本研究的目的是探討中國傳統中草藥複方甘露飲（GLY）乙醇萃取物對WEHI-3細胞是否有影響增生、移行和分化的作用以及對WEHI-3細胞在BALB/c小鼠產生的腫瘤是否具有抗腫瘤作用。結果發現GLY會顯著減少WEHI-3細胞增生、移行及誘導分化。WEHI-3細胞處理GLY會使磷酸化的FAK、Akt、ERK1/2和Rb的蛋白質表現下降，而使p21的表現增加。細胞週期分析的結果也顯示GLY能顯著誘導G1期阻滯，並減少S期的情形。此外實驗結果也指出GLY會使MMP-2、MMP-9的蛋白質表現和活性的降低。GLY也減少WEHI-3白血病細胞浸潤到肝臟、脾臟和抑制腫瘤生長。因此GLY的抑制機制部分是通過抑制WEHI-3細胞中磷酸化的FAK、Akt和ERK的表現進而對腫瘤的生長產生抑制作用。在臨床應用中GLY可能會提供一個有潛力的抗白血病的方法。
此外我們也探討樟芝乙醇提取物(EEAC)是否會影響WEHI-3細胞的增生和移行及對WEHI-3細胞在BALB/c小鼠產生的腫瘤是否有抗腫瘤作用。結果顯示EEAC會抑制WEHI-3細胞的增生，而利用流式細胞儀分析細胞週期，發現EEAC會導致細胞分佈累積在G0/G1和G2/M期。由
Transwell assay發現EEAC顯著降低WEHI-3細胞的移行。在蛋白質表
現方面，EEAC明顯降低WEHI-3細胞中MMP-9蛋白和活性的表現。另外
磷酸化的Akt、ERK1/2蛋白表現也有所下降，卻相反增加p21和p27的表現。在體內腫瘤模式中，EEAC減少WEHI-3細胞進入肝臟和脾臟的浸潤並減少腫瘤的生長。其他活性化合物，如cordycepin和zhankuic acid A已被證明會減少MMP-9、cyclin E、cyclin D1的表現和增加p21、p27的表現。這個研究探討了EEAC減少WEHI-3細胞的體外增生和移行的機制以及EEAC減少WEHI-3細胞進入體內肝、脾的浸潤能力，在未來的抗白血病治療策略中，樟芝治療血癌被證明可能是有潛力的。

The aim of this study was to explore the antitumor effect of Gan-Lu-Yin (GLY), a traditional Chinese herbal formula on leukemia. Ethanolic extract of GLY was applied to evaluate its regulatory mechanisms on proliferation, migration and differentiation of WEHI-3 leukemic cells as well as antitumor effect on BALB/c mice model. The results showed that GLY markedly reduced cell proliferation and migration whereas induced differentiation of WEHI-3 cells. The expression level of phosphorylated FAK, Akt, ERK1/2 and Rb was decreased while p21 expression level was increased in WEHI-3 treated with GLY. The results of cell cycle analysis revealed that GLY treatment could markedly induce G1 phase arrest and decrease cell population in S phase. Moreover, experimental results demonstrated that GLY decreased the protein expression level and enzyme activity of MMP-2 and MMP-9. GLY treatment also reduced WEHI-3 leukemic infiltration to liver, spleen and tumor growth in animal model. Accordingly, GLY demonstrated an inhibitory effect on tumor growth with a regulatory mechanism partially through inhibiting FAK, Akt and ERK expression in WEHI-3 cells. GLY may provide a promising antileukemic approach in the clinical application.
Moreover, we also aimed to explore whether the ethanolic extract of Antrodia cinnamomea (EEAC), a medicinal mushroom from Taiwan, could affect the proliferation and migration of WEHI-3 cells in vitro. And also explore the antitumor effects of EEAC in BALB/c mice engrafted with WEHI-3 cells. Our results showed that EEAC inhibited the proliferation of WEHI-3 cells, resulting in the accumulation of cell in G0/G1 and G2/M phases, as determined by flow cytometry. Moreover, EEAC markedly reduced the migration of WEHI-3 cells, as determined by a transwell assay. Treatment of WEHI-3 cells with EEAC also decreased MMP-9 protein expression level and enzyme activity as well as the protein levels of p-Akt, p-ERK1/2 , whereas the expression level of p21 and p27 was increased. Furthermore, in our in vivo model, EEAC treatment reduced the infiltration of WEHI-3 cells into the liver and spleens and decreased tumor growth. Other bioactive compounds, such as cordycepin and zhankuic acid A, have been demonstrated to reduce the expression level of MMP-9, cyclin E, cyclin D1 and to increase the expression of p21 and p27. To sum up, this study was to investigate the mechanisms by which EEAC can reduce the proliferation and migration of WEHI-3 cells in vitro, as well as the ability of EEAC to reduced infiltration of WEHI-3 cells into the liver and spleen in vivo. The results suggest that EEAC can be developed as a potential candidate for antileukemic therapies.

