Chemopreventive drugs: Mechanisms via inhibition of cancer stem cells in colorectal cancer

World Journal of Gastroenterology

Volumn 20, Issue 14, 2014, Pages 3835-3846

  Kim, Tae Il ^a  

^a Yonsei University College of Medicine   (South Korea)

Author keywords

Cancer stem cell; Carcinogenesis; Chemoprevention; Colorectal cancer; Microenvironment

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ACETYLSALICYLIC ACID; CYCLOOXYGENASE 2 INHIBITOR; EFLORNITHINE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; METFORMIN; NONSTEROID ANTIINFLAMMATORY AGENT; NOTCH RECEPTOR; SULINDAC; WNT PROTEIN; ADENYLATE KINASE; ANTINEOPLASTIC AGENT; BONE MORPHOGENETIC PROTEIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA;

APOPTOSIS; ARTICLE; BLEEDING; CANCER MORTALITY; CANCER STEM CELL; CARCINOGENESIS; CELL CYCLE ARREST; CELL PROLIFERATION; CHEMOPROPHYLAXIS; COLORECTAL CANCER; DNA METHYLATION; GENE MUTATION; HUMAN; INFLAMMATION; NONHUMAN; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT; AGONISTS; ANIMAL; CELL DIFFERENTIATION; CLINICAL TRIAL (TOPIC); COLORECTAL NEOPLASMS; CYTOLOGY; DRUG EFFECTS; INTESTINE; METABOLISM; MOUSE; STEM CELL;

ADENYLATE KINASE; ANIMALS; ANTICARCINOGENIC AGENTS; BONE MORPHOGENETIC PROTEINS; CELL DIFFERENTIATION; CLINICAL TRIALS AS TOPIC; COLORECTAL NEOPLASMS; HUMANS; INTESTINES; METFORMIN; MICE; NEOPLASTIC STEM CELLS; NF-KAPPA B; PPAR GAMMA; STEM CELLS;

EID: 84898493841     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v20.i14.3835     Document Type: Article

References (140)

1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127: 2893-2917 [PMID: 21351269 DOI: 10.1002/ijc.25516]
2. Cersosimo RJ. Management of advanced colorectal cancer, Part 1. Am J Health Syst Pharm 2013; 70: 395-406 [PMID: 23413162 DOI: 10.2146/ajhp110532]
3. Winawer S, Fletcher R, Rex D, Bond J, Burt R, Ferrucci J, Ganiats T, Levin T, Woolf S, Johnson D, Kirk L, Litin S, Simmang C. Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence. Gastroenterology 2003; 124: 544-560 [PMID: 12557158 DOI: 10.1053/gast.2003.50044]
4. Lieberman DA, Rex DK, Winawer SJ, Giardiello FM, Johnson DA, Levin TR. Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2012; 143: 844-857 [PMID: 22763141 DOI: 10.1053/ j.gastro.2012.06.001]
5. Umar A, Dunn BK, Greenwald P. Future directions in cancer prevention. Nat Rev Cancer 2012; 12: 835-848 [PMID: 23151603 DOI: 10.1038/nrc3397]
6. Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R, McKeown-Eyssen G, Summers RW, Rothstein R, Burke CA, Snover DC, Church TR, Allen JI, Beach M, Beck GJ, Bond JH, Byers T, Greenberg ER, Mandel JS, Marcon N, Mott LA, Pearson L, Saibil F, van Stolk RU. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 2003; 348: 891-899 [PMID: 12621133 DOI: 10.1056/NEJMoa021735]
7. Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES, Curhan GC, Fuchs CS. Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA 2005; 294: 914-923 [PMID: 16118381 DOI: 10.1001/jama.294.8.914]
8. Jacoby RF, Seibert K, Cole CE, Kelloff G, Lubet RA. The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis. Cancer Res 2000; 60: 5040-5044 [PMID: 11016626]
9. Beazer-Barclay Y, Levy DB, Moser AR, Dove WF, Hamilton SR, Vogelstein B, Kinzler KW. Sulindac suppresses tumorigenesis in the Min mouse. Carcinogenesis 1996; 17: 1757-1760 [PMID: 8761438 DOI: 10.1093/carcin/17.8.1757]
10. Sandler RS, Halabi S, Baron JA, Budinger S, Paskett E, Keresztes R, Petrelli N, Pipas JM, Karp DD, Loprinzi CL, Steinbach G, Schilsky R. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 2003; 348: 883-890 [PMID: 12621132 DOI: 10.1056/NEJMoa021633]
11. Benamouzig R, Deyra J, Martin A, Girard B, Jullian E, Piednoir B, Couturier D, Coste T, Little J, Chaussade S. Daily soluble aspirin and prevention of colorectal adenoma recurrence: one-year results of the APACC trial. Gastroenterology 2003; 125: 328-336 [PMID: 12891533 DOI: 10.1016/ S0016-5085(03)00887-4]
12. Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein G, Olschwang S, Eccles D, Evans DG, Maher ER, Bertario L, Bisgaard ML, Dunlop MG, Ho JW, Hodgson SV, Lindblom A, Lubinski J, Morrison PJ, Murday V, Ramesar R, Side L, Scott RJ, Thomas HJ, Vasen HF, Barker G, Crawford G, Elliott F, Movahedi M, Pylvanainen K, Wijnen JT, Fodde R, Lynch HT, Mathers JC, Bishop DT. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 2011; 378: 2081-2087 [PMID: 22036019 DOI: 10.1016/ s0140-6736(11)61049-0]
