新穎HDAC抑制劑抗大腸直腸癌機轉之探討

Anticancer mechanism of novel HDAC inhibitors toward colorectal cancer

10.6342/NTU.2012.2012.03420

詹鈞硯

自噬作用 ； 細胞凋亡 ； 組蛋白去乙醯酶大腸直腸癌 ； autophagy ； apoptosis ； HDAC ； colorectal cancer

臺灣大學藥理學研究所學位論文

2012年

碩士

陳青周

繁體中文

大腸直腸癌已躍居國人發生率最高的癌症，目前以手術切除最為有效，藥物用於手術後之輔助及晚期治療，我們開發新穎抗癌藥物JMF compounds，可同時抑制HDAC及HMG Co-A還原酶的活性，在大腸直腸癌細胞可誘發apoptosis，亦可透過抑制Akt及活化ER stress而在大腸直腸癌細胞及azoxymethane (AOM)/dextran sulphate sodium (DSS)動物模式誘發autophagy。Atg5 knockdown可抑制JMF-1所誘發的autophagy，並增加JMF-1對細胞存活率之影響，表示JMF-1誘發的autophagy可能為autophagic cell death。抑制p53可減少JMF-1誘發之apoptosis，但增加autophagy；而抑制p21則是減少JMF-1誘發之apoptosis及autophagy，這些結果指出，JMF-1可能是透過誘發apoptosis及autophagic cell death抑制癌細胞的生長，極具潛力成為抗癌新藥。

Colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide. Although anticancer agents for CRC have been grown in the past decade, the 5-year overall survival is still poor. Hydroxymethylglutaryl coenzyme A reductase inhibitors (HMGRi, Statins) and Histone deacetylase inhibitors (HDACi) show promising anticancer activity in preclinical studies. Several dual-targeted inhibitors of HDAC and HMGR have been developed (JMF compound). In this study, we showed that JMF-1 inhibited the growth of CRC cells via induction of apoptosis. JMF-1 induced autophagy through downregulation of Akt and induction of ER stress. JMF-1 also induced autophagy in azoxymethane (AOM)/dextran sulphate sodium (DSS) animal model. Inhibition of autophagy reduced JMF-1-induced cytotoxicity, indicating that JMF-1 induced autophagic cell death. JMF-1 promoted p53 and p21 expression. Inhibition of p53 reduced JMF-1-induced apoptosis, but promoted autophagy. However, inhibition of p21 reduced JMF-1-induced apoptosis and autophagy. These findings demonstrated that JMF-1 exhibited anticancer effect via apoptosis and autophagic cell death, and may be a potential drug for the treatment of CRC.

1. Aaltonen, L. A., P. Peltomaki, et al. (1993). "Clues to the pathogenesis of familial colorectal cancer." Science 260(5109): 812-816.
   連結：
2. Agarwal, B., S. Bhendwal, et al. (1999). "Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells." Clin Cancer Res 5(8): 2223-2229.
   連結：
3. Allen-Mersh, T. G., S. Earlam, et al. (1994). "Quality of life and survival with continuous hepatic-artery floxuridine infusion for colorectal liver metastases." Lancet 344(8932): 1255-1260.
   連結：
4. Anh, T. D., M. Y. Ahn, et al. (2012). "The histone deacetylase inhibitor, Trichostatin A, induces G2/M phase arrest and apoptosis in YD-10B oral squamous carcinoma cells." Oncol Rep 27(2): 455-460.
   連結：
5. Balasubramanian, S., E. Verner, et al. (2009). "Isoform-specific histone deacetylase inhibitors: The next step?" Cancer Letters 280(2): 211-221.
   連結：
6. Barber, T. D., K. McManus, et al. (2008). "Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers." Proc Natl Acad Sci U S A 105(9): 3443-3448.
   連結：
7. Bardou, M., A. Barkun, et al. (2010). "Effect of statin therapy on colorectal cancer." Gut 59(11): 1572-1585.
   連結：
8. Barth, S., D. Glick, et al. (2010). "Autophagy: assays and artifacts." J Pathol 221(2): 117-124.
   連結：
9. Baselga, J. (2002). "Why the epidermal growth factor receptor? The rationale for cancer therapy." Oncologist 7 Suppl 4: 2-8.
   連結：
10. Bertino, E. M. and G. A. Otterson (2011). "Romidepsin: a novel histone deacetylase inhibitor for cancer." Expert Opinion on Investigational Drugs 20(8): 1151-1158.
    連結：
11. Bipat, S., A. S. Glas, et al. (2004). "Rectal cancer: local staging and assessment of lymph node involvement with endoluminal US, CT, and MR imaging--a meta-analysis." Radiology 232(3): 773-783.
    連結：
12. Birgisson, H., L. Pahlman, et al. (2005). "Adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish Rectal Cancer Trial." J Clin Oncol 23(34): 8697-8705.
    連結：
13. Blackwell, L., J. Norris, et al. (2008). "The use of diversity profiling to characterize chemical modulators of the histone deacetylases." Life Sciences 82(21-22): 1050-1058.
