Vitamins in pancreatic cancer: A review of underlying mechanisms and future applications

Advances in Nutrition

Volumn 6, Issue 6, 2015, Pages 774-802

  Davis Yadley, Ashley H ^a,b   Malafa, Mokenge P ^b  

^a UNIVERSITY OF SOUTH FLORIDA   (United States)

^b H LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA TOCOPHEROL; ASCORBIC ACID; RETINOL; VITAMIN; VITAMIN D; VITAMIN K GROUP;

ADENOCARCINOMA; APOPTOSIS; CELL PROLIFERATION; DIETARY SUPPLEMENT; DRUG EFFECTS; HUMAN; MULTIMODALITY CANCER THERAPY; PANCREATIC NEOPLASMS; PATHOLOGY; PREVENTION AND CONTROL; SURVIVAL RATE; TUMOR INVASION;

ADENOCARCINOMA; APOPTOSIS; ASCORBIC ACID; CELL PROLIFERATION; COMBINED MODALITY THERAPY; DIETARY SUPPLEMENTS; HUMANS; NEOPLASM INVASIVENESS; PANCREATIC NEOPLASMS; SURVIVAL RATE; VITAMIN A; VITAMIN D; VITAMIN E; VITAMIN K; VITAMINS;

EID: 84953258639     PISSN: 21618313     EISSN: 21565376     Source Type: Journal    
DOI: 10.3945/an.115.009456     Document Type: Review

References (146)