13. Meyskens FL, McLaren CE, Pelot D, Fujikawa-Brooks S, Carpenter PM, Hawk E, Kelloff G, Lawson MJ, Kidao J, Mc-Cracken J, Albers CG, Ahnen DJ, Turgeon DK, Goldschmid S, Lance P, Hagedorn CH, Gillen DL, Gerner EW. Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial. Cancer Prev Res (Phila) 2008; 1: 32-38 [PMID: 18841250 DOI: 10.1158/1940-6207.capr-08-0042]
14. Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, Imamura Y, Qian ZR, Baba Y, Shima K, Sun R, Nosho K, Meyerhardt JA, Giovannucci E, Fuchs CS, Chan AT, Ogino S. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 2012; 367: 1596-1606 [PMID: 23094721 DOI: 10.1056/NEJMoa1207756]
15. Chia WK, Ali R, Toh HC. Aspirin as adjuvant therapy for colorectal cancer--reinterpreting paradigms. Nat Rev Clin Oncol 2012; 9: 561-570 [PMID: 22910681 DOI: 10.1038/nrclinonc. 2012.137]
16. Langley RE, Rothwell PM. Potential biomarker for aspirin use in colorectal cancer therapy. Nat Rev Clin Oncol 2013; 10: 8-10 [PMID: 23207797 DOI: 10.1038/nrclinonc.2012.216]
17. Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, Wakabayashi N, Saunders B, Shen Y, Fujimura T, Su LK, Levin B, Godio L, Patterson S, Rodriguez-Bigas MA, Jester SL, King KL, Schumacher M, Abbruzzese J, DuBois RN, Hittelman WN, Zimmerman S, Sherman JW, Kelloff G. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342: 1946-1952 [PMID: 10874062 DOI: 10.1056/nejm200006293422603]
18. Arber N, Eagle CJ, Spicak J, Rácz I, Dite P, Hajer J, Zavoral M, Lechuga MJ, Gerletti P, Tang J, Rosenstein RB, Macdonald K, Bhadra P, Fowler R, Wittes J, Zauber AG, Solomon SD, Levin B. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006; 355: 885-895 [PMID: 16943401 DOI: 10.1056/NEJMoa061652]
19. Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K, Tang J, Rosenstein RB, Wittes J, Corle D, Hess TM, Woloj GM, Boisserie F, Anderson WF, Viner JL, Bagheri D, Burn J, Chung DC, Dewar T, Foley TR, Hoffman N, Macrae F, Pruitt RE, Saltzman JR, Salzberg B, Sylwestrowicz T, Gordon GB, Hawk ET. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006; 355: 873-884 [PMID: 16943400 DOI: 10.1056/NEJMoa061355]
20. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092-1102 [PMID: 15713943 DOI: 10.1056/ NEJMoa050493]
21. Kerr DJ, Dunn JA, Langman MJ, Smith JL, Midgley RS, Stanley A, Stokes JC, Julier P, Iveson C, Duvvuri R, McConkey CC. Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. N Engl J Med 2007; 357: 360-369 [PMID: 17652651 DOI: 10.1056/NEJMoa071841]
22. Solomon DH, Avorn J, Stürmer T, Glynn RJ, Mogun H, Schneeweiss S. Cardiovascular outcomes in new users of coxibs and nonsteroidal antiinflammatory drugs: high-risk subgroups and time course of risk. Arthritis Rheum 2006; 54: 1378-1389 [PMID: 16645966 DOI: 10.1002/art.21887]
23. Chan KK, Oza AM, Siu LL. The statins as anticancer agents. Clin Cancer Res 2003; 9: 10-19 [PMID: 12538446]
24. Wong WW, Dimitroulakos J, Minden MD, Penn LZ. HMGCoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia 2002; 16: 508-519 [PMID: 11960327 DOI: 10.1038/ sj.leu.2402476]
25. Taylor ML, Wells BJ, Smolak MJ. Statins and cancer: a metaanalysis of case-control studies. Eur J Cancer Prev 2008; 17: 259-268 [PMID: 18414198 DOI: 10.1097/CEJ.0b013e3282b721fe]
26. Friedman GD, Flick ED, Udaltsova N, Chan J, Quesenberry CP, Habel LA. Screening statins for possible carcinogenic risk: up to 9 years of follow-up of 361,859 recipients. Pharmacoepidemiol Drug Saf 2008; 17: 27-36 [PMID: 17944002 DOI: 10.1002/pds.1507]
27. Shadman M, Newcomb PA, Hampton JM, Wernli KJ, Trentham-Dietz A. Non-steroidal anti-inflammatory drugs and statins in relation to colorectal cancer risk. World J Gastroenterol 2009; 15: 2336-2339 [PMID: 19452574 DOI: 10.3748/ wjg.15.2336]
28. Lipkin SM, Chao EC, Moreno V, Rozek LS, Rennert H, Pinchev M, Dizon D, Rennert G, Kopelovich L, Gruber SB. Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase modifies the chemopreventive activity of statins for colorectal cancer. Cancer Prev Res (Phila) 2010; 3: 597-603 [PMID: 20403997 DOI: 10.1158/1940-6207.capr-10-0007]