    連結：
14. Boland, C. R., M. Koi, et al. (2008). "The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch syndrome: from bench to bedside." Fam Cancer 7(1): 41-52.
    連結：
15. Bradner, J. E., N. West, et al. (2010). "Chemical phylogenetics of histone deacetylases." Nat Chem Biol 6(3): 238-243.
    連結：
16. Brenner, D. J. and E. J. Hall (2007). "Computed tomography--an increasing source of radiation exposure." N Engl J Med 357(22): 2277-2284.
    連結：
17. Bronner, C. E., S. M. Baker, et al. (1994). "Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer." Nature 368(6468): 258-261.
    連結：
18. Brown, G., A. G. Radcliffe, et al. (2003). "Preoperative assessment of prognostic factors in rectal cancer using high-resolution magnetic resonance imaging." Br J Surg 90(3): 355-364.
    連結：
19. Camma, C., M. Giunta, et al. (2000). "Preoperative radiotherapy for resectable rectal cancer: A meta-analysis." JAMA 284(8): 1008-1015.
    連結：
20. Cao, S. S., A. P. Su, et al. (2012). "[The expressions and correlation of bcl-2 and Beclin-1 in pancreatic cancer]." Sichuan Da Xue Xue Bao Yi Xue Ban 43(2): 156-160.
    連結：
21. Chagpar, R., Y. Xing, et al. (2012). "Adherence to Stage-Specific Treatment Guidelines for Patients With Colon Cancer." Journal of Clinical Oncology 30(9): 972-979.
    連結：
22. Chan, K. K., A. M. Oza, et al. (2003). "The statins as anticancer agents." Clin Cancer Res 9(1): 10-19.
    連結：
23. Chang, H. H., C. P. Chiang, et al. (2009). "Histone deacetylase 2 expression predicts poorer prognosis in oral cancer patients." Oral Oncol 45(7): 610-614.
    連結：
24. Chen, W. D., Z. J. Han, et al. (2005). "Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene." J Natl Cancer Inst 97(15): 1124-1132.
    連結：
25. Chen, Y., Y. Lu, et al. (2009). "Beclin-1 Expression is a Predictor of Clinical Outcome in Patients with Esophageal Squamous Cell Carcinoma and Correlated to Hypoxia-Inducible Factor (HIF)-1α Expression." Pathology & Oncology Research 15(3): 487-493.
    連結：
26. Cho, D. H., Y. K. Jo, et al. (2009). "Caspase-mediated cleavage of ATG6/Beclin-1 links apoptosis to autophagy in HeLa cells." Cancer Lett 274(1): 95-100.
    連結：
27. Choi, J. H., H. J. Kwon, et al. (2001). "Expression profile of histone deacetylase 1 in gastric cancer tissues." Jpn J Cancer Res 92(12): 1300-1304.
    連結：
28. Chou, C. W. and C. C. Chen (2008). "HDAC inhibition upregulates the expression of angiostatic ADAMTS1." FEBS Lett 582(29): 4059-4065.
    連結：
29. Cmielova, J. and M. Rezacova (2011). "p21Cip1/Waf1 protein and its function based on a subcellular localization [corrected]." J Cell Biochem 112(12): 3502-3506.
    連結：
30. Codogno, P. and A. J. Meijer (2005). "Autophagy and signaling: their role in cell survival and cell death." Cell Death Differ 12 Suppl 2: 1509-1518.
    連結：
31. Colakoglu, T., T. Z. Nursal, et al. (2010). "Effects of different doses of statins on liver regeneration through angiogenesis and possible relation between these effects and acute phase responses." Transplant Proc 42(9): 3823-3827.
    連結：
32. Collins, J. F., D. A. Lieberman, et al. (2005). "Accuracy of screening for fecal occult blood on a single stool sample obtained by digital rectal examination: a comparison with recommended sampling practice." Ann Intern Med 142(2): 81-85.
    連結：
33. Condorelli, F., I. Gnemmi, et al. (2008). "Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells." Br J Pharmacol 153(4): 657-668.
    連結：
34. Cunningham, D., W. Atkin, et al. (2010). "Colorectal cancer." Lancet 375(9719): 1030-1047.
    連結：
35. Danesh, F. R., M. M. Sadeghi, et al. (2002). "3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/ p21 signaling pathway: Implications for diabetic nephropathy." Proc Natl Acad Sci U S A 99(12): 8301-8305.
    連結：
36. Dargemont, C. and B. Ossareh-Nazari (2012). "Cdc48/p97, a key actor in the interplay between autophagy and ubiquitin/proteasome catabolic pathways." Biochim Biophys Acta 1823(1): 138-144.
    連結：
37. De Robertis, M., E. Massi, et al. (2011). "The AOM/DSS murine model for the study of colon carcinogenesis: From pathways to diagnosis and therapy studies." J Carcinog 10: 9.
    連結：
38. Degenhardt, K., R. Mathew, et al. (2006). "Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis." Cancer Cell 10(1): 51-64.
