises, promises and challenges," Nat Med, vol. 17, pp. 313-9, Mar 2011.
[95]I. Shats, M. L. Gatza, J. T. Chang, et al., "Using a stem cell-based signature to guide therapeutic selection in cancer," Cancer Res, vol. 71, pp. 1772-80, Mar 1 2011.
[96]D. J. Wong, H. Liu, T. W. Ridky, et al., "Module map of stem cell genes guides creation of epithelial cancer stem cells," Cell stem cell, vol. 2, pp. 333-44, Apr 10 2008.
[97]J. Kim, A. J. Woo, J. Chu, et al., "A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs," Cell, vol. 143, pp. 313-24, Oct 15 2010.
[98]M. Ramalho-Santos, S. Yoon, Y. Matsuzaki, R. C. Mulligan, and D. A. Melton, ""Stemness": transcriptional profiling of embryonic and adult stem cells," Science, vol. 298, pp. 597-600, Oct 18 2002.
[99]M. L. Suva, N. Riggi, M. Janiszewska, et al., "EZH2 is essential for glioblastoma cancer stem cell maintenance," Cancer research, vol. 69, pp. 9211-8, Dec 15 2009.
[100]H. Liu, M. R. Patel, J. A. Prescher, et al., "Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models," Proceedings of the National Academy of Sciences of the United States of America, vol. 107, pp. 18115-20, Oct 19 2010.
[101]M. Zhang and J. M. Rosen, "Stem cells in the etiology and treatment of cancer," Current opinion in genetics & development, vol. 16, pp. 60-4, Feb 2006.
[102]E. Sachlos, R. M. Risueno, S. Laronde, et al., "Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells," Cell, vol. 149, pp. 1284-97, Jun 8 2012.
[103]A. Prat and C. M. Perou, "Mammary development meets cancer genomics," Nat Med, vol. 15, pp. 842-4, Aug 2009.
[104]W. R. Miller, A. A. Larionov, L. Renshaw, et al., "Changes in breast cancer transcriptional profiles after treatment with the aromatase inhibitor, letrozole," Pharmacogenet Genomics, vol. 17, pp. 813-26, Oct 2007.
[105]G. Mariani, A. Fasolo, E. De Benedictis, and L. Gianni, "Trastuzumab as adjuvant systemic therapy for HER2-positive breast cancer," Nat Clin Pract Oncol, vol. 6, pp. 93-104, Feb 2009.
[106]A. Prat, J. S. Parker, O. Karginova, et al., "Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer," Breast Cancer Res, vol. 12, p. R68, 2010.
[107]P. Moreau, P. G. Richardson, M. Cavo, et al., "Proteasome inhibitors in multiple myeloma: 10 years later," Blood, vol. 120, pp. 947-59, Aug 2 2012.
[108]C. P. B, X. A. M, C. A. K, et al., "Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials," Curr Cancer Drug Targets, vol. 11, pp. 254-84, Mar 2011.
[109]M. M. Seavey, L. D. Lu, K. L. Stump, N. H. Wallace, and B. A. Ruggeri, "Novel, orally active, proteasome inhibitor, delanzomib (CEP-18770), ameliorates disease symptoms and glomerulonephritis in two preclinical mouse models of SLE," Int Immunopharmacol, vol. 12, pp. 257-70, Jan 2012.
[110]R. C. Kane, P. F. Bross, A. T. Farrell, and R. Pazdur, "Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy," Oncologist, vol. 8, pp. 508-13, 2003.
[111]L. M. Tseng, C. Y. Liu, K. C. Chang, et al., "CIP2A is a target of bortezomib in human triple negative breast cancer cells," Breast Cancer Res, vol. 14, p. R68, 2012.
[112]R. W. Johnstone, "Histone-deacetylase inhibitors: novel drugs for the treatment of cancer," Nat Rev Drug Discov, vol. 1, pp. 287-99, Apr 2002.
[113]R. R. KN Bhalla, P Sharma, S Das Gupta, L Chauhan, S Stecklein, and W Fiskus, "Treatment with Histone Deacetylase Inhibitors Creates ‘BRCAness’ and Sensitizes Human Triple Negative Breast Cancer Cells to PARP Inhibitors and Cisplatin," Cancer Res, vol. 72, pp. 3-7, 2012.
[114]S. Kummar, A. Chen, R. E. Parchment, et al., "Advances in using PARP inhibitors to treat cancer," BMC Med, vol. 10, p. 25, 2012.