1. Howlander N, Noone AM, Krapcho M, Garshell J, Miller D, AltekruseSF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, et al. [Internet]. [cited 2014Jul 19]. Available from: http://seer.cancer.gov/csr/1975_2011/, basedon November 2013 data submission, posted to the SEER website.
2. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, BecouarnY, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C,et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.N Engl J Med 2011;364:1817-25.
3. Jones LW, Demark-Wahnefried W. Diet, exercise, and complementarytherapies after primary treatment for cancer. Lancet Oncol 2006;7:1017-26.
4. Velicer CM, Ulrich CM. Vitamin and mineral supplement use amongUS adults after cancer diagnosis: a systematic review. J Clin Oncol2008;26:665-73.
5. Giovannucci E, Chan AT. Role of vitamin and mineral supplementationand aspirin use in cancer survivors. J Clin Oncol 2010;28:4081-5.
6. Rock CL, Doyle C, Demark-Wahnefried W, Meyerhardt J, CourneyaKS, Schwartz AL, Bandera EV, Hamilton KK, Grant B, McCulloughM, et al. Nutrition and physical activity guidelines for cancer survivors.CA Cancer J Clin 2012;62:243-74.
7. National Institutes of HealthOffice of Dietary SupplementsVitamin A. [cited2015 Jun 29]. Available from: http://ods.od.nih.gov/factsheets/VitaminAHealthProfessional.
8. Alizadeh F, Bolhassani A, Khavari A, Bathaie SZ, Naji T, Bidgoli SA.Retinoids and their biological effects against cancer. Int Immunopharmacol2014;18:43-9.
9. Pili R, Salumbides B, Zhao M, Altiok S, Qian D, Zwiebel J, CarducciMA, Rudek MA. Phase I study of the histone deacetylase inhibitor entinostatin combination with 13-cis retinoic acid in patients with solidtumours. Br J Cancer 2012;106:77-84.
10. Kaiser A, Herbst H, Fisher G, KoenigsmannM, Berdel WE, Riecken EO,Rosewicz S. Retinoic acid receptor b regulates growth and differentiationin human pancreatic carcinoma cells. Gastroenterology 1997;113:920-9.
11. Riecken EO, Rosewicz S. Retinoids in pancreatic cancer. Ann Oncol1999;10: Suppl 4:197-200.
12. Rosewicz S, Vogt D, Harth N, Grund C, Franke WW, Ruppert S,Schweitzer E, Riecken EO, Wiedenmann B. An amphicrine pancreaticcell line: AR42J cells combine exocrine and neuroendocrine properties.Eur J Cell Biol 1992;59:80-91.
13. Boylan JF, Lohnes D, Taneja R, Chambon P, Gudas LJ. Loss of retinoicacid receptor g function in F9 cells by gene disruption results in aberrantHoxa-1 expression and differentiation upon retinoic acid treatment.Proc Natl Acad Sci USA 1993;90:9601-5.
14. Brembeck FH, Kaiser A, Detjen K, Hotz H, Foitzik T, Buhr HJ, Riecken EO,Rosewicz S. Retinoic acid receptor a mediates growth inhibition byretinoids in rat pancreatic carcinoma DSL-6A/C1 cells. Br J Cancer1998;78:1288-95.
15. Rosewicz S, Brembeck F, Kaiser A, Marschall ZV, Riecken EO. Differentialgrowth regulation by all-trans retinoic acid is determined byprotein kinase C a in human pancreatic carcinoma cells. Endocrinology1996;137:3340-7.
16. Terranova VP, Liotta LA, Russo RG, Martin GR. Role of laminin in the attachmentand metastasis ofmurine tumor cells. Cancer Res 1982;42:2265-9.
17. Graf J, Iwamoto Y, Sasaki M, Martin GR, Kleinman HK, Robey FA,Yamada Y. Identification of an amino acid sequence in laminin mediatingcell attachment, chemotaxis, and receptor binding. Cell 1987;48:989-96.
18. Grant DS, Tashiro K, Segui-Real B, Yamada Y, Martin GR, Kleinman HK.Two different laminin domains mediate the differentiation of human endothelialcells into capillary-like structures in vitro. Cell 1989;58:933-43.
19. Iwamoto Y, Robey FA, Graf J, Sasaki M, Kleinman HK, Yamada Y,Martin GR. YIGSR, a synthetic laminin pentapeptide, inhibits experimentalmetastasis formation. Science 1987;238:1132-4.
20. Rosewicz S, Wollbergs K, Von Lampe B, Matthes H, Kaiser A, RieckenEO. Retinoids inhibit adhesion to laminin in human pancreatic carcinomacells via the a 6 b 1-integrin receptor. Gastroenterology 1997;112:532-42.
21. Guan J, Zhang H, Wen Z, Gu Y, Cheng Y, Sun Y, Zhang T, Jia C, Lu Z,Chen J. Retinoic acid inhibits pancreatic cancer cell migration andEMT through the downregulation of IL-6 in cancer associated fibroblastcells. Cancer Lett 2014;345:132-9.
22. Hsu HC, Tsai WH, Chen PG, Hsu ML, Ho CK,Wang SY. In vitro effectof granulocyte-colony stimulating factor and all-trans retinoic acid onthe expression of inflammatory cytokines and adhesion molecules inacute promyelocytic leukemic cells. Eur J Haematol 1999;63:11-8.