    連結：
39. DeNardo, D. G., P. Andreu, et al. (2010). "Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity." Cancer Metastasis Rev 29(2): 309-316.
    連結：
40. Eaden, J. A., K. R. Abrams, et al. (2001). "The risk of colorectal cancer in ulcerative colitis: a meta-analysis." Gut 48(4): 526-535.
    連結：
41. Efeyan, A. and D. M. Sabatini (2010). "mTOR and cancer: many loops in one pathway." Curr Opin Cell Biol 22(2): 169-176.
    連結：
42. Eisenberg-Lerner, A., S. Bialik, et al. (2009). "Life and death partners: apoptosis, autophagy and the cross-talk between them." Cell Death Differ 16(7): 966-975.
    連結：
43. Eskelinen, E. L. (2011). "The dual role of autophagy in cancer." Curr Opin Pharmacol 11(4): 294-300.
    連結：
44. Ferlay, J., H. R. Shin, et al. (2010). "Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008." Int J Cancer 127(12): 2893-2917.
    連結：
45. Fishel, R., M. K. Lescoe, et al. (1993). "The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer." Cell 75(5): 1027-1038.
    連結：
46. Fleming, A., T. Noda, et al. (2011). "Chemical modulators of autophagy as biological probes and potential therapeutics." Nat Chem Biol 7(1): 9-17.
    連結：
47. Friend, C., W. Scher, et al. (1971). "Hemoglobin synthesis in murine virus-induced leukemic cells in vitro: stimulation of erythroid differentiation by dimethyl sulfoxide." Proc Natl Acad Sci U S A 68(2): 378-382.
    連結：
48. Fritzsche, F. R., W. Weichert, et al. (2008). "Class I histone deacetylases 1, 2 and 3 are highly expressed in renal cell cancer." BMC Cancer 8: 381.
    連結：
49. Frye, R. A. (2000). "Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins." Biochem Biophys Res Commun 273(2): 793-798.
    連結：
50. Fujita, N., T. Itoh, et al. (2008). "The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy." Mol Biol Cell 19(5): 2092-2100.
    連結：
51. Fullgrabe, J., E. Kavanagh, et al. (2011). "Histone onco-modifications." Oncogene 30(31): 3391-3403.
    連結：
52. Furumai, R., A. Matsuyama, et al. (2002). "FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases." Cancer Res 62(17): 4916-4921.
    連結：
53. Gao, L., M. A. Cueto, et al. (2002). "Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family." J Biol Chem 277(28): 25748-25755.
    連結：
54. Gauthaman, K., C. Y. Fong, et al. (2009). "Statins, stem cells, and cancer." J Cell Biochem 106(6): 975-983.
    連結：
55. Gillespie, S., J. Borrow, et al. (2006). "Bim plays a crucial role in synergistic induction of apoptosis by the histone deacetylase inhibitor SBHA and TRAIL in melanoma cells." Apoptosis 11(12): 2251-2265.
    連結：
56. Glick, D., S. Barth, et al. (2010). "Autophagy: cellular and molecular mechanisms." J Pathol 221(1): 3-12.
    連結：
57. Gniadecki, R. (2004). "Depletion of membrane cholesterol causes ligand-independent activation of Fas and apoptosis." Biochem Biophys Res Commun 320(1): 165-169.
    連結：
58. Goodwin, R. A. and T. R. Asmis (2009). "Overview of systemic therapy for colorectal cancer." Clin Colon Rectal Surg 22(4): 251-256.
    連結：
59. Gordy, C. and Y. W. He (2012). "The crosstalk between autophagy and apoptosis: where does this lead?" Protein Cell 3(1): 17-27.
    連結：
60. Green, D. R. and G. Kroemer (2009). "Cytoplasmic functions of the tumour suppressor p53." Nature 458(7242): 1127-1130.
    連結：
61. Grivennikov, S. I., F. R. Greten, et al. (2010). "Immunity, inflammation, and cancer." Cell 140(6): 883-899.
    連結：
62. Haberland, M., R. L. Montgomery, et al. (2009). "The many roles of histone deacetylases in development and physiology: implications for disease and therapy." Nat Rev Genet 10(1): 32-42.
    連結：
63. Hailey, D. W., A. S. Rambold, et al. (2010). "Mitochondria supply membranes for autophagosome biogenesis during starvation." Cell 141(4): 656-667.
    連結：
64. Hampel, H., W. L. Frankel, et al. (2005). "Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer)." N Engl J Med 352(18): 1851-1860.
    連結：
65. Harper, J. W., G. R. Adami, et al. (1993). "The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases." Cell 75(4): 805-816.
    連結：
66. Harris, J. (2011). "Autophagy and cytokines." Cytokine 56(2): 140-144.
    連結：
67. Hawk, E. and J. L. Viner (2005). "Statins and cancer--beyond the "one drug, one disease" model." N Engl J Med 352(21): 2238-2239.
    連結：
68. Hayashi-Nishino, M., N. Fujita, et al. (2009). "A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation." Nat Cell Biol 11(12): 1433-1437.