[115]M. C. Machado, M. Bellodi-Privato, M. S. Kubrusly, et al., "Valproic acid inhibits human hepatocellular cancer cells growth in vitro and in vivo," J Exp Ther Oncol, vol. 9, pp. 85-92, 2011.
[116]A. Sidana, M. Wang, S. Shabbeer, et al., "Mechanism of growth inhibition of prostate cancer xenografts by valproic acid," J Biomed Biotechnol, vol. 2012, p. 180363, 2012.
[117]X. Chen, P. Wong, E. Radany, and J. Y. Wong, "HDAC inhibitor, valproic acid, induces p53-dependent radiosensitization of colon cancer cells," Cancer Biother Radiopharm, vol. 24, pp. 689-99, Dec 2009.
[118]Z. Shan, R. Feng-Nian, G. Jie, and Z. Ting, "Effects of valproic acid on proliferation, apoptosis, angiogenesis and metastasis of ovarian cancer in vitro and in vivo," Asian Pac J Cancer Prev, vol. 13, pp. 3977-82, 2012.
[119]T. M. Motawi, Y. Bustanji, S. El-Maraghy, M. O. Taha, and M. A. Al-Ghussein, "Evaluation of naproxen and cromolyn activities against cancer cells viability, proliferation, apoptosis, p53 and gene expression of survivin and caspase-3," J Enzyme Inhib Med Chem, Jan 31 2013.
[120]V. E. Steele, C. V. Rao, Y. Zhang, et al., "Chemopreventive efficacy of naproxen and nitric oxide-naproxen in rodent models of colon, urinary bladder, and mammary cancers," Cancer Prev Res (Phila), vol. 2, pp. 951-6, Nov 2009.
[121]C. R. Tate, L. V. Rhodes, H. C. Segar, et al., "Targeting triple-negative breast cancer cells with the histone deacetylase inhibitor panobinostat," Breast Cancer Res, vol. 14, p. R79, 2012.
[122]X. Li, Y. Zhu, H. He, et al., "Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells," Biochem Biophys Res Commun, May 30 2013.
[123]M. D. Michaelson, A. X. Zhu, D. P. Ryan, et al., "Sunitinib in combination with gemcitabine for advanced solid tumours: a phase I dose-finding study," Br J Cancer, vol. 108, pp. 1393-401, Apr 16 2013.
[124]X. Paoletti, B. Geoerger, F. Doz, et al., "A comparative analysis of paediatric dose-finding trials of molecularly targeted agent with adults'' trials," Eur J Cancer, vol. 49, pp. 2392-402, Jul 2013.
[125]E. E. Harris, V. J. Christensen, W. T. Hwang, K. Fox, and L. J. Solin, "Impact of concurrent versus sequential tamoxifen with radiation therapy in early-stage breast cancer patients undergoing breast conservation treatment," J Clin Oncol, vol. 23, pp. 11-6, Jan 1 2005.
[126]T. Whelan and M. Levine, "Radiation therapy and tamoxifen: concurrent or sequential? That is the question," J Clin Oncol, vol. 23, pp. 1-4, Jan 1 2005.
[127]P. J. Marroum, R. S. Uppoor, T. Parmelee, et al., "In vivo drug-drug interaction studies--a survey of all new molecular entities approved from 1987 to 1997," Clin Pharmacol Ther, vol. 68, pp. 280-5, Sep 2000.
[128]P. Borst, R. Evers, M. Kool, and J. Wijnholds, "A family of drug transporters: the multidrug resistance-associated proteins," J Natl Cancer Inst, vol. 92, pp. 1295-302, Aug 16 2000.
[129]D. B. Longley and P. G. Johnston, "Molecular mechanisms of drug resistance," J Pathol, vol. 205, pp. 275-92, Jan 2005.
[130]Y. Baran, B. Gur, P. Kaya, et al., "Upregulation of multi drug resistance genes in doxorubicin resistant human acute myelogeneous leukemia cells and reversal of the resistance," Hematology, vol. 12, pp. 511-7, Dec 2007.
[131]K. F. Ejendal and C. A. Hrycyna, "Multidrug resistance and cancer: the role of the human ABC transporter ABCG2," Curr Protein Pept Sci, vol. 3, pp. 503-11, Oct 2002.
[132]M. D. Vesely, M. H. Kershaw, R. D. Schreiber, and M. J. Smyth, "Natural innate and adaptive immunity to cancer," Annu Rev Immunol, vol. 29, pp. 235-71, 2011.