目錄-------------------------------------------------------I
表目錄----------------------------------------------------II
圖目錄----------------------------------------------------IV
中文摘要--------------------------------------------------VI
英文摘要------------------------------------------------VIII
第一章 緒論------------------------------------------------1
第二章 總論------------------------------------------------4
第一節 甘露飲與樟芝之文獻考察----------------------------4
第二節 白血病簡介----------------------------------------7
第三節 細胞週期的調控-----------------------------------14
第四節 研究目的-----------------------------------------18
第三章 研究材料和方法-------------------------------------19
第一節 實驗設計-----------------------------------------19
第二節 研究材料-----------------------------------------20
第三節 實驗方法-----------------------------------------33
第四節 統計方法------------------------------------------43
第四章 結果-----------------------------------------------44
第五章 討論-----------------------------------------------54
第六章 結論-----------------------------------------------66
參考文獻-------------------------------------------------109

[1] 行政院衛生署. "100年國人主要死因統計," http://wwwdohgovtw/CHT2006/DM/DM2_p01aspx?class_no=25&level_no=1&doc_no=84788, 2012.
[2] D. Pulte, A. Gondos, H. Brenner. "Expected long-term survival of patients diagnosed with acute myeloblastic leukemia during 2006-2010," Ann Oncol, vol. 21, no. 2, pp. 335-341, 2010.
[3] M. Y. Lee, T. D. Tan, A. C. Feng. "Clinicopathologic analysis of acute myeloid leukemia in a single institution: biphenotypic acute myeloid leukemia may not be an aggressive subtype," J Chin Med Assoc, vol. 70, no. 7, pp. 269-273, 2007.
[4] C. Nishioka, T. Ikezoe, J. Yang, A. Yokoyama. "Inhibition of MEK signaling enhances the ability of cytarabine to induce growth arrest and apoptosis of acute myelogenous leukemia cells," Apoptosis, vol. 14, no. 9, pp. 1108-1120, 2009.
[5] S. Amadori, P. Fenaux, H. Ludwig, M. O''Dwyer, M. Sanz. "Use of arsenic trioxide in haematological malignancies: insight into the clinical development of a novel agent," Current Medical Research and Opinion, vol. 21, no. 3, pp. 403-411, 2005.
[6] A. Glasow, N. Prodromou, K. Xu, M. von Lindern, A. Zelent. "Retinoids and myelomonocytic growth factors cooperatively activate RARA and induce human myeloid leukemia cell differentiation via MAP kinase pathways," Blood, vol. 105, no. 1, pp. 341-349, 2005.
[7] J. X. Li, Y. Q. Shen, B. Z. Cai, et al. "Arsenic trioxide induces the apoptosis in vascular smooth muscle cells via increasing intracellular calcium and ROS formation," Molecular Biology Reports, vol. 37, no. 3, pp. 1569-1576, 2010.
[8] E. Patatanian, D. F. Thompson. "Retinoic acid syndrome: a review," Journal of Clinical Pharmacy and Therapeutics, vol. 33, no. 4, pp. 331-338, 2008.
[9] A. Gandillet, A. G. Serrano, S. Pearson, et al. "Sox7-sustained expression alters the balance between proliferation and differentiation of hematopoietic progenitors at the onset of blood specification," Blood, vol. 114, no. 23, pp. 4813-4822, 2009.
[10] Y. Y. Cha, E. O. Lee, H. J. Lee, et al. "Methylene chloride fraction of Scutellaria barbata induces apoptosis in human U937 leukemia cells via the mitochondrial signaling pathway," Clinica Chimica Acta, vol. 348, no. 1-2, pp. 41-48, 2004.
[11] W. J. Ruan, M. D. Lai, J. G. Zhou. "Anticancer effects of Chinese herbal medicine, science or myth?," J Zhejiang Univ Sci B, vol. 7, no. 12, pp. 1006-1014, 2006.
[12] T. C. Wang, C. N. Fang, C. C. Shen, et al. "Yang-Dan-Tang, Identified from 15 Chinese Herbal Formulae, Inhibits Human Lung Cancer Cell Proliferation via Cell Cycle Arrest," Evidence-Based Complementary and Alternative Medicine, 2012.
[13] 謝宜君. "研究開發抑制血管新生之中草藥相關製劑及其機理之探討," 中國醫藥大學碩士論文, p. 16, 2009.
[14] H. Kim, E. Lee, S. Lee, et al. "Effect of Rehmannia glutinosa on immediate type allergic reaction," International Journal of Immunopharmacology, vol. 20, no. 4-5, pp. 231-240, 1998.
[15] H. M. Kim, C. S. An, K. Y. Jung, et al. "Rehmannia glutinosa inhibits tumour necrosis factor-alpha and interleukin-1 secretion from mouse astrocytes," Pharmacol Res, vol. 40, no. 2, pp. 171-176, 1999.
[16] J. C. Chao, S. W. Chiang, C. C. Wang, Y. H. Tsai, M. S. Wu. "Hot water-extracted Lycium barbarum and Rehmannia glutinosa inhibit proliferation and induce apoptosis of hepatocellular carcinoma cells," World J Gastroenterol, vol. 12, no. 28, pp. 4478-4484, 2006.
[17] H. Ito, E. Kobayashi, Y. Takamatsu, et al. "Polyphenols from Eriobotrya japonica and their cytotoxicity against human oral tumor cell lines," Chem Pharm Bull (Tokyo), vol. 48, no. 5, pp. 687-693, 2000.
[18] 林宜信. "中醫方劑「甘露飲」配合放射線治療鼻咽癌引起口乾和黏膜發炎（Mucositis）之治療," 行政院衛生署中醫藥年報, pp. 127-145, 2000.
[19] C. H. Pan, I. C. Hsieh, F. C. Liu, et al. "Effects of a Chinese Herbal Health Formula, "Gan-Lu-Yin", on Angiogenesis," Journal of Agricultural and Food Chemistry, vol. 58, no. 13, pp. 7685-7692, 2010.