    連結：
69. He, C. and D. J. Klionsky (2009). "Regulation mechanisms and signaling pathways of autophagy." Annu Rev Genet 43: 67-93.
    連結：
70. Herbst, S., U. E. Schaible, et al. (2011). "Interferon gamma activated macrophages kill mycobacteria by nitric oxide induced apoptosis." PLoS One 6(5): e19105.
    連結：
71. Hindler, K., C. S. Cleeland, et al. (2006). "The role of statins in cancer therapy." Oncologist 11(3): 306-315.
    連結：
72. Hizume, K., S. H. Yoshimura, et al. (2005). "Linker histone H1 per se can induce three-dimensional folding of chromatin fiber." Biochemistry 44(39): 12978-12989.
    連結：
73. Hoshino, I. and H. Matsubara (2010). "Recent advances in histone deacetylase targeted cancer therapy." Surg Today 40(9): 809-815.
    連結：
74. Hu, Y. L., M. DeLay, et al. (2012). "Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma." Cancer Res 72(7): 1773-1783.
    連結：
75. Hubbert, C., A. Guardiola, et al. (2002). "HDAC6 is a microtubule-associated deacetylase." Nature 417(6887): 455-458.
    連結：
76. Insinga, A., S. Monestiroli, et al. (2005). "Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway." Nat Med 11(1): 71-76.
    連結：
77. Ionov, Y., M. A. Peinado, et al. (1993). "Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis." Nature 363(6429): 558-561.
    連結：
78. Istvan, E. S. and J. Deisenhofer (2001). "Structural mechanism for statin inhibition of HMG-CoA reductase." Science 292(5519): 1160-1164.
    連結：
79. Janku, F., D. J. McConkey, et al. (2011). "Autophagy as a target for anticancer therapy." Nat Rev Clin Oncol 8(9): 528-539.
    連結：
80. Jeffers, J. R., E. Parganas, et al. (2003). "Puma is an essential mediator of p53-dependent and -independent apoptotic pathways." Cancer Cell 4(4): 321-328.
    連結：
81. Jemal, A., F. Bray, et al. (2011). "Global cancer statistics." CA Cancer J Clin 61(2): 69-90.
    連結：
82. Jiang, Z., X. Zheng, et al. (2004). "Lovastatin-induced up-regulation of the BH3-only protein, Bim, and cell death in glioblastoma cells." J Neurochem 89(1): 168-178.
    連結：
83. Jung, K. H., J. H. Noh, et al. (2012). "HDAC2 overexpression confers oncogenic potential to human lung cancer cells by deregulating expression of apoptosis and cell cycle proteins." J Cell Biochem 113(6): 2167-2177.
    連結：
84. Kachhap, S. K., N. Rosmus, et al. (2010). "Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor." PLoS One 5(6): e11208.
    連結：
85. Kapiteijn, E., C. A. M. Marijnen, et al. (2001). "Preoperative Radiotherapy Combined with Total Mesorectal Excision for Resectable Rectal Cancer." New England Journal of Medicine 345(9): 638-646.
    連結：
86. Karagiannis, T. C. and K. Ververis (2012). "Potential of chromatin modifying compounds for the treatment of Alzheimer's disease." Pathobiology of Aging & Age-related Diseases 2(0).
    連結：
87. Karapetis, C. S., S. Khambata-Ford, et al. (2008). "K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer." New England Journal of Medicine 359(17): 1757-1765.
    連結：
88. Khan, O. and N. B. La Thangue (2012). "HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications." Immunol Cell Biol 90(1): 85-94.
    連結：
89. Kirisako, T., Y. Ichimura, et al. (2000). "The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway." J Cell Biol 151(2): 263-276.
    連結：
90. Klampfer, L., J. Huang, et al. (2007). "Histone deacetylase inhibitors induce cell death selectively in cells that harbor activated kRasV12: The role of signal transducers and activators of transcription 1 and p21." Cancer Res 67(18): 8477-8485.
    連結：
91. Klionsky, D. J., J. M. Cregg, et al. (2003). "A unified nomenclature for yeast autophagy-related genes." Dev Cell 5(4): 539-545.
    連結：
92. Kondo, Y. and J. P. Issa (2004). "Epigenetic changes in colorectal cancer." Cancer Metastasis Rev 23(1-2): 29-39.
    連結：
93. Kondo, Y., T. Kanzawa, et al. (2005). "The role of autophagy in cancer development and response to therapy." Nat Rev Cancer 5(9): 726-734.
    連結：
94. Kondo, Y. and S. Kondo (2006). "Autophagy and cancer therapy." Autophagy 2(2): 85-90.
    連結：
95. Kornberg, R. D. and Y. Lorch (1999). "Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome." Cell 98(3): 285-294.
    連結：
96. Kouzminova, N., T. Lu, et al. (2010). "Molecular basis of colorectal cancer." N Engl J Med 362(13): 1245-1246; author reply 1246-1247.