[133]S. Mocellin, "Cancer vaccines: the challenge of developing an ideal tumor killing system," Front Biosci, vol. 10, pp. 2285-305, 2005.
[134]D. M. Zou, M. Brewer, F. Garcia, et al., "Cactus pear: a natural product in cancer chemoprevention," Nutr J, vol. 4, p. 25, 2005.
[135]W. Tan, J. Lu, M. Huang, et al., "Anti-cancer natural products isolated from chinese medicinal herbs," Chin Med, vol. 6, p. 27, 2011.
[136]N. Wang, D. Zhang, X. Mao, et al., "Astragalus polysaccharides decreased the expression of PTP1B through relieving ER stress induced activation of ATF6 in a rat model of type 2 diabetes," Mol Cell Endocrinol, vol. 307, pp. 89-98, Aug 13 2009.
[137]X. Q. Mao, Y. Wu, K. Wu, et al., "Astragalus polysaccharide reduces hepatic endoplasmic reticulum stress and restores glucose homeostasis in a diabetic KKAy mouse model," Acta Pharmacol Sin, vol. 28, pp. 1947-56, Dec 2007.
[138]Q. E. Tian, H. D. Li, M. Yan, et al., "Astragalus polysaccharides can regulate cytokine and P-glycoprotein expression in H22 tumor-bearing mice," World J Gastroenterol, vol. 18, pp. 7079-86, Dec 21 2012.
[139]Q. E. Tian, H. De Li, M. Yan, et al., "Effects of Astragalus polysaccharides on P-glycoprotein efflux pump function and protein expression in H22 hepatoma cells in vitro," BMC Complement Altern Med, vol. 12, p. 94, 2012.
[140]W. Q. Hu, C. W. Peng, and Y. Li, "The expression and significance of P-glycoprotein, lung resistance protein and multidrug resistance-associated protein in gastric cancer," J Exp Clin Cancer Res, vol. 28, p. 144, 2009.
[141]Z. E. Sauna, M. M. Smith, M. Muller, K. M. Kerr, and S. V. Ambudkar, "The mechanism of action of multidrug-resistance-linked P-glycoprotein," J Bioenerg Biomembr, vol. 33, pp. 481-91, Dec 2001.
[142]H. Li, X. Duan, H. Ma, and G. B. Ning, "Effects of astragalus polysaccharides on vaccine immunity of Newcastle disease and infectious bronchitis disease," Chinese Journal of Veterinary Science and Technology vol. 31, pp. 12-14, 2001.
[143]X. Huang, D. Wang, Y. Hu, et al., "Effect of sulfated astragalus polysaccharide on cellular infectivity of infectious bursal disease virus," Int J Biol Macromol, vol. 42, pp. 166-71, Mar 1 2008.
[144]J. Jiang, C. Wu, H. Gao, J. Song, and H. Li, "Effects of astragalus polysaccharides on immunologic function of erythrocyte in chickens infected with infectious bursa disease virus," Vaccine, vol. 28, pp. 5614-6, Aug 2 2010.
[145]L. H. Zhao, Z. X. Ma, J. Zhu, X. H. Yu, and D. P. Weng, "Characterization of polysaccharide from Astragalus radix as the macrophage stimulator," Cell Immunol, vol. 271, pp. 329-34.
[146]H. W. Chen, I. H. Lin, Y. J. Chen, et al., "A novel infusible botanically-derived drug, PG2, for cancer-related fatigue: a phase II double-blind, randomized placebo-controlled study," Clinical and investigative medicine. Medecine clinique et experimentale, vol. 35, pp. E1-11, 2012.
[147]"Phase III Clinical Development of PHN011/012/013 (PG2): Prophylaxis of Neutropenia."
[148]R. C. Gentleman, V. J. Carey, D. M. Bates, et al., "Bioconductor: open software development for computational biology and bioinformatics," Genome Biol, vol. 5, p. R80, 2004.
[149]L. Gautier, L. Cope, B. M. Bolstad, and R. A. Irizarry, "affy--analysis of Affymetrix GeneChip data at the probe level," Bioinformatics, vol. 20, pp. 307-15, Feb 12 2004.
[150]R. A. Irizarry, B. Hobbs, F. Collin, et al., "Exploration, normalization, and summaries of high density oligonucleotide array probe level data," Biostatistics, vol. 4, pp. 249-64, Apr 2003.