[20] Y. C. Chien, M. J. Sheu, C. H. Wu, et al. "A Chinese herbal formula "Gan-Lu-Yin" suppresses vascular smooth muscle cell migration by inhibiting matrix metalloproteinase-2/9 through the PI3K/AKT and ERK signaling pathways," Bmc Complementary and Alternative Medicine, vol. 12, 2012.
[21] 黃智芬, 施智嚴, 羅勇. "甘露飲治療化療引致的口腔潰瘍50例臨床觀察," 河北中醫, vol. 23, no. 3, pp. 198-199, 2001.
[22] 劉朝暉. "甘露飲配合超聲波潔治治療肥大性齦炎31例," 中國民間療法, vol. 8, no. 8, p. 27, 2000.
[23] 廖永賽. "甘露飲治療萎縮性性胃炎," 四川中醫, vol. 29, no. 12, pp. 73-74, 2011.
[24] 蔡 凱, 李譜智, 蔡恕一, et al. "甘露飲防治超分割放療鼻咽癌所致放射性口腔黏膜損傷臨床研究," 河北中醫, vol. 22, no. 11, pp. 807-808, 2000.
[25] 李鴻泓. "甘露飲合二甲雙胍治療濕熱困脾型糖尿病30例臨床觀察," 北京中醫藥, vol. 10, no. 27, pp. 797-799, 2008.
[26] Tsai ZT, L. SL. "The Use and the Effect of Ganoderma," Taichung, vol. Taiwan, no. San Yun Press, 1985.
[27] Z. H. Ao, Z. H. Xu, Z. M. Lu, et al. "Niuchangchih (Antrodia camphorata) and its potential in treating liver diseases," J Ethnopharmacol, vol. 121, no. 2, pp. 194-212, 2009.
[28] C. C. Chen, Y. W. Liu, Y. B. Ker, et al. "Chemical characterization and anti-inflammatory effect of polysaccharides fractionated from submerge-
cultured Antrodia camphorata mycelia," J Agric Food Chem, vol. 55, no. 13, pp. 5007-5012, 2007.
[29] H. L. Yang, Y. C. Hseu, J. Y. Chen, et al. "Antrodia camphorata in submerged culture protects low density lipoproteins against oxidative modification," Am J Chin Med, vol. 34, no. 2, pp. 217-231, 2006.
[30] H. L. Yang, Y. H. Kuo, C. T. Tsai, et al. "Anti-metastatic activities of Antrodia camphorata against human breast cancer cells mediated through suppression of the MAPK signaling pathway," Food Chem Toxicol, vol. 49, no. 1, pp. 290-298, 2011.
[31] H. Wu, C. L. Pan, Y. C. Yao, et al. "Proteomic analysis of the effect of Antrodia camphorata extract on human lung cancer A549 cell," Proteomics, vol. 6, no. 3, pp. 826-835, 2006.
[32] Y. C. Hseu, S. C. Chen, H. C. Chen, J. W. Liao, H. L. Yang. "Antrodia camphorata inhibits proliferation of human breast cancer cells in vitro and in vivo," Food Chem Toxicol, vol. 46, no. 8, pp. 2680-2688, 2008.
[33] Y. W. Lin, J. H. Pan, R. H. Liu, et al. "The 4-acetylantroquinonol B isolated from mycelium of Antrodia cinnamomea inhibits proliferation of hepatoma cells," J Sci Food Agric, vol. 90, no. 10, pp. 1739-1744, 2010.
[34] C. T. Yeh, Y. K. Rao, C. J. Yao, et al. "Cytotoxic triterpenes from Antrodia camphorata and their mode of action in HT-29 human colon cancer cells," Cancer Letters, vol. 285, no. 1, pp. 73-79, 2009.
[35] 黃明哲, 林建鴻. "淺談急性白血病," 財團法人台灣癌症基金會電子報, vol. www.canceraway.org.tw/cancerpageshow.asp?IDno=529.
[36] 盧冠宏. "血藤莖部粗抽物誘導人類血癌細胞凋亡並透過活性氧化物途徑與三氧化二砷產生協同效果之抗血癌作用," 中國醫藥大學博士論文, 2011.
[37] E. Puccetti, M. Ruthardt. "Acute promyelocytic leukemia: PML/RARalpha and the leukemic stem cell," Leukemia, vol. 18, no. 7, pp. 1169-1175, 2004.
[38] 劉姿妙. "三氧化二砷誘導人類子宮頸上皮癌A431細胞p21WAF1/CIP1基因表現轉錄機制之探討," 成功大學基礎醫學研究所博士論文, pp. 1-169, 2008.
[39] J. Zhu, J. Zhou, L. Peres, et al. "A sumoylation site in PML/RARA is essential for leukemic transformation," Cancer Cell, vol. 7, no. 2, pp. 143-153, 2005.
[40] H. K. Lai, K. L. Borden. "The promyelocytic leukemia (PML) protein suppresses cyclin D1 protein production by altering the nuclear cytoplasmic distribution of cyclin D1 mRNA," Oncogene, vol. 19, no. 13, pp. 1623-1634, 2000.
[41] P. Vodicka, S. Sevcikova, J. Smardova, K. Soucek, J. Smarda. "The effects of RARalpha and RXRalpha proteins on growth, viability, and differentiation of v-myb-transformed monoblasts," Blood Cells Mol Dis, vol. 26, no. 4, pp. 395-406, 2000.