    連結：
97. Kovacs, J. J., P. J. Murphy, et al. (2005). "HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor." Mol Cell 18(5): 601-607.
    連結：
98. Kristensen, L. S., H. M. Nielsen, et al. (2009). "Epigenetics and cancer treatment." Eur J Pharmacol 625(1-3): 131-142.
    連結：
99. Krusche, C. A., P. W. lfing, et al. (2005). "."
    連結：
100. Kuma, A., M. Matsui, et al. (2007). "LC3, an autophagosome marker, can be incorporated into protein aggregates independent of autophagy: caution in the interpretation of LC3 localization." Autophagy 3(4): 323-328.
     連結：
101. Lee, J. H., M. L. Choy, et al. (2010). "Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair." Proceedings of the National Academy of Sciences 107(33): 14639-14644.
     連結：
102. Lee, S. J., M. J. Ha, et al. (1998). "Inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway induces p53-independent transcriptional regulation of p21(WAF1/CIP1) in human prostate carcinoma cells." J Biol Chem 273(17): 10618-10623.
     連結：
103. Lengauer, C., K. W. Kinzler, et al. (1997). "Genetic instability in colorectal cancers." Nature 386(6625): 623-627.
     連結：
104. Levine, B. (2007). "Cell biology: autophagy and cancer." Nature 446(7137): 745-747.
     連結：
105. Levine, B. and V. Deretic (2007). "Unveiling the roles of autophagy in innate and adaptive immunity." Nat Rev Immunol 7(10): 767-777.
     連結：
106. Levine, B. and G. Kroemer (2008). "Autophagy in the pathogenesis of disease." Cell 132(1): 27-42.
     連結：
107. Levine, B., N. Mizushima, et al. (2011). "Autophagy in immunity and inflammation." Nature 469(7330): 323-335.
     連結：
108. Li, B. X., C. Y. Li, et al. (2009). "The expression of beclin 1 is associated with favorable prognosis in stage IIIB colon cancers." Autophagy 5(3): 303-306.
     連結：
109. Li, X., J. Wang, et al. (2012). "Oridonin Up-regulates Expression of P21 and Induces Autophagy and Apoptosis in Human Prostate Cancer Cells." Int J Biol Sci 8(6): 901-912.
     連結：
110. Lieberman, D. A. (2009). "Screening for Colorectal Cancer." New England Journal of Medicine 361(12): 1179-1187.
     連結：
111. Lin, Y. C., J. H. Lin, et al. (2008). "Statins increase p21 through inhibition of histone deacetylase activity and release of promoter-associated HDAC1/2." Cancer Res 68(7): 2375-2383.
     連結：
112. Lindstrom, E., P. Norlen, et al. (2000). "Histamine depletion does not affect pancreastatin secretion from isolated rat stomach ECL cells." Eur J Pharmacol 387(1): 19-25.
     連結：
113. Liu, E. Y. and K. M. Ryan (2012). "Autophagy and cancer - issues we need to digest." J Cell Sci 125(Pt 10): 2349-2358.
     連結：
114. Liu, Y. L., P. M. Yang, et al. (2010). "Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma." Autophagy 6(8): 1057-1065.
     連結：
115. Luger, K., A. W. Mader, et al. (1997). "Crystal structure of the nucleosome core particle at 2.8 A resolution." Nature 389(6648): 251-260.
     連結：
116. Maiuri, M. C., E. Tasdemir, et al. (2009). "Control of autophagy by oncogenes and tumor suppressor genes." Cell Death Differ 16(1): 87-93.
     連結：
117. Maiuri, M. C., E. Zalckvar, et al. (2007). "Self-eating and self-killing: crosstalk between autophagy and apoptosis." Nat Rev Mol Cell Biol 8(9): 741-752.
     連結：
118. Marks, P. A. and R. Breslow (2007). "Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug." Nat Biotechnol 25(1): 84-90.
     連結：
119. Martin, A. P., C. Mitchell, et al. (2009). "Inhibition of MCL-1 enhances lapatinib toxicity and overcomes lapatinib resistance via BAK-dependent autophagy." Cancer Biol Ther 8(21): 2084-2096.
     連結：
120. McCormack, E., I. Haaland, et al. (2011). "Synergistic induction of p53 mediated apoptosis by valproic acid and nutlin-3 in acute myeloid leukemia." Leukemia 26(5): 910-917.
     連結：
121. McKinsey, T. A., C. L. Zhang, et al. (2000). "Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation." Nature 408(6808): 106-111.
     連結：
122. Meijer, A. J. and P. Codogno (2004). "Regulation and role of autophagy in mammalian cells." Int J Biochem Cell Biol 36(12): 2445-2462.
     連結：
123. Meng, J., H. H. Zhang, et al. (2012). "The histone deacetylase inhibitor trichostatin A induces cell cycle arrest and apoptosis in colorectal cancer cells via p53-dependent and -independent pathways." Oncol Rep 28(1): 384-388.
     連結：
124. Mercer, C. A., A. Kaliappan, et al. (2009). "A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy." Autophagy 5(5): 649-662.