29. Hachem C, Morgan R, Johnson M, Kuebeler M, El-Serag H. Statins and the risk of colorectal carcinoma: a nested case-control study in veterans with diabetes. Am J Gastroenterol 2009; 104: 1241-1248 [PMID: 19352344 DOI: 10.1038/ ajg.2009.64]
30. Broughton T, Sington J, Beales IL. Statin use is associated with a reduced incidence of colorectal cancer: a colonoscopycontrolled case-control study. BMC Gastroenterol 2012; 12: 36 [PMID: 22530742 DOI: 10.1186/1471-230X-12-36]
31. Poynter JN, Gruber SB, Higgins PD, Almog R, Bonner JD, Rennert HS, Low M, Greenson JK, Rennert G. Statins and the risk of colorectal cancer. N Engl J Med 2005; 352: 2184-2192 [PMID: 15917383 DOI: 10.1056/NEJMoa043792]
32. Singh H, Mahmud SM, Turner D, Xue L, Demers AA, Bernstein CN. Long-term use of statins and risk of colorectal cancer: a population-based study. Am J Gastroenterol 2009; 104: 3015-3023 [PMID: 19809413 DOI: 10.1038/ajg.2009.574]
33. Haukka J, Sankila R, Klaukka T, Lonnqvist J, Niskanen L, Tanskanen A, Wahlbeck K, Tiihonen J. Incidence of cancer and statin usage--record linkage study. Int J Cancer 2010; 126: 279-284 [PMID: 19739258 DOI: 10.1002/ijc.24536]
34. Coogan PF, Smith J, Rosenberg L. Statin use and risk of colorectal cancer. J Natl Cancer Inst 2007; 99: 32-40 [PMID: 17202111 DOI: 10.1093/jnci/djk003]
35. Vinogradova Y, Hippisley-Cox J, Coupland C, Logan RF. Risk of colorectal cancer in patients prescribed statins, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2 inhibitors: nested case-control study. Gastroenterology 2007; 133: 393-402 [PMID: 17681160 DOI: 10.1053/j.gastro.2007.05.023]
36. Kaye JA, Jick H. Statin use and cancer risk in the General Practice Research Database. Br J Cancer 2004; 90: 635-637 [PMID: 14760377 DOI: 10.1038/sj.bjc.6601566]
37. Vinogradova Y, Coupland C, Hippisley-Cox J. Exposure to statins and risk of common cancers: a series of nested casecontrol studies. BMC Cancer 2011; 11: 409 [PMID: 21943022 DOI: 10.1186/1471-2407-11-409]
38. Siddiqui AA, Nazario H, Mahgoub A, Pandove S, Cipher D, Spechler SJ. The long-term use of statins is associated with a decreased incidence of adenomatous colon polyps. Digestion 2009; 79: 17-22 [PMID: 19246916 DOI: 10.1159/000203636]
39. Siddiqui AA, Nazario H, Mahgoub A, Patel M, Cipher D, Spechler SJ. For patients with colorectal cancer, the longterm use of statins is associated with better clinical outcomes. Dig Dis Sci 2009; 54: 1307-1311 [PMID: 19337834 DOI: 10.1007/s10620-009-0790-8]
40. Drori S, Girnun GD, Tou L, Szwaya JD, Mueller E, Xia K, Shivdasani RA, Spiegelman BM. Hic-5 regulates an epithelial program mediated by PPARgamma. Genes Dev 2005; 19: 362-375 [PMID: 15687259 DOI: 10.1101/gad.1240705]
41. Gupta RA, Brockman JA, Sarraf P, Willson TM, DuBois RN. Target genes of peroxisome proliferator-activated receptor gamma in colorectal cancer cells. J Biol Chem 2001; 276: 29681-29687 [PMID: 11397807 DOI: 10.1074/jbc.M103779200]
42. Sarraf P, Mueller E, Jones D, King FJ, DeAngelo DJ, Partridge JB, Holden SA, Chen LB, Singer S, Fletcher C, Spiegelman BM. Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nat Med 1998; 4: 1046-1052 [PMID: 9734398 DOI: 10.1038/2030]
43. Yoshizumi T, Ohta T, Ninomiya I, Terada I, Fushida S, Fujimura T, Nishimura G, Shimizu K, Yi S, Miwa K. Thiazolidinedione, a peroxisome proliferator-activated receptorgamma ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation-promoting effects. Int J Oncol 2004; 25: 631-639 [PMID: 15289864]
44. Peters JM, Shah YM, Gonzalez FJ. The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat Rev Cancer 2012; 12: 181-195 [PMID: 22318237 DOI: 10.1038/nrc3214]
45. Colmers IN, Bowker SL, Johnson JA. Thiazolidinedione use and cancer incidence in type 2 diabetes: a systematic review and meta-analysis. Diabetes Metab 2012; 38: 475-484 [PMID: 23041441 DOI: 10.1016/j.diabet.2012.06.003]
46. Chen SW, Tsan YT, Chen JD, Hsieh HI, Lee CH, Lin HH, Wang JD, Chen PC. Use of thiazolidinediones and the risk of colorectal cancer in patients with diabetes: a nationwide, population-based, case-control study. Diabetes Care 2013; 36: 369-375 [PMID: 23043163 DOI: 10.2337/dc11-2197]