[42] C. Du, R. L. Redner, M. P. Cooke, C. Lavau. "Overexpression of wild-type retinoic acid receptor alpha (RARalpha) recapitulates retinoic acid-sensitive transformation of primary myeloid progenitors by acute promyelocytic leukemia RARalpha-fusion genes," Blood, vol. 94, no. 2, pp. 793-802, 1999.
[43] S. Castaigne, S. Chevret, E. Archimbaud, et al. "Randomized comparison of double induction and timed-sequential induction to a "3 + 7" induction in adults with AML: long-term analysis of the Acute Leukemia French Association (ALFA) 9000 study," Blood, vol. 104, no. 8, pp. 2467-2474, 2004.
[44] 陳昱璇. "急性骨髓性白血病抗體治療藥物 Gemtuzumab ozogamicin (Mylotarg®) " Chimei Foundation Hospital Drug Bulletin, no. 88, pp. 1-4, 2007.
[45] O. Bruserud, B. T. Gjertsen, T. Huang. "Induction of differentiation and apoptosis- a possible strategy in the treatment of adult acute myelogenous leukemia," Oncologist, vol. 5, no. 6, pp. 454-462, 2000.
[46] D. Fabbro. "Bcr-Abl Signaling a New Status in Cml," Nature Chemical Biology, vol. 8, no. 3, pp. 228-229, 2012.
[47] J. P. Radich, T. Gooley, E. Bryant, et al. "The significance of bcr-abl molecular detection in chronic myeloid leukemia patients "late," 18 months or more after transplantation," Blood, vol. 98, no. 6, pp. 1701-1707, 2001.
[48] Y. Maru. "Molecular biology of chronic myeloid leukemia," Int J Hematol, vol. 73, no. 3, pp. 308-322, 2001.
[49] C. L. Sawyers. "Chronic myeloid leukemia," N Engl J Med, vol. 340, no. 17, pp. 1330-1340, 1999.
[50] M. J. Mauro, B. J. Druker. "STI571: Targeting BCR-ABL as therapy for CML," Oncologist, vol. 6, no. 3, pp. 233-238, 2001.
[51] S. G. O''Brien, F. Guilhot, R. A. Larson, et al. "Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia," N Engl J Med, vol. 348, no. 11, pp. 994-1004, 2003.
[52] B. J. Druker, F. Guilhot, S. G. O''Brien, et al. "Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia," New England Journal of Medicine, vol. 355, no. 23, pp. 2408-2417, 2006.
[53] 陳玉美, 李建瑩, 蔡敏鈴. "慢性骨髓性白血病," 藥學雜誌, vol. 27, no. 2, pp. 85-89, 2011.
[54] C. H. Pui. "Acute lymphoblastic leukemia," Pediatr Clin North Am, vol. 44, no. 4, pp. 831-846, 1997.
[55] U. Ozgen, Y. Turkoz, M. Stout, et al. "Degradation of vincristine by myeloperoxidase and hypochlorous acid in children with acute lymphoblastic leukemia," Leuk Res, vol. 27, no. 12, pp. 1109-1113, 2003.
[56] G. Garay, J. Milone, E. Dibar, et al. "Vindesine, prednisone, and daunomycin in acute lymphoblastic leukemia in relapse," Cancer Chemother Pharmacol, vol. 10, no. 3, pp. 224-226, 1983.
[57] D. Hoelzer, W. D. Ludwig, E. Thiel, et al. "Improved outcome in adult B-cell acute lymphoblastic leukemia," Blood, vol. 87, no. 2, pp. 495-508, 1996.
[58] 吳建廷, 莊美華. "Fludarabine治療趨勢與近況發展," 藥學雜誌, vol. 25, no. 3, pp. 41-47, 2009.
[59] M. A. Garrett. "Cell cycle control and cancer," Current Science, vol. 81, no. 5, pp. 515-522, 2001.
[60] K. Vermeulen, D. R. Van Bockstaele, Z. N. Berneman. "The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer," Cell Proliferation, vol. 36, no. 3, pp. 131-149, 2003.
[61] A. W. Murray. "Recycling the cell cycle: Cyclins revisited," Cell, vol. 116, no. 2, pp. 221-234, 2004.
[62] M. Fujita, H. Takeshita, H. Sawa. "Cyclin E and CDK2 repress the terminal differentiation of quiescent cells after asymmetric division in C. elegans," Plos One, vol. 2, no. 5, 2007.
[63] A. Sancar, L. A. Lindsey-Boltz, K. Unsal-Kacmaz, S. Linn. "Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints," Annu Rev Biochem, vol. 73, pp. 39-85, 2004.
[64] S. N. Khleif, J. DeGregori, C. L. Yee, et al. "Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity," Proc Natl Acad Sci U S A, vol. 93, no. 9, pp. 4350-4354, 1996.
[65] J. Botz, K. Zerfass-Thome, D. Spitkovsky, et al. "Cell cycle regulation of the murine cyclin E gene depends on an E2F binding site in the promoter," Mol Cell Biol, vol. 16, no. 7, pp. 3401-3409, 1996.
[66] T. Urano, H. Yashiroda, M. Muraoka, et al. "p57(Kip2) is degraded through the proteasome in osteoblasts stimulated to proliferation by transforming growth factor beta 1," Journal of Biological Chemistry, vol. 274, no. 18, pp. 12197-12200, 1999.