     連結：
125. Milano, V., Y. Piao, et al. (2009). "Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma." Mol Cancer Ther 8(2): 394-406.
     連結：
126. Miller, K. M., J. V. Tjeertes, et al. (2010). "Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining." Nat Struct Mol Biol 17(9): 1144-1151.
     連結：
127. Miyake, K., T. Yoshizumi, et al. (2008). "Expression of hypoxia-inducible factor-1alpha, histone deacetylase 1, and metastasis-associated protein 1 in pancreatic carcinoma: correlation with poor prognosis with possible regulation." Pancreas 36(3): e1-9.
     連結：
128. Mizushima, N., B. Levine, et al. (2008). "Autophagy fights disease through cellular self-digestion." Nature 451(7182): 1069-1075.
     連結：
129. Mizushima, N., T. Noda, et al. (1998). "A protein conjugation system essential for autophagy." Nature 395(6700): 395-398.
     連結：
130. Moreno, D. A., C. A. Scrideli, et al. (2010). "Differential expression of HDAC3, HDAC7 and HDAC9 is associated with prognosis and survival in childhood acute lymphoblastic leukaemia." Br J Haematol 150(6): 665-673.
     連結：
131. Muratani, M. and W. P. Tansey (2003). "How the ubiquitin-proteasome system controls transcription." Nat Rev Mol Cell Biol 4(3): 192-201.
     連結：
132. Nebbioso, A., N. Clarke, et al. (2005). "Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells." Nat Med 11(1): 77-84.
     連結：
133. Newcomb, P. A., B. E. Storer, et al. (2003). "Long-term efficacy of sigmoidoscopy in the reduction of colorectal cancer incidence." J Natl Cancer Inst 95(8): 622-625.
     連結：
134. Nightingale, K. P., L. P. O'Neill, et al. (2006). "Histone modifications: signalling receptors and potential elements of a heritable epigenetic code." Curr Opin Genet Dev 16(2): 125-136.
     連結：
135. Nishida, Y., S. Arakawa, et al. (2009). "Discovery of Atg5/Atg7-independent alternative macroautophagy." Nature 461(7264): 654-658.
     連結：
136. Nordlinger, B., H. Sorbye, et al. (2008). "Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial." The Lancet 371(9617): 1007-1016.
     連結：
137. Ocker, M. and R. Schneider-Stock (2007). "Histone deacetylase inhibitors: signalling towards p21cip1/waf1." Int J Biochem Cell Biol 39(7-8): 1367-1374.
     連結：
138. Oehme, I., H. E. Deubzer, et al. (2009). "Targeting of HDAC8 and investigational inhibitors in neuroblastoma." Expert Opinion on Investigational Drugs 18(11): 1605-1617.
     連結：
139. Papadopoulos, N., N. C. Nicolaides, et al. (1994). "Mutation of a mutL homolog in hereditary colon cancer." Science 263(5153): 1625-1629.
     連結：
140. Pedersen, T. R., L. Wilhelmsen, et al. (2000). "Follow-up study of patients randomized in the Scandinavian simvastatin survival study (4S) of cholesterol lowering." Am J Cardiol 86(3): 257-262.
     連結：
141. Perez-Perarnau, A., L. Coll-Mulet, et al. (2011). "Analysis of apoptosis regulatory genes altered by histone deacetylase inhibitors in chronic lymphocytic leukemia cells." Epigenetics 6(10): 1228-1235.
     連結：
142. Petiot, A., E. Ogier-Denis, et al. (2000). "Distinct classes of phosphatidylinositol 3'-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells." J Biol Chem 275(2): 992-998.
     連結：
143. Qian, B.-Z. and J. W. Pollard (2010). "Macrophage Diversity Enhances Tumor Progression and Metastasis." Cell 141(1): 39-51.
     連結：
144. Qian, D. Z., X. Wang, et al. (2004). "The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584." Cancer Res 64(18): 6626-6634.
     連結：
145. Qu, X., J. Yu, et al. (2003). "Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene." J Clin Invest 112(12): 1809-1820.
     連結：
146. Rabinowitz, J. D. and E. White (2010). "Autophagy and metabolism." Science 330(6009): 1344-1348.
     連結：
147. Rao, S., D. C. Porter, et al. (1999). "Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase." Proc Natl Acad Sci U S A 96(14): 7797-7802.
     連結：
148. Ravikumar, B., K. Moreau, et al. (2010). "Plasma membrane contributes to the formation of pre-autophagosomal structures." Nat Cell Biol 12(8): 747-757.
     連結：
149. Ray, K. K. and C. P. Cannon (2005). "The potential relevance of the multiple lipid-independent (pleiotropic) effects of statins in the management of acute coronary syndromes." J Am Coll Cardiol 46(8): 1425-1433.
     連結：
150. Reggiori, F., T. Shintani, et al. (2005). "Atg9 Cycles Between Mitochondria and the Pre-Autophagosomal Structure in Yeasts." Autophagy 1(2): 101-109.