47. Grommes C, Landreth GE, Heneka MT. Antineoplastic effects of peroxisome proliferator-activated receptor gamma agonists. Lancet Oncol 2004; 5: 419-429 [PMID: 15231248 DOI: 10.1016/S1470-2045(04)01509-8]
48. Koeffler HP. Peroxisome proliferator-activated receptor gamma and cancers. Clin Cancer Res 2003; 9: 1-9 [PMID: 12538445]
49. Ogino S, Shima K, Baba Y, Nosho K, Irahara N, Kure S, Chen L, Toyoda S, Kirkner GJ, Wang YL, Giovannucci EL, Fuchs CS. Colorectal cancer expression of peroxisome proliferatoractivated receptor gamma (PPARG, PPARgamma) is associated with good prognosis. Gastroenterology 2009; 136: 1242-1250 [PMID: 19186181 DOI: 10.1053/j.gastro.2008.12.048]
50. McAlpine CA, Barak Y, Matise I, Cormier RT. Intestinalspecific PPARgamma deficiency enhances tumorigenesis in ApcMin/+ mice. Int J Cancer 2006; 119: 2339-2346 [PMID: 16858678 DOI: 10.1002/ijc.22115]
51. Lefebvre AM, Chen I, Desreumaux P, Najib J, Fruchart JC, Geboes K, Briggs M, Heyman R, Auwerx J. Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. Nat Med 1998; 4: 1053-1057 [PMID: 9734399 DOI: 10.1038/2036]
52. Saez E, Tontonoz P, Nelson MC, Alvarez JG, Ming UT, Baird SM, Thomazy VA, Evans RM. Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat Med 1998; 4: 1058-1061 [PMID: 9734400 DOI: 10.1038/2042]
53. Pino MV, Kelley MF, Jayyosi Z. Promotion of colon tumors in C57BL/6J-APC(min)/+ mice by thiazolidinedione PPARgamma agonists and a structurally unrelated PPARgamma agonist. Toxicol Pathol 2004; 32: 58-63 [PMID: 14713549 DOI: 10.1080/01926230490261320]
54. Yang K, Fan KH, Lamprecht SA, Edelmann W, Kopelovich L, Kucherlapati R, Lipkin M. Peroxisome proliferator-activated receptor gamma agonist troglitazone induces colon tumors in normal C57BL/6J mice and enhances colonic carcinogenesis in Apc1638 N/+ Mlh1+/-double mutant mice. Int J Cancer 2005; 116: 495-499 [PMID: 15818612 DOI: 10.1002/ ijc.21018]
55. Erdmann E, Charbonnel B, Wilcox R. Thiazolidinediones and cardiovascular risk-a question of balance. Curr Cardiol Rev 2009; 5: 155-165 [PMID: 20676274 DOI: 10.2174/15734030 9788970333]
56. Grey A, Bolland M, Gamble G, Wattie D, Horne A, Davidson J, Reid IR. The peroxisome proliferator-activated receptorgamma agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab 2007; 92: 1305-1310 [PMID: 17264176 DOI: 10.1210/jc.2006-2646]
57. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O'Neill MC, Zinman B, Viberti G. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355: 2427-2443 [PMID: 17145742 DOI: 10.1056/NEJMoa066224]
58. Schwartz AV, Sellmeyer DE. Thiazolidinedione therapy gets complicated: is bone loss the price of improved insulin resistance? Diabetes Care 2007; 30: 1670-1671 [PMID: 17526825 DOI: 10.2337/dc07-0554]
59. Piccinni C, Motola D, Marchesini G, Poluzzi E. Assessing the association of pioglitazone use and bladder cancer through drug adverse event reporting. Diabetes Care 2011; 34: 1369-1371 [PMID: 21515844 DOI: 10.2337/dc10-2412]
60. Currie CJ, Poole CD, Gale EA. The influence of glucoselowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009; 52: 1766-1777 [PMID: 19572116 DOI: 10.1007/ s00125-009-1440-6]
61. Lee JH, Kim TI, Jeon SM, Hong SP, Cheon JH, Kim WH. The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus. Int J Cancer 2012; 131: 752-759 [PMID: 21913184 DOI: 10.1002/ijc.26421]
62. Garrett CR, Hassabo HM, Bhadkamkar NA, Wen S, Baladandayuthapani V, Kee BK, Eng C, Hassan MM. Survival advantage observed with the use of metformin in patients with type II diabetes and colorectal cancer. Br J Cancer 2012; 106: 1374-1378 [PMID: 22421948 DOI: 10.1038/bjc.2012.71]
63. Zhang ZJ, Zheng ZJ, Kan H, Song Y, Cui W, Zhao G, Kip KE. Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis. Diabetes Care 2011; 34: 2323-2328 [PMID: 21949223 DOI: 10.2337/ dc11-0512]
64. Hsieh MC, Lee TC, Cheng SM, Tu ST, Yen MH, Tseng CH. The influence of type 2 diabetes and glucose-lowering therapies on cancer risk in the Taiwanese. Exp Diabetes Res 2012; 2012: 413782 [PMID: 22719752 DOI: 10.1155/2012/413782]
65. Lee JH, Jeon SM, Hong SP, Cheon JH, Kim TI, Kim WH. Metformin use is associated with a decreased incidence of colorectal adenomas in diabetic patients with previous colorectal cancer. Dig Liver Dis 2012; 44: 1042-1047 [PMID: 22789400 DOI: 10.1016/j.dld.2012.06.007]