[67] H. F. Lu, W. L. Tung, J. S. Yang, et al. "In vitro suppression of growth of murine WEHI-3 leukemia cells and in vivo promotion of phagocytosis in a leukemia mice model by indole-3-carbinol," J Agric Food Chem, 2012.
[68] Y. Y. Chen, F. C. Liu, P. Y. Chou, et al. "Ethanol extracts of fruiting bodies of Antrodia cinnamomea suppress CL1-5 human lung adenocarcinoma cells migration by inhibiting matrix metalloproteinase-2/9 through ERK, JNK, p38, and PI3K/Akt signaling pathways," Evid Based Complement Alternat Med, vol. 2012, p. 378415, 2012.
[69] H. Li, L. Guo, S. Jie, et al. "Berberine inhibits SDF-1-induced AML cells and leukemic stem cells migration via regulation of SDF-1 level in bone marrow stromal cells," Biomed Pharmacother, vol. 62, no. 9, pp. 573-578, 2008.
[70] J. W. Hsu, H. C. Huang, S. T. Chen, C. H. Wong, H. F. Juan. "Ganoderma lucidum polysaccharides induce macrophage-like differentiation in human leukemia THP-1 cells via Caspase and p53 Activation," Evid Based Complement Alternat Med, vol. 2011, p. 358717, 2011.
[71] 廖紋瑩. "巨峰葡萄籽之抑制細胞增殖活性成分研究," 中國醫藥大學藥物化學研究所碩士論文, 2005.
[72] C. Y. Chang, M. Y. Lue, T. M. Pan. "Determination of adenosine, cordycepin and ergosterol contents in cultivated Antrodia camphorata by HPLC method," Journal of Food and Drug Analysis, vol. 13, no. 4, pp. 338-342, 2005.
[73] Y. H. Chang, J. S. Yang, J. L. Yang, et al. "Ganoderma lucidum extracts inhibited leukemia WEHI-3 Cells in BALB/c mice and promoted an immune response in vivo," Bioscience Biotechnology and Biochemistry, vol. 73, no. 12, pp. 2589-2594, 2009.
[74] Y. H. Choi, W. H. Lee, K. Y. Park, L. Zhang. "p53-independent induction of p21 (WAF1/CIP1), reduction of cyclin B1 and G2/M arrest by the isoflavone genistein in human prostate carcinoma cells," Jpn J Cancer Res, vol. 91, no. 2, pp. 164-173, 2000.
[75] C. Recher, L. Ysebaert, O. Beyne-Rauzy, et al. "Expression of focal adhesion kinase in acute myeloid leukemia is associated with enhanced blast migration, increased cellularity, and poor prognosis," Cancer Res, vol. 64, no. 9, pp. 3191-3197, 2004.
[76] Y. Sonoda, N. Aiba, R. Utsubo, et al. "Induction of antioxidant enzymes by FAK in a human leukemic cell line, HL-60," Biochim Biophys Acta, vol. 1683, no. 1-3, pp. 22-32, 2004.
[77] Y. R. Pan, C. L. Chen, H. C. Chen. "FAK is required for the assembly of podosome rosettes," J Cell Biol, vol. 195, no. 1, pp. 113-129, 2011.
[78] B. T. Hennessy, D. L. Smith, P. T. Ram, Y. Lu, G. B. Mills. "Exploiting the PI3K/AKT pathway for cancer drug discovery," Nat Rev Drug Discov, vol. 4, no. 12, pp. 988-1004, 2005.
[79] J. LoPiccolo, C. A. Granville, J. J. Gills, P. A. Dennis. "Targeting Akt in cancer therapy," Anticancer Drugs, vol. 18, no. 8, pp. 861-874, 2007.
[80] T. Yamadori, Y. Ishii, S. Homma, et al. "Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers," Oncogene, vol. 31, no. 45, pp. 4768-4777, 2012.
[81] J. You, D. Mi, X. Zhou, et al. "A positive feedback between activated extracellularly regulated kinase and cyclooxygenase/lipoxygenase maintains proliferation and migration of breast cancer cells," Endocrinology, vol. 150, no. 4, pp. 1607-1617, 2009.
[82] C. Y. Chiu, K. K. Kuo, T. L. Kuo, K. T. Lee, K. H. Cheng. "The activation of MEK/ERK signaling pathway by bone morphogenetic protein 4 to increase hepatocellular carcinoma cell proliferation and migration," Mol Cancer Res, vol. 10, no. 3, pp. 415-427, 2012.
[83] S. C. Kim, J. S. Hahn, Y. H. Min, et al. "Constitutive activation of extracellular signal-regulated kinase in human acute leukemias: combined role of activation of MEK, hyperexpression of extracellular signal-regulated kinase, and downregulation of a phosphatase, PAC1," Blood, vol. 93, no. 11, pp. 3893-3899, 1999.
[84] N. Giuliani, P. Lunghi, F. Morandi, et al. "Downmodulation of ERK protein kinase activity inhibits VEGF secretion by human myeloma cells and myeloma-induced angiogenesis," Leukemia, vol. 18, no. 3, pp. 628-635, 2004.
[85] C. Nishioka, T. Ikezoe, J. Yang, A. Yokoyama. "Inhibition of MEK/ERK signaling induces apoptosis of acute myelogenous leukemia cells via inhibition of eukaryotic initiation factor 4E-binding protein 1 and down-regulation of Mcl-1," Apoptosis, vol. 15, no. 7, pp. 795-804, 2010.