[151]X. F. Huang, S. K. Luo, J. Xu, et al., "Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia," Blood, vol. 111, pp. 2854-65, Mar 1 2008.
[152]M. Y. Lan, C. L. Chen, K. T. Lin, et al., "From NPC therapeutic target identification to potential treatment strategy," Mol Cancer Ther, vol. 9, pp. 2511-23, Sep 2010.
[153]H. Yu, A. Paccanaro, V. Trifonov, and M. Gerstein, "Predicting interactions in protein networks by completing defective cliques," Bioinformatics, vol. 22, pp. 823-9, Apr 1 2006.
[154]D. Bu, Y. Zhao, L. Cai, et al., "Topological structure analysis of the protein-protein interaction network in budding yeast," Nucleic acids research, vol. 31, pp. 2443-50, May 1 2003.
[155]A. Kamburov, U. Stelzl, H. Lehrach, and R. Herwig, "The ConsensusPathDB interaction database: 2013 update," Nucleic acids research, vol. 41, pp. D793-800, Jan 1 2013.
[156]M. Kuhn, D. Szklarczyk, A. Franceschini, et al., "STITCH 3: zooming in on protein-chemical interactions," Nucleic acids research, vol. 40, pp. D876-80, Jan 2012.
[157]U. Stelzl, U. Worm, M. Lalowski, et al., "A human protein-protein interaction network: a resource for annotating the proteome," Cell, vol. 122, pp. 957-68, Sep 23 2005.
[158]J. F. Rual, K. Venkatesan, T. Hao, et al., "Towards a proteome-scale map of the human protein-protein interaction network," Nature, vol. 437, pp. 1173-8, Oct 20 2005.
[159]A. Cerwenka and L. L. Lanier, "Natural killer cells, viruses and cancer," Nat Rev Immunol, vol. 1, pp. 41-9, Oct 2001.
[160]L. S. Metelitsa, O. V. Naidenko, A. Kant, et al., "Human NKT cells mediate antitumor cytotoxicity directly by recognizing target cell CD1d with bound ligand or indirectly by producing IL-2 to activate NK cells," J Immunol, vol. 167, pp. 3114-22, Sep 15 2001.
[161]Y. J. Chang, J. R. Huang, Y. C. Tsai, et al., "Potent immune-modulating and anticancer effects of NKT cell stimulatory glycolipids," Proc Natl Acad Sci U S A, vol. 104, pp. 10299-304, Jun 19 2007.
[162]R. Tabakman, S. Lecht, S. Sephanova, H. Arien-Zakay, and P. Lazarovici, "Interactions between the cells of the immune and nervous system: neurotrophins as neuroprotection mediators in CNS injury," Prog Brain Res, vol. 146, pp. 387-401, 2004.
[163]C. Ginzkey, S. O. Eicker, M. Marget, et al., "Increase in tumor size following intratumoral injection of immunostimulatory CpG-containing oligonucleotides in a rat glioma model," Cancer Immunol Immunother, vol. 59, pp. 541-51, Apr 2010.
[164]A. Ghosh, M. Bhattacharya, P. Sarkar, S. Acharya, and S. Chaudhuri, "T11 target structure exerts effector function by activating immune cells in CNS against glioma where cytokine modulation provide favorable microenvironment," Indian J Exp Biol, vol. 48, pp. 879-88, Sep 2010.
[165]Z. Huang, Y. Yang, Y. Jiang, et al., "Anti-tumor immune responses of tumor-associated macrophages via toll-like receptor 4 triggered by cationic polymers," Biomaterials, vol. 34, pp. 746-55, Jan 2013.
[166]M. Hedayat, K. Takeda, and N. Rezaei, "Prophylactic and therapeutic implications of toll-like receptor ligands," Med Res Rev, vol. 32, pp. 294-325, Mar 2012.
[167]C. A. Chambers, M. S. Kuhns, J. G. Egen, and J. P. Allison, "CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy," Annu Rev Immunol, vol. 19, pp. 565-94, 2001.
[168]H. Schneider, J. Downey, A. Smith, et al., "Reversal of the TCR stop signal by CTLA-4," Science, vol. 313, pp. 1972-5, Sep 29 2006.
[169]X. Y. Wang, D. Zuo, D. Sarkar, and P. B. Fisher, "Blockade of cytotoxic T-lymphocyte antigen-4 as a new therapeutic approach for advanced melanoma," Expert Opin Pharmacother, vol. 12, pp. 2695-706, Dec 2011.