66. Algire C, Amrein L, Zakikhani M, Panasci L, Pollak M. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer 2010; 17: 351-360 [PMID: 20228137 DOI: 10.1677/ ERC-09-0252]
67. Hosono K, Endo H, Takahashi H, Sugiyama M, Uchiyama T, Suzuki K, Nozaki Y, Yoneda K, Fujita K, Yoneda M, Inamori M, Tomatsu A, Chihara T, Shimpo K, Nakagama H, Nakajima A. Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase. Mol Carcinog 2010; 49: 662-671 [PMID: 20564343 DOI: 10.1002/mc.20637]
68. Emami Riedmaier A, Fisel P, Nies AT, Schaeffeler E, Schwab M. Metformin and cancer: from the old medicine cabinet to pharmacological pitfalls and prospects. Trends Pharmacol Sci 2013; 34: 126-135 [PMID: 23277337 DOI: 10.1016/ j.tips.2012.11.005]
69. Sarbassov DD, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol 2005; 17: 596-603 [PMID: 16226444 DOI: 10.1016/j.ceb.2005.09.009]
70. Hosono K, Endo H, Takahashi H, Sugiyama M, Sakai E, Uchiyama T, Suzuki K, Iida H, Sakamoto Y, Yoneda K, Koide T, Tokoro C, Abe Y, Inamori M, Nakagama H, Nakajima A. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res (Phila) 2010; 3: 1077-1083 [PMID: 20810669 DOI: 10.1158/1940-6207. capr-10-0186]
71. Higurashi T, Takahashi H, Endo H, Hosono K, Yamada E, Ohkubo H, Sakai E, Uchiyama T, Hata Y, Fujisawa N, Uchiyama S, Ezuka A, Nagase H, Kessoku T, Matsuhashi N, Yamanaka S, Inayama Y, Morita S, Nakajima A. Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial. BMC Cancer 2012; 12: 118 [PMID: 22443173 DOI: 10.1186/1471-2407-12-118]
72. Asano TK, McLeod RS. Non steroidal anti-inflammatory drugs (NSAID) and Aspirin for preventing colorectal adenomas and carcinomas. Cochrane Database Syst Rev 2004; (2): CD004079 [PMID: 15106236 DOI: 10.1002/14651858. CD004079.pub2]
73. Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk E, Bertagnolli M. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005; 352: 1071-1080 [PMID: 15713944 DOI: 10.1056/NEJMoa050405]
74. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487: 330-337 [PMID: 22810696 DOI: 10.1038/nature11252]
75. van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 2009; 71: 241-260 [PMID: 18808327 DOI: 10.1146/annurev. physiol.010908.163145]
76. Vaiopoulos AG, Kostakis ID, Koutsilieris M, Papavassiliou AG. Colorectal cancer stem cells. Stem Cells 2012; 30: 363-371 [PMID: 22232074 DOI: 10.1002/stem.1031]
77. Yan KS, Chia LA, Li X, Ootani A, Su J, Lee JY, Su N, Luo Y, Heilshorn SC, Amieva MR, Sangiorgi E, Capecchi MR, Kuo CJ. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc Natl Acad Sci USA 2012; 109: 466-471 [PMID: 22190486 DOI: 10.1073/ pnas.1118857109]
78. Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007; 449: 1003-1007 [PMID: 17934449 DOI: 10.1038/nature06196]
79. Montgomery RK, Carlone DL, Richmond CA, Farilla L, Kranendonk ME, Henderson DE, Baffour-Awuah NY, Ambruzs DM, Fogli LK, Algra S, Breault DT. Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proc Natl Acad Sci USA 2011; 108: 179-184 [PMID: 21173232 DOI: 10.1073/pnas.1013004108]
80. Powell AE, Wang Y, Li Y, Poulin EJ, Means AL, Washington MK, Higginbotham JN, Juchheim A, Prasad N, Levy SE, Guo Y, Shyr Y, Aronow BJ, Haigis KM, Franklin JL, Coffey RJ. The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 2012; 149: 146-158 [PMID: 22464327 DOI: 10.1016/j.cell.2012.02.042]
81. Harada K, Higaki S, Amano A, Hashimoto K, Hashimoto S, Gondo T, Sakaida I. A reduced COX-2 expression and a reduced number of pericryptal myofibroblasts are associated with depressed adenoma of the colon. Oncol Rep 2007; 17: 1353-1358 [PMID: 17487390]
82. Andoh A, Bamba S, Brittan M, Fujiyama Y, Wright NA. Role of intestinal subepithelial myofibroblasts in inflammation and regenerative response in the gut. Pharmacol Ther 2007; 114: 94-106 [PMID: 17328956 DOI: 10.1016/j.pharmthera.200 6.12.004]
83. Kim JH, Oh SH, Kim EJ, Park SJ, Hong SP, Cheon JH, Kim TI, Kim WH. The role of myofibroblasts in upregulation of S100A8 and S100A9 and the differentiation of myeloid cells in the colorectal cancer microenvironment. Biochem Biophys Res Commun 2012; 423: 60-66 [PMID: 22634002 DOI: 10.1016/ j.bbrc.2012.05.081]
84. Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 2007; 117: 1155-1166 [PMID: 17476345 DOI: 10.1172/JCI31422]