[86] J. Rodriguez, F. Calvo, J. M. Gonzalez, et al. "ERK1/2 MAP kinases promote cell cycle entry by rapid, kinase-independent disruption of retinoblastoma-lamin A complexes," J Cell Biol, vol. 191, no. 5, pp. 967-979, 2010.
[87] W. H. Liu, L. S. Chang. "Caffeine induces matrix metalloproteinase-2 (MMP-2) and MMP-9 down-regulation in human leukemia U937 cells via Ca2+/ROS-mediated suppression of ERK/c-fos pathway and activation of p38 MAPK/c-jun pathway," J Cell Physiol, vol. 224, no. 3, pp. 775-785, 2010.
[88] M. Liu, M. H. Lee, M. Cohen, M. Bommakanti, L. P. Freedman. "Transcriptional activation of the Cdk inhibitor p21 by vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937," Genes Dev, vol. 10, no. 2, pp. 142-153, 1996.
[89] F. Chang, J. T. Lee, P. M. Navolanic, et al. "Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy," Leukemia, vol. 17, no. 3, pp. 590-603, 2003.
[90] Y. Li, D. Dowbenko, L. A. Lasky. "AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival," Journal of Biological Chemistry, vol. 277, no. 13, pp. 11352-11361, 2002.
[91] E. V. Broude, M. E. Swift, C. Vivo, et al. "p21(Waf1/Cip1/Sdi1) mediates retinoblastoma protein degradation," Oncogene, vol. 26, no. 48, pp. 6954-6958, 2007.
[92] A. Pivoriunas, J. Savickiene, G. Treigyte, et al. "PI3K signaling pathway suppresses PMA-induced expression of p21WAF1/Cip1 in human leukemia cells," Mol Cell Biochem, vol. 302, no. 1-2, pp. 9-18, 2007.
[93] H. Chen, B. Zhang, Y. Yao, et al. "NADPH oxidase-derived reactive oxygen species are involved in the HL-60 cell monocytic differentiation induced by isoliquiritigenin," Molecules, vol. 17, no. 11, pp. 13424-13438, 2012.
[94] C. Lin, H. Wang. "NADPH oxidase is involved in H2O2-induced differentiation of human promyelocytic leukaemia HL-60 cells," Cell Biol Int, vol. 36, no. 4, pp. 391-395, 2012.
[95] D. Richard, H. Morjani, B. Chenais. "Free radical production and labile iron pool decrease triggered by subtoxic concentration of aclarubicin in human leukemia cell lines," Leuk Res, vol. 26, no. 10, pp. 927-931, 2002.
[96] H. F. Lu, S. C. Hsueh, Y. T. Ho, et al. "ROS mediates baicalin-induced apoptosis in human promyelocytic leukemia HL-60 cells through the expression of the Gadd153 and mitochondrial-dependent pathway," Anticancer Res, vol. 27, no. 1A, pp. 117-125, 2007.
[97] E. Burgos-Moron, J. M. Calderon-Montano, M. L. Orta, et al. "The coffee constituent chlorogenic acid induces cellular DNA damage and formation of topoisomerase I- and II-DNA complexes in cells," J Agric Food Chem, 2012.
[98] M. Segarra, C. Vilardell, K. Matsumoto, et al. "Dual function of focal adhesion kinase in regulating integrin-induced MMP-2 and MMP-9 release by human T lymphoid cells," FASEB J, vol. 19, no. 13, pp. 1875-1877, 2005.
[99] J. Paupert, V. Mansat-De Mas, C. Demur, B. Salles, C. Muller. "Cell-surface MMP-9 regulates the invasive capacity of leukemia blast cells with monocytic features," Cell Cycle, vol. 7, no. 8, pp. 1047-1053, 2008.
[100] S. Feng, J. Cen, Y. Huang, et al. "Matrix metalloproteinase-2 and -9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins," Plos One, vol. 6, no. 8, p. e20599, 2011.
[101] I. H. Lin, M. C. Lee, W. C. Chuang. "Application of LC/MS and ICP/MS for establishing the fingerprint spectrum of the traditional chinese medicinal preparation Gan-Lu-Yin," Journal of Separation Science, vol. 29, no. 1, pp. 172-179, 2006.
[102] J. J. Liu, T. S. Huang, W. F. Cheng, F. J. Lu. "Baicalein and baicalin are potent inhibitors of angiogenesis: Inhibition of endothelial cell proliferation, migration and differentiation," Int J Cancer, vol. 106, no. 4, pp. 559-565, 2003.
[103] S. S. T. Ikezoe, D. H. Chen, H. Taguchi, H. P. Koeffler. "Baicalin is a major component of PC-SPES which inhibits the proliferation of human cancer cells via apoptosis and cell cycle arrest," Prostate, vol. 49, no. 4, pp. 285-292, 2001.
[104] K. Zhang, Q. L. Guo, Q. D. You, et al. "Wogonin induces the granulocytic differentiation of human NB4 promyelocytic leukemia cells and up-regulates phospholipid scramblase 1 gene expression," Cancer Sci, vol. 99, no. 4, pp. 689-695, 2008.
[105] U. H. Jin, J. Y. Lee, S. K. Kang, et al. "A phenolic compound, 5-caffeoylquinic acid (chlorogenic acid), is a new type and strong matrix metalloproteinase-9 inhibitor: isolation and identification from methanol extract of Euonymus alatus," Life Sci, vol. 77, no. 22, pp. 2760-2769, 2005.