     連結：
151. Rikimaru, T., A. Taketomi, et al. (2007). "Clinical significance of histone deacetylase 1 expression in patients with hepatocellular carcinoma." Oncology 72(1-2): 69-74.
     連結：
152. Rocchi, P., R. Tonelli, et al. (2005). "p21Waf1/Cip1 is a common target induced by short-chain fatty acid HDAC inhibitors (valproic acid, tributyrin and sodium butyrate) in neuroblastoma cells." Oncol Rep 13(6): 1139-1144.
     連結：
153. Ropero, S., M. F. Fraga, et al. (2006). "A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition." Nat Genet 38(5): 566-569.
     連結：
154. Rosato, R. R., J. A. Almenara, et al. (2008). "Role of histone deacetylase inhibitor-induced reactive oxygen species and DNA damage in LAQ-824/fludarabine antileukemic interactions." Molecular Cancer Therapeutics 7(10): 3285-3297.
     連結：
155. Sakuma, T., K. Uzawa, et al. (2006). "Aberrant expression of histone deacetylase 6 in oral squamous cell carcinoma." Int J Oncol 29(1): 117-124.
     連結：
156. Sargent, D. J., S. Patiyil, et al. (2007). "End points for colon cancer adjuvant trials: observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group." J Clin Oncol 25(29): 4569-4574.
     連結：
157. Shackelford, D. B. and R. J. Shaw (2009). "The LKB1-AMPK pathway: metabolism and growth control in tumour suppression." Nat Rev Cancer 9(8): 563-575.
     連結：
158. Shen, H.-M. and P. Codogno (2011). "Autophagic cell death: Loch Ness monster or endangered species?" Autophagy 7(5): 457-465.
     連結：
159. Shintani, T., N. Mizushima, et al. (1999). "Apg10p, a novel protein-conjugating enzyme essential for autophagy in yeast." EMBO J 18(19): 5234-5241.
     連結：
160. Spiegel, S., S. Milstien, et al. (2012). "Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapy." Oncogene 31(5): 537-551.
     連結：
161. Strahl, B. D. and C. D. Allis (2000). "The language of covalent histone modifications." Nature 403(6765): 41-45.
     連結：
162. Sun, P. C., C. Tzao, et al. (2010). "Suberoylanilide hydroxamic acid induces apoptosis and sub-G1 arrest of 320 HSR colon cancer cells." J Biomed Sci 17: 76.
     連結：
163. Tanida, I., N. Mizushima, et al. (1999). "Apg7p/Cvt2p: A novel protein-activating enzyme essential for autophagy." Mol Biol Cell 10(5): 1367-1379.
     連結：
164. Tanida, I., T. Ueno, et al. (2004). "LC3 conjugation system in mammalian autophagy." Int J Biochem Cell Biol 36(12): 2503-2518.
     連結：
165. Taunton, J., C. A. Hassig, et al. (1996). "A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p." Science 272(5260): 408-411.
     連結：
166. Towler, B., L. Irwig, et al. (1998). "A systematic review of the effects of screening for colorectal cancer using the faecal occult blood test, hemoccult." BMJ 317(7158): 559-565.
     連結：
167. Tsan, Y. T., C. H. Lee, et al. (2012). "Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection." J Clin Oncol 30(6): 623-630.
     連結：
168. Ueda, H., H. Nakajima, et al. (1994). "FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity." J Antibiot (Tokyo) 47(3): 301-310.
     連結：
169. Vega, R. B., B. C. Harrison, et al. (2004). "Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5." Mol Cell Biol 24(19): 8374-8385.
     連結：
170. Venugopal, B. and T. R. Evans (2011). "Developing histone deacetylase inhibitors as anti-cancer therapeutics." Curr Med Chem 18(11): 1658-1671.
     連結：
171. Vousden, K. H. and D. P. Lane (2007). "p53 in health and disease." Nat Rev Mol Cell Biol 8(4): 275-283.
     連結：
172. Wagner, J. M., B. Hackanson, et al. (2010). "Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy." Clin Epigenetics 1(3-4): 117-136.
     連結：
173. Wang, I. K., S. Y. Lin-Shiau, et al. (2000). "Induction of apoptosis by lovastatin through activation of caspase-3 and DNase II in leukaemia HL-60 cells." Pharmacol Toxicol 86(2): 83-91.
     連結：
174. Weichert, W., A. Roske, et al. (2008). "Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy." Br J Cancer 98(3): 604-610.
     連結：
175. Weis, M., C. Heeschen, et al. (2002). "Statins have biphasic effects on angiogenesis." Circulation 105(6): 739-745.
     連結：
176. Weisenberger, D. J., K. D. Siegmund, et al. (2006). "CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer." Nat Genet 38(7): 787-793.