85. Adegboyega PA, Mifflin RC, DiMari JF, Saada JI, Powell DW. Immunohistochemical study of myofibroblasts in normal colonic mucosa, hyperplastic polyps, and adenomatous colorectal polyps. Arch Pathol Lab Med 2002; 126: 829-836 [PMID: 12088453 DOI: 10.1043/0003-9985(2002)126]
86. Medema JP, Vermeulen L. Microenvironmental regulation of stem cells in intestinal homeostasis and cancer. Nature 2011; 474: 318-326 [PMID: 21677748 DOI: 10.1038/nature10212]
87. Zhu L, Gibson P, Currle DS, Tong Y, Richardson RJ, Bayazitov IT, Poppleton H, Zakharenko S, Ellison DW, Gilbertson RJ. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 2009; 457: 603-607 [PMID: 19092805 DOI: 10.1038/nature07589]
88. Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, Danenberg E, Clarke AR, Sansom OJ, Clevers H. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 2009; 457: 608-611 [PMID: 19092804 DOI: 10.1038/nature07602]
89. Ziskin JL, Dunlap D, Yaylaoglu M, Fodor IK, Forrest WF, Patel R, Ge N, Hutchins GG, Pine JK, Quirke P, Koeppen H, Jubb AM. In situ validation of an intestinal stem cell signature in colorectal cancer. Gut 2013; 62: 1012-1023 [PMID: 22637696 DOI: 10.1136/gutjnl-2011-301195]
90. O'Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007; 445: 106-110 [PMID: 17122772 DOI: 10.1038/nature05372]
91. Merlos-Suárez A, Barriga FM, Jung P, Iglesias M, Céspedes MV, Rossell D, Sevillano M, Hernando-Momblona X, da Silva-Diz V, Muñoz P, Clevers H, Sancho E, Mangues R, Batlle E. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 2011; 8: 511-524 [PMID: 21419747 DOI: 10.1016/ j.stem.2011.02.020]
92. Todaro M, Francipane MG, Medema JP, Stassi G. Colon cancer stem cells: promise of targeted therapy. Gastroenterology 2010; 138: 2151-2162 [PMID: 20420952 DOI: 10.1053/ j.gastro.2009.12.063]
93. Nakanishi Y, Seno H, Fukuoka A, Ueo T, Yamaga Y, Maruno T, Nakanishi N, Kanda K, Komekado H, Kawada M, Isomura A, Kawada K, Sakai Y, Yanagita M, Kageyama R, Kawaguchi Y, Taketo MM, Yonehara S, Chiba T. Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nat Genet 2013; 45: 98-103 [PMID: 23202126 DOI: 10.1038/ng.2481]
94. Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994; 107: 1183-1188 [PMID: 7926468]
95. Xia D, Wang D, Kim SH, Katoh H, DuBois RN. Prostaglandin E2 promotes intestinal tumor growth via DNA methylation. Nat Med 2012; 18: 224-226 [PMID: 22270723 DOI: 10.1038/nm.2608]
96. Wang D, Dubois RN. The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene 2010; 29: 781-788 [PMID: 19946329 DOI: 10.1038/onc.2009.421]
97. Williams CS, Luongo C, Radhika A, Zhang T, Lamps LW, Nanney LB, Beauchamp RD, DuBois RN. Elevated cyclooxygenase-2 levels in Min mouse adenomas. Gastroenterology 1996; 111: 1134-1140 [PMID: 8831610 DOI: 10.1016/ S0016-5085(96)70083-5]
98. Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, Trzaskos JM, Evans JF, Taketo MM. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 1996; 87: 803-809 [PMID: 8945508 DOI: 10.1016/S0092-8674(00)81988-1]
99. Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science 2005; 310: 1504-1510 [PMID: 16293724 DOI: 10.1126/science. 1116221]
100. Takahashi-Yanaga F, Kahn M. Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin Cancer Res 2010; 16: 3153-3162 [PMID: 20530697 DOI: 10.1158/1078-0432. ccr-09-2943]
101. Moon CM, Kwon JH, Kim JS, Oh SH, Jin Lee K, Park JJ, Pil Hong S, Cheon JH, Kim TI, Kim WH. Nonsteroidal antiinflammatory drugs suppress cancer stem cells via inhibiting PTGS2 (cyclooxygenase 2) and NOTCH/HES1 and activating PPARG in colorectal cancer. Int J Cancer 2014; 134: 519-529 [PMID: 23852449 DOI: 10.1002/ijc.28381]
102. Tegeder I, Pfeilschifter J, Geisslinger G. Cyclooxygenaseindependent actions of cyclooxygenase inhibitors. FASEB J 2001; 15: 2057-2072 [PMID: 11641233 DOI: 10.1096/fj.01-0390rev]
103. Zhang H, Ye Y, Bai Z, Wang S. The COX-2 selective inhibitorindependent COX-2 effect on colon carcinoma cells is associated with the Delta1/Notch1 pathway. Dig Dis Sci 2008; 53: 2195-2203 [PMID: 18320325 DOI: 10.1007/s10620-007-0139-0]
104. Beher D, Clarke EE, Wrigley JD, Martin AC, Nadin A, Churcher I, Shearman MS. Selected non-steroidal antiinflammatory drugs and their derivatives target gammasecretase at a novel site. Evidence for an allosteric mechanism. J Biol Chem 2004; 279: 43419-43426 [PMID: 15304503 DOI: 10.1074/jbc.M404937200]
105. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA. Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem 1997; 272: 3406-3410 [PMID: 9013583 DOI: 10.1074/jbc.272.6.3406]
106. Vaish V, Tanwar L, Sanyal SN. The role of NF-κB and PPARγ in experimentally induced colorectal cancer and chemoprevention by cyclooxygenase-2 inhibitors. Tumour Biol 2010; 31: 427-436 [PMID: 20514536 DOI: 10.1007/ s13277-010-0051-7]
107. Katoh M, Katoh M. Notch signaling in gastrointestinal tract (review). Int J Oncol 2007; 30: 247-251 [PMID: 17143535]
108. Sikandar SS, Pate KT, Anderson S, Dizon D, Edwards RA, Waterman ML, Lipkin SM. NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer. Cancer Res 2010; 70: 1469-1478 [PMID: 20145124 DOI: 10.1158/0008-5472.can-09-2557]
109. Chearwae W, Bright JJ. PPARgamma agonists inhibit growth and expansion of CD133+ brain tumour stem cells. Br J Cancer 2008; 99: 2044-2053 [PMID: 19018263 DOI: 10.1038/ sj.bjc.6604786]
110. Qiu W, Wang X, Leibowitz B, Liu H, Barker N, Okada H, Oue N, Yasui W, Clevers H, Schoen RE, Yu J, Zhang L. Chemoprevention by nonsteroidal anti-inflammatory drugs eliminates oncogenic intestinal stem cells via SMAC-dependent apoptosis. Proc Natl Acad Sci USA 2010; 107: 20027-20032 [PMID: 21041628 DOI: 10.1073/pnas.1010430107]
111. Li Y, Wicha MS, Schwartz SJ, Sun D. Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds. J Nutr Biochem 2011; 22: 799-806 [PMID: 21295962 DOI: 10.1016/j.jnutbio.2010.11.001]
112. Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C, Liu S, Dontu G, Wicha MS. Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat 2010; 122: 777-785 [PMID: 19898931 DOI: 10.1007/s10549-009-0612-x]
113. Li Y, Zhang T, Korkaya H, Liu S, Lee HF, Newman B, Yu Y, Clouthier SG, Schwartz SJ, Wicha MS, Sun D. Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res 2010; 16: 2580-2590 [PMID: 20388854 DOI: 10.1158/1078-0432.ccr-09-2937]
114. Kodach LL, Jacobs RJ, Voorneveld PW, Wildenberg ME, Verspaget HW, van Wezel T, Morreau H, Hommes DW, Peppelenbosch MP, van den Brink GR, Hardwick JC. Statins augment the chemosensitivity of colorectal cancer cells inducing epigenetic reprogramming and reducing colorectal cancer cell 'stemness' via the bone morphogenetic protein pathway. Gut 2011; 60: 1544-1553 [PMID: 21551187 DOI: 10.1136/gut.2011.237495]
115. Vermeulen L, De Sousa E, Melo F, van der Heijden M, Cameron K, de Jong JH, Borovski T, Tuynman JB, Todaro M, Merz C, Rodermond H, Sprick MR, Kemper K, Richel DJ, Stassi G, Medema JP. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 2010; 12: 468-476 [PMID: 20418870 DOI: 10.1038/ncb2048]
116. Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Göktuna SI, Ziegler PK, Canli O, Heijmans J, Huels DJ, Moreaux G, Rupec RA, Gerhard M, Schmid R, Barker N, Clevers H, Lang R, Neumann J, Kirchner T, Taketo MM, van den Brink GR, Sansom OJ, Arkan MC, Greten FR. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stemcell-like properties. Cell 2013; 152: 25-38 [PMID: 23273993 DOI: 10.1016/j.cell.2012.12.012]
117. Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci USA 2013; 110: 972-977 [PMID: 23277563 DOI: 10.1073/ pnas.1221055110]
118. Arai M, Uchiba M, Komura H, Mizuochi Y, Harada N, Okajima K. Metformin, an antidiabetic agent, suppresses the production of tumor necrosis factor and tissue factor by inhibiting early growth response factor-1 expression in human monocytes in vitro. J Pharmacol Exp Ther 2010; 334: 206-213 [PMID: 20371705 DOI: 10.1124/jpet.109.164970]
119. Salminen A, Hyttinen JM, Kaarniranta K. AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. J Mol Med (Berl) 2011; 89: 667-676 [PMID: 21431325 DOI: 10.1007/s00109-011-0748-0]
120. Pascual G, Fong AL, Ogawa S, Gamliel A, Li AC, Perissi V, Rose DW, Willson TM, Rosenfeld MG, Glass CK. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 2005; 437: 759-763 [PMID: 16127449 DOI: 10.1038/nature03988]