[106] K. Yagasaki, Y. Miura, R. Okauchi, T. Furuse. "Inhibitory effects of chlorogenic acid and its related compounds on the invasion of hepatoma cells in culture," Cytotechnology, vol. 33, no. 1-3, pp. 229-235, 2000.
[107] T. Tanaka, T. Kojima, T. Kawamori, et al. "Inhibition of 4-nitroquinoline-1-oxide-induced rat tongue carcinogenesis by the naturally occurring plant phenolics caffeic, ellagic, chlorogenic and ferulic acids," Carcinogenesis, vol. 14, no. 7, pp. 1321-1325, 1993.
[108] J. M. Cherng, K. D. Tsai, Y. W. Yu, J. C. Lin. "Molecular mechanisms underlying chemopreventive activities of glycyrrhizic acid against UVB-radiation-induced carcinogenesis in SKH-1 hairless mouse epidermis," Radiat Res, vol. 176, no. 2, pp. 177-186, 2011.
[109] S. Thirugnanam, L. Xu, K. Ramaswamy, M. Gnanasekar. "Glycyrrhizin induces apoptosis in prostate cancer cell lines DU-145 and LNCaP," Oncol Rep, vol. 20, no. 6, pp. 1387-1392, 2008.
[110] H. Luo, B. H. Jiang, S. M. King, Y. C. Chen. "Inhibition of cell growth and VEGF expression in ovarian cancer cells by flavonoids," Nutr Cancer, vol. 60, no. 6, pp. 800-809, 2008.
[111] C. M. Lin, H. Chang, Y. H. Chen, I. H. Wu, J. H. Chiu. "Wogonin inhibits IL-6-induced angiogenesis via down-regulation of VEGF and VEGFR-1, not VEGFR-2," Planta Med, vol. 72, no. 14, pp. 1305-1310, 2006.
[112] N. Lu, Y. Gao, Y. Ling, et al. "Wogonin suppresses tumor growth in vivo and VEGF-induced angiogenesis through inhibiting tyrosine phosphorylation of VEGFR2," Life Sci, vol. 82, no. 17-18, pp. 956-963, 2008.
[113] A. W. Harmon, Y. M. Patel. "Naringenin inhibits glucose uptake in MCF-7 breast cancer cells: a mechanism for impaired cellular proliferation," Breast Cancer Res Treat, vol. 85, no. 2, pp. 103-110, 2004.
[114] S. Kanno, A. Tomizawa, T. Hiura, et al. "Inhibitory effects of naringenin on tumor growth in human cancer cell lines and sarcoma S-180-implanted mice," Biol Pharm Bull, vol. 28, no. 3, pp. 527-530, 2005.
[115] H. R. Frydoonfar, D. R. McGrath, A. D. Spigelman. "The variable effect on proliferation of a colon cancer cell line by the citrus fruit flavonoid Naringenin," Colorectal Dis, vol. 5, no. 2, pp. 149-152, 2003.
[116] G. Ekambaram, P. Rajendran, V. Magesh, D. Sakthisekaran. "Naringenin reduces tumor size and weight lost in N-methyl-N''-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats," Nutr Res, vol. 28, no. 2, pp. 106-112, 2008.
[117] K. Lirdprapamongkol, H. Sakurai, N. Kawasaki, et al. "Vanillin suppresses in vitro invasion and in vivo metastasis of mouse breast cancer cells," Eur J Pharm Sci, vol. 25, no. 1, pp. 57-65, 2005.
[118] J. A. Liang, S. L. Wu, H. Y. Lo, C. Y. Hsiang, T. Y. Ho. "Vanillin inhibits matrix metalloproteinase-9 expression through down-regulation of nuclear factor-kappaB signaling pathway in human hepatocellular carcinoma cells," Mol Pharmacol, vol. 75, no. 1, pp. 151-157, 2009.
[119] K. Lirdprapamongkol, J. P. Kramb, T. Suthiphongchai, et al. "Vanillin suppresses metastatic potential of human cancer cells through PI3K inhibition and decreases angiogenesis in vivo," J Agric Food Chem, vol. 57, no. 8, pp. 3055-3063, 2009.
[120] A. Belkaid, J. C. Currie, J. Desgagnes, B. Annabi. "The chemopreventive properties of chlorogenic acid reveal a potential new role for the microsomal glucose-6-phosphate translocase in brain tumor progression," Cancer Cell Int, vol. 6, p. 7, 2006.
[121] P. Fishman, S. Bar-Yehuda, G. Ohana, et al. "Adenosine acts as an inhibitor of lymphoma cell growth: a major role for the A3 adenosine receptor," European Journal of Cancer, vol. 36, no. 11, pp. 1452-1458, 2000.
[122] J. H. Lee, S. M. Hong, J. Y. Yoon, H. Myoung, M. J. Kim. "Anti-cancer effects of cordycepin on oral squamous cell carcinoma proliferation and apoptosis in vitro," Journal of Cancer Therapy, vol. 2, pp. 224-234, 2011.
[123] K. Nakamura, N. Yoshikawa, Y. Yamaguchi, et al. "Antitumor effect of cordycepin (3''-deoxyadenosine) on mouse melanoma and lung carcinoma cells involves adenosine A3 receptor stimulation," Anticancer Res, vol. 26, no. 1A, pp. 43-47, 2006.
[124] B. S. Pan, C. Y. Lin, B. M. Huang. "The effect of cordycepin on steroidogenesis and apoptosis in MA-10 mouse leydig tumor cells," Evid Based Complement Alternat Med, vol. 2011, p. 750468, 2011.