[170]J. A. Van Ginderachter, Y. Liu, A. B. Geldhof, et al., "B7-1, IFN gamma and anti-CTLA-4 co-operate to prevent T-cell tolerization during immunotherapy against a murine T-lymphoma," Int J Cancer, vol. 87, pp. 539-47, Aug 15 2000.
[171]J. F. Grosso and M. N. Jure-Kunkel, "CTLA-4 blockade in tumor models: an overview of preclinical and translational research," Cancer Immun, vol. 13, p. 5, 2013.
[172]M. B. Atkins, "Interleukin-2: clinical applications," Semin Oncol, vol. 29, pp. 12-7, Jun 2002.
[173]S. Mocellin, S. Pasquali, C. R. Rossi, and D. Nitti, "Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis," J Natl Cancer Inst, vol. 102, pp. 493-501, Apr 7 2010.
[174]J. Richter, N. Neparidze, L. Zhang, et al., "Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma," Blood, vol. 121, pp. 423-30, Jan 17 2013.
[175]T. Zhang and D. Herlyn, "Combination of active specific immunotherapy or adoptive antibody or lymphocyte immunotherapy with chemotherapy in the treatment of cancer," Cancer Immunol Immunother, vol. 58, pp. 475-92, Apr 2009.
[176]R. Ramakrishnan, D. Assudani, S. Nagaraj, et al., "Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice," J Clin Invest, vol. 120, pp. 1111-24, Apr 2010.
[177]K. E. Reinicke, E. A. Bey, M. S. Bentle, et al., "Development of beta-lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels," Clin Cancer Res, vol. 11, pp. 3055-64, Apr 15 2005.
[178]R. Gozzelino, V. Jeney, and M. P. Soares, "Mechanisms of cell protection by heme oxygenase-1," Annu Rev Pharmacol Toxicol, vol. 50, pp. 323-54, 2010.
[179]E. C. Pietsch, J. Y. Chan, F. M. Torti, and S. V. Torti, "Nrf2 mediates the induction of ferritin H in response to xenobiotics and cancer chemopreventive dithiolethiones," J Biol Chem, vol. 278, pp. 2361-9, Jan 24 2003.
[180]K. Terai, G. Z. Dong, E. T. Oh, et al., "Cisplatin enhances the anticancer effect of beta-lapachone by upregulating NQO1," Anticancer Drugs, vol. 20, pp. 901-9, Nov 2009.
[181]B. M. Kim, Y. J. Choi, Y. H. Lee, Y. A. Joe, and S. H. Hong, "N,N-Dimethyl phytosphingosine sensitizes HL-60/MX2, a multidrug-resistant variant of HL-60 cells, to doxorubicin-induced cytotoxicity through ROS-mediated release of cytochrome c and AIF," Apoptosis, vol. 15, pp. 982-93, Aug 2010.
[182]J. Alexandre, Y. Hu, W. Lu, H. Pelicano, and P. Huang, "Novel action of paclitaxel against cancer cells: bystander effect mediated by reactive oxygen species," Cancer Res, vol. 67, pp. 3512-7, Apr 15 2007.
[183]C. Gangadharan, M. Thoh, and S. K. Manna, "Late phase activation of nuclear transcription factor kappaB by doxorubicin is mediated by interleukin-8 and induction of apoptosis via FasL," Breast Cancer Res Treat, vol. 120, pp. 671-83, Apr 2010.
[184]I. J. Samudio, S. Duvvuri, K. Clise-Dwyer, et al., "Activation of p53 signaling by MI-63 induces apoptosis in acute myeloid leukemia cells," Leuk Lymphoma, vol. 51, pp. 911-9, May 2010.
[185]L. Liu, L. Fan, C. Fang, et al., "S-MDM4 mRNA overexpression indicates a poor prognosis and marks a potential therapeutic target in chronic lymphocytic leukemia," Cancer Sci, vol. 103, pp. 2056-63, Dec 2012.
[186]J. T. Leek, R. B. Scharpf, H. C. Bravo, et al., "Tackling the widespread and critical impact of batch effects in high-throughput data," Nature reviews. Genetics, vol. 11, pp. 733-9, Oct 2010.
[187]M. Benito, J. Parker, Q. Du, et al., "Adjustment of systematic microarray data biases," Bioinformatics, vol. 20, pp. 105-14, Jan 1 2004.