121. Suh N, Reddy BS, DeCastro A, Paul S, Lee HJ, Smolarek AK, So JY, Simi B, Wang CX, Janakiram NB, Steele V, Rao CV. Combination of atorvastatin with sulindac or naproxen profoundly inhibits colonic adenocarcinomas by suppressing the p65/β-catenin/cyclin D1 signaling pathway in rats. Cancer Prev Res (Phila) 2011; 4: 1895-1902 [PMID: 21764859 DOI: 10.1158/1940-6207.capr-11-0222]
122. Schreiber S, Nikolaus S, Hampe J. Activation of nuclear factor kappa B inflammatory bowel disease. Gut 1998; 42: 477-484 [PMID: 9616307 DOI: 10.1136/gut.42.4.477]
123. Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 2012; 21: 297-308 [PMID: 22439925 DOI: 10.1016/j.ccr.2012.02.014]
124. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149: 274-293 [PMID: 22500797 DOI: 10.1016/j.cell.2012.03.017]
125. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007; 12: 9-22 [PMID: 17613433 DOI: 10.1016/j.ccr.2007.05.008]
126. Morgensztern D, McLeod HL. PI3K/Akt/mTOR pathway as a target for cancer therapy. Anticancer Drugs 2005; 16: 797-803 [PMID: 16096426 DOI: 10.1097/01.cad.0000173476.67239.3b]
127. Pollak MN. Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov 2012; 2: 778-790 [PMID: 22926251 DOI: 10.1158/2159-8290. CD-12-0263]
128. Ben Sahra I, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, Le Marchand-Brustel Y, Giorgetti-Peraldi S, Cormont M, Bertolotto C, Deckert M, Auberger P, Tanti JF, Bost F. Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res 2010; 70: 2465-2475 [PMID: 20215500 DOI: 10.1158/0008-5472.CAN-09-2782]
129. Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Marchand-Brustel Y, Bost F. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 2008; 27: 3576-3586 [PMID: 18212742 DOI: 10.1038/ sj.onc.1211024]
130. Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 2009; 69: 7507-7511 [PMID: 19752085 DOI: 10.1158/0008-5472.can-09-2994]
131. Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res 2011; 71: 3196-3201 [PMID: 21415163 DOI: 10.1158/0008-5472.can-10-3471]
132. Gou S, Cui P, Li X, Shi P, Liu T, Wang C. Low concentrations of metformin selectively inhibit CD133+ cell proliferation in pancreatic cancer and have anticancer action. PLoS One 2013; 8: e63969 [PMID: 23667692 DOI: 10.1371/journal. pone.0063969]
133. Cai Z, Ke J, He X, Yuan R, Chen Y, Wu X, Wang L, Wang J, Lan P, Wu X. Significance of mTOR signaling and its inhibitor against cancer stem-like cells in colorectal cancer. Ann Surg Oncol 2014; 21: 179-188 [PMID: 23907312 DOI: 10.1245/ s10434-013-3146-8]
134. Fang DD, Zhang CC, Gu Y, Jani JP, Cao J, Tsaparikos K, Yuan J, Thiel M, Jackson-Fisher A, Zong Q, Lappin PB, Hayashi T, Schwab RB, Wong A, John-Baptiste A, Bagrodia S, Los G, Bender S, Christensen J, Vanarsdale T. Antitumor Efficacy of the Dual PI3K/mTOR Inhibitor PF-04691502 in a Human Xenograft Tumor Model Derived from Colorectal Cancer Stem Cells Harboring a PIK3CA Mutation. PLoS One 2013; 8: e67258 [PMID: 23826249 DOI: 10.1371/journal. pone.0067258]
135. Huang J, Nguyen-McCarty M, Hexner EO, Danet-Desnoyers G, Klein PS. Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways. Nat Med 2012; 18: 1778-1785 [PMID: 23142822 DOI: 10.1038/nm.2984]
136. Ma L, Niknejad N, Gorn-Hondermann I, Dayekh K, Dimitroulakos J. Lovastatin induces multiple stress pathways including LKB1/AMPK activation that regulate its cytotoxic effects in squamous cell carcinoma cells. PLoS One 2012; 7: e46055 [PMID: 23029387 DOI: 10.1371/journal.pone.0046055]
137. Yasuda Y, Shimizu M, Shirakami Y, Sakai H, Kubota M, Hata K, Hirose Y, Tsurumi H, Tanaka T, Moriwaki H. Pitavastatin inhibits azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice. Cancer Sci 2010; 101: 1701-1707 [PMID: 20398056 DOI: 10.1111/ j.1349-7006.2010.01579.x]
138. Guh JH, Chang WL, Yang J, Lee SL, Wei S, Wang D, Kulp SK, Chen CS. Development of novel adenosine monophosphate-activated protein kinase activators. J Med Chem 2010; 53: 2552-2561 [PMID: 20170185 DOI: 10.1021/jm901773d]
139. Din FV, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K, Alessi DR, Dunlop MG. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 2012; 142: 1504-15.e3 [PMID: 22406476 DOI: 10.1053/ j.gastro.2012.02.050]
140. Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, Kemp BE, Sakamoto K, Steinberg GR, Hardie DG. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 2012; 336: 918-922 [PMID: 22517326 DOI: 10.1126/science.1215327]