[125] Y. Y. Wong, A. Moon, R. Duffin, et al. "Cordycepin inhibits protein synthesis and cell adhesion through effects on signal transduction," Journal of Biological Chemistry, vol. 285, no. 4, pp. 2610-2621, 2010.
[126] J. W. Jeong, C. Y. Jin, C. Park, et al. "Inhibition of migration and invasion of LNCaP human prostate carcinoma cells by cordycepin through inactivation of Akt," International Journal of Oncology, vol. 40, no. 5, pp. 1697-1704, 2012.
[127] M. C. Lu, Y. C. Du, J. J. Chuu, et al. "Active extracts of wild fruiting bodies of Antrodia camphorata (EEAC) induce leukemia HL 60 cells apoptosis partially through histone hypoacetylation and synergistically promote anticancer effect of trichostatin A," Archives of Toxicology, vol. 83, no. 2, pp. 121-129, 2009.
[128] S. R. Feng, J. N. Cen, Y. H. Huang, et al. "Matrix Metalloproteinase-2 and-9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins," Plos One, vol. 6, no. 8, 2011.
[129] J. Redondo-Munoz, E. Escobar-Diaz, R. Samaniego, et al. "MMP-9 in B-cell chronic lymphocytic leukemia is up-regulated by alpha 4 beta 1 integrin or CXCR4 engagement via distinct signaling pathways, localizes to podosomes, and is involved in cell invasion and migration," Blood, vol. 108, no. 9, pp. 3143-3151, 2006.
[130] Y. Y. Chen, F. C. Liu, P. Y. Chou, et al. "Ethanol extracts of fruiting bodies of Antrodia cinnamomea exihibit anti-migration action in human adenocarcinoma CL1-0 cells through the MAPK and PI3K/AKT signaling pathways (vol 19, pg 768, 2012)," Phytomedicine, vol. 20, no. 1, pp. 1-2, 2013.
[131] S. J. Cho, M. J. Chae, B. K. Shin, H. K. Kim, A. Kim. "Akt- and MAPK-mediated activation and secretion of MMP-9 into stroma in breast cancer cells upon heregulin treatment," Molecular Medicine Reports, vol. 1, no. 1, pp. 83-88, 2008.
[132] K. Lirdprapamongkol, J. P. Kramb, T. Suthiphongchai, et al. "Vanillin suppresses metastatic potential of human cancer cells through PI3K Inhibition and decreases angiogenesis in vivo," Journal of Agricultural and Food Chemistry, vol. 57, no. 8, pp. 3055-3063, 2009.
[133] Y. W. Shih, P. S. Chen, C. H. Wu, Y. F. Jeng, C. J. Wang. "alpha-chaconine-reduced metastasis involves a PI3K/Akt signaling pathway with downregulation of NF-kappa B in human lung adenocarcinoma a549 cells," Journal of Agricultural and Food Chemistry, vol. 55, no. 26, pp. 11035-11043, 2007.
[134] C. B. Yeh, M. J. Hsieh, Y. H. Hsieh, et al. "Antimetastatic effects of norcantharidin on hepatocellular carcinoma by transcriptional inhibition of MMP-9 through modulation of NF-kB activity," Plos One, vol. 7, no. 2, 2012.
[135] P. Song, S. X. Wang, C. Y. He, et al. "AMPK alpha 2 deletion exacerbates neointima formation by upregulating Skp2 in vascular smooth muscle cells," Circulation Research, vol. 109, no. 11, pp. 1230-U1291, 2011.
[136] G. Deep, R. P. Singh, C. Agarwal, D. J. Kroll, R. Agarwal. "Silymarin and silibinin cause G1 and G2-M cell cycle arrest via distinct circuitries in human prostate cancer PC3 cells: a comparison of flavanone silibinin with flavanolignan mixture silymarin," Oncogene, vol. 25, no. 7, pp. 1053-1069, 2006.
[137] A. B. Niculescu, X. B. Chen, M. Smeets, et al. "Effects of p21(Cip1/Waf1) at both the G(1)/S and the G(2)/M cell cycle transitions: pRb is a critical determinant in blocking DNA replication and in preventing endoreduplication (vol 18, pg 629, 1998)," Molecular and Cellular Biology, vol. 18, no. 3, pp. 1763-1763, 1998.
[138] S. R. Payne, S. Zhang, K. Tsuchiya, et al. "p27(kip1) deficiency impairs G(2)/M arrest in response to DNA damage, leading to an increase in genetic instability," Molecular and Cellular Biology, vol. 28, no. 1, pp. 258-268, 2008.
[139] D. Q. Sun, H. Ren, M. Oertel, R. S. Sellers, L. Zhu. "Loss of p27Kip1 enhances tumor progression in chronic hepatocyte injury-induced liver tumorigenesis with widely ranging effects on Cdk2 or Cdc2 activation," Carcinogenesis, vol. 28, no. 9, pp. 1859-1866, 2007.
[140] E. Aleem, H. Kiyokawa, P. Kaldis. "Cdc2-cyclin E complexes regulate the G1/S phase transition," Nature Cell Biology, vol. 7, no. 8, pp. 831-U893, 2005.
[141] A. Saha, S. Halder, S. K. Upadhyay, et al. "Epstein-barr virus nuclear antigen 3C facilitates G1-S transition by stabilizing and enhancing the function of cyclin D1," Plos Pathogens, vol. 7, no. 2, 2011.