     連結：
177. Wirawan, E., T. Vanden Berghe, et al. (2012). "Autophagy: for better or for worse." Cell Res 22(1): 43-61.
     連結：
178. Wu, W. K., S. B. Coffelt, et al. (2012). "The autophagic paradox in cancer therapy." Oncogene 31(8): 939-953.
     連結：
179. Xiao, G. (2007). "Autophagy and NF-kappaB: fight for fate." Cytokine Growth Factor Rev 18(3-4): 233-243.
     連結：
180. Xie, Z. and D. J. Klionsky (2007). "Autophagosome formation: core machinery and adaptations." Nat Cell Biol 9(10): 1102-1109.
     連結：
181. Xu, N., J. Zhang, et al. (2012). "Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell." Biochem Biophys Res Commun.
     連結：
182. Yan, W., S. Liu, et al. (2012). "Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8." Oncogene.
     連結：
183. Yang, P. M. and C. C. Chen (2011). "Life or death? Autophagy in anticancer therapies with statins and histone deacetylase inhibitors." Autophagy 7(1): 107-108.
     連結：
184. Yang, P. M., Y. L. Liu, et al. (2010). "Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies." Cancer Res 70(19): 7699-7709.
     連結：
185. Yin, X. M., W. X. Ding, et al. (2008). "Autophagy in the liver." Hepatology 47(5): 1773-1785.
     連結：
186. Yoshioka, A., H. Miyata, et al. (2008). "LC3, an autophagosome marker, is highly expressed in gastrointestinal cancers." Int J Oncol 33(3): 461-468.
     連結：
187. Yoshioka, K., S. Nakamori, et al. (1999). "Overexpression of small GTP-binding protein RhoA promotes invasion of tumor cells." Cancer Res 59(8): 2004-2010.
     連結：
188. You, B. R. and W. H. Park (2010). "Suberoyl bishydroxamic acid inhibits the growth of A549 lung cancer cells via caspase-dependent apoptosis." Mol Cell Biochem 344(1-2): 203-210.
     連結：
189. Yousefi, S., R. Perozzo, et al. (2006). "Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis." Nat Cell Biol 8(10): 1124-1132.
     連結：
190. Yue, Z., S. Jin, et al. (2003). "Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor." Proc Natl Acad Sci U S A 100(25): 15077-15082.
     連結：
191. Zhang, K. and R. J. Kaufman (2008). "From endoplasmic-reticulum stress to the inflammatory response." Nature 454(7203): 455-462.
     連結：
192. Zhang, W., J. Wu, et al. (2010). "Fluvastatin, a lipophilic statin, induces apoptosis in human hepatocellular carcinoma cells through mitochondria-operated pathway." Indian J Exp Biol 48(12): 1167-1174.
     連結：
193. Zhang, Z., H. Yamashita, et al. (2005). "Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast*." Breast Cancer Res Treat 94(1): 11-16.
     連結：
194. Zhang, Z., H. Yamashita, et al. (2004). "HDAC6 expression is correlated with better survival in breast cancer." Clin Cancer Res 10(20): 6962-6968.
     連結：
195. Zhou, Q., C. L. Dalgard, et al. (2011). "Histone deacetylase inhibitors SAHA and sodium butyrate block G1-to-S cell cycle progression in neurosphere formation by adult subventricular cells." BMC Neurosci 12: 50.
     連結：
196. Zopf, S., D. Neureiter, et al. (2007). "Differential response of p53 and p21 on HDAC inhibitor-mediated apoptosis in HCT116 colon cancer cells in vitro and in vivo." Int J Oncol 31(6): 1391-1402.
     連結：
197. Zuco, V., M. De Cesare, et al. (2011). "Synergistic antitumor effects of novel HDAC inhibitors and paclitaxel in vitro and in vivo." PLoS One 6(12): e29085.
     連結：
198. Zupkovitz, G., R. Grausenburger, et al. (2010). "The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation." Mol Cell Biol 30(5): 1171-1181.
     連結：
199. Ichimura, Y., T. Kirisako, et al. (2000). "A ubiquitin-like system mediates protein lipidation." Nature 408(6811): 488-492.
200. Keyomarsi, K., L. Sandoval, et al. (1991). "Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin." Cancer Res 51(13): 3602-3609.
201. Kusama, T., M. Mukai, et al. (2001). "Inhibition of epidermal growth factor-induced RhoA translocation and invasion of human pancreatic cancer cells by 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors." Cancer Res 61(12): 4885-4891.
202. Levine, B. and D. J. Klionsky (2004). "Development by self-digestion: molecular mechanisms and biological functions of autophagy." Dev Cell 6(4): 463-477.
203. Marquez, R. T. and L. Xu (2012). "Bcl-2:Beclin 1 complex: multiple, mechanisms regulating autophagy/apoptosis toggle switch." Am J Cancer Res 2(2): 214-221.
204. Meyerhardt, J. A. and R. J. Mayer (2005). "Systemic Therapy for Colorectal Cancer." New England Journal of Medicine 352(5): 476-487.
205. Ozdag, H., A. E. Teschendorff, et al. (2006). "Differential expression of selected histone modifier genes in human solid cancers." BMC Genomics 7: 90.
206. Zhao, Y., J. Tan, et al. (2005). "Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim." Proc Natl Acad Sci U S A 102(44): 16090-16095.