[188]W. E. Johnson, C. Li, and A. Rabinovic, "Adjusting batch effects in microarray expression data using empirical Bayes methods," Biostatistics, vol. 8, pp. 118-27, Jan 2007.
[189]J. T. Leek and J. D. Storey, "Capturing heterogeneity in gene expression studies by surrogate variable analysis," PLoS genetics, vol. 3, pp. 1724-35, Sep 2007.
[190]J. Luo, M. Schumacher, A. Scherer, et al., "A comparison of batch effect removal methods for enhancement of prediction performance using MAQC-II microarray gene expression data," The pharmacogenomics journal, vol. 10, pp. 278-91, Aug 2010.
[191]A. H. Sims, G. J. Smethurst, Y. Hey, et al., "The removal of multiplicative, systematic bias allows integration of breast cancer gene expression datasets - improving meta-analysis and prediction of prognosis," BMC medical genomics, vol. 1, p. 42, 2008.
[192]C. Chen, K. Grennan, J. Badner, et al., "Removing batch effects in analysis of expression microarray data: an evaluation of six batch adjustment methods," PloS one, vol. 6, p. e17238, 2011.
[193]C. A. Dinarello, "Immunological and inflammatory functions of the interleukin-1 family," Annual review of immunology, vol. 27, pp. 519-50, 2009.
[194]O. Boyman and J. Sprent, "The role of interleukin-2 during homeostasis and activation of the immune system," Nature reviews. Immunology, vol. 12, pp. 180-90, Mar 2012.
[195]P. Lee, F. Wang, J. Kuniyoshi, et al., "Effects of interleukin-12 on the immune response to a multipeptide vaccine for resected metastatic melanoma," Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol. 19, pp. 3836-47, Sep 15 2001.
[196]S. Olver, S. Apte, A. Baz, and N. Kienzle, "The duplicitous effects of interleukin 4 on tumour immunity: how can the same cytokine improve or impair control of tumour growth?," Tissue antigens, vol. 69, pp. 293-8, Apr 2007.
[197]J. A. Baugh and R. Bucala, "Mechanisms for modulating TNF alpha in immune and inflammatory disease," Current opinion in drug discovery & development, vol. 4, pp. 635-50, Sep 2001.
[198]D. Tracey, L. Klareskog, E. H. Sasso, J. G. Salfeld, and P. P. Tak, "Tumor necrosis factor antagonist mechanisms of action: a comprehensive review," Pharmacology & therapeutics, vol. 117, pp. 244-79, Feb 2008.
[199]W. Vainchenker, A. Dusa, and S. N. Constantinescu, "JAKs in pathology: role of Janus kinases in hematopoietic malignancies and immunodeficiencies," Seminars in cell & developmental biology, vol. 19, pp. 385-93, Aug 2008.
[200]S. Uddin, A. R. Hussain, K. A. Al-Hussein, et al., "Inhibition of phosphatidylinositol 3''-kinase/AKT signaling promotes apoptosis of primary effusion lymphoma cells," Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 11, pp. 3102-8, Apr 15 2005.
[201]W. H. Hoffman, S. Biade, J. T. Zilfou, J. Chen, and M. Murphy, "Transcriptional repression of the anti-apoptotic survivin gene by wild type p53," J Biol Chem, vol. 277, pp. 3247-57, Feb 1 2002.
[202]P. O. Esteve, H. G. Chin, and S. Pradhan, "Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters," Proc Natl Acad Sci U S A, vol. 102, pp. 1000-5, Jan 25 2005.
[203]P. Obexer, J. Hagenbuchner, T. Unterkircher, et al., "Repression of BIRC5/survivin by FOXO3/FKHRL1 sensitizes human neuroblastoma cells to DNA damage-induced apoptosis," Mol Biol Cell, vol. 20, pp. 2041-8, Apr 2009.
[204]H. A. Hirsch, D. Iliopoulos, P. N. Tsichlis, and K. Struhl, "Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission," Cancer research, vol. 69, pp. 7507-11, Oct 1 2009.
[205]D. Iliopoulos, H. A. Hirsch, and K. Struhl, "Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types," Cancer Res, vol. 71, pp. 3196-201, May 1 2011.
[206]D. Staedler, E. Idrizi, B. H. Kenzaoui, and L. Juillerat-Jeanneret, "Drug combinations with quercetin: doxorubicin plus quercetin in human breast cancer cells," Cancer Chemother Pharmacol, vol. 68, pp. 1161-72, Nov 2011.