23. van Neerven S, Nemes A, Imholz P, Regen T, Denecke B, Johann S,Beyer C, Hanisch UK, Mey J. Inflammatory cytokine release of astrocytesin vitro is reduced by all-trans retinoic acid. J Neuroimmunol2010;229:169-79.
24. Wieser F, Wu J, Shen Z, Taylor RN, Sidell N. Retinoic acid suppressesgrowth of lesions, inhibits peritoneal cytokine secretion, and promotesmacrophage differentiation in an immunocompetent mousemodel of endometriosis. Fertil Steril 2012;97:1430-7.
25. Hasebe T. Tumor-stromal interactions in breast tumor progression-significance of histological heterogeneity of tumor-stromal fibroblasts.Expert Opin Ther Targets 2013;17:449-60.
26. Karagiannis GS, Poutahidis T, Erdman SE, Kirsch R, Riddell RH,Diamandis EP. Cancer-associated fibroblasts drive the progression ofmetastasis through both paracrine and mechanical pressure on cancertissue. Mol Cancer Res 2012;10:1403-18.
27. Leef G, Thomas SM. Molecular communication between tumorassociatedfibroblasts and head and neck squamous cell carcinoma.Oral Oncol 2013;49:381-6.
28. Mahadevan D, Von Hoff DD. Tumor-stroma interactions in pancreaticductal adenocarcinoma. Mol Cancer Ther 2007;6:1186-97.
29. Mao Y, Keller ET, Garfield DH, Shen K, Wang J. Stromal cells in tumormicroenvironment and breast cancer. Cancer Metastasis Rev 2013;32:303-15.
30. Recchia F, Sica G, Candeloro G, Bisegna R, Bratta M, Bonfili P,Necozione S, Tombolini V, Rea S. Chemoradioimmunotherapy in locallyadvanced pancreatic and biliary tree adenocarcinoma: a multicenterphase II study. Pancreas 2009;38:e163-8.
31. Moore DF, Jr., Pazdur R, Sugarman S, Jones, 3rd D, Lippman SM,Bready B, Abbruzzese JL. Pilot phase II trial of 13-cis-retinoic acidand interferon-a combination therapy for advanced pancreatic adenocarcinoma.Am J Clin Oncol 1995;18:525-7.
32. Brembeck FH, Schoppmeyer K, Leupold U, Gornistu C, Keim V,Mossner J, Riecken EO, Rosewicz S. A phase II pilot trial of 13-cis retinoicacid and interferon-a in patients with advanced pancreatic carcinoma.Cancer 1998;83:2317-23.
33. Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D, Gerbing RB, London WB, Villablanca JG. Long-term resultsfor children with high-risk neuroblastoma treated on a randomized trialof myeloablative therapy followed by 13-cis-retinoic acid: a children'soncology group study. J Clin Oncol 2009;27:1007-13.
34. Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, RamsayNK, Swift P, Shimada H, Black CT, Brodeur GM, et al. Treatment ofhigh-risk neuroblastoma with intensive chemotherapy, radiotherapy,autologous bone marrow transplantation, and 13-cis-retinoic acid.Children's Cancer Group. N Engl J Med 1999;341:1165-73.
35. Villablanca JG, Khan AA, Avramis VI, Seeger RC, Matthay KK,Ramsay NK, Reynolds CP. Phase I trial of 13-cis-retinoic acid inchildren with neuroblastoma following bone marrow transplantation.J Clin Oncol 1995;13:894-901.
36. Chen Q, Espey MG, Krishna MC, Mitchell JB, Corpe CP, BuettnerGR, Shacter E, Levine M. Pharmacologic ascorbic acid concentrationsselectively kill cancer cells: action as a pro-drug to deliver hydrogenperoxide to tissues. Proc Natl Acad Sci USA 2005;102:13604-9.
37. Du J, Martin SM, Levine M, Wagner BA, Buettner GR, Wang SH,Taghiyev AF, Du C, Knudson CM, Cullen JJ. Mechanisms of ascorbateinducedcytotoxicity in pancreatic cancer. Clin Cancer Res 2010;16:509-20.
38. Chen Q, Espey MG, Sun AY, Lee JH, Krishna MC, Shacter E, ChoykePL, Pooput C, Kirk KL, Buettner GR, et al. Ascorbate in pharmacologicconcentrations selectively generates ascorbate radical and hydrogenperoxide in extracellular fluid in vivo. Proc Natl Acad Sci USA2007;104:8749-54.
39. Pike JW, Meyer MB, Bishop KA. Regulation of target gene expressionby the vitamin D receptor - an update on mechanisms. Rev EndocrMetab Disord 2012;13:45-55.
40. Rattan R, Giri S, Singh AK, Singh I. 5-Aminoimidazole-4-carboxamide-1-b-D-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo viaAMP-activated protein kinase. J Biol Chem 2005;280:39582-93.
41. Persons KS, EddyVJ, Chadid S, Deoliveira R, Saha AK,Ray R. Anti-growtheffect of 1,25-dihydroxyvitamin D3-3-bromoacetate alone or in combinationwith 5-amino-imidazole-4-carboxamide-1-b-4-ribofuranoside inpancreatic cancer cells. Anticancer Res 2010;30:1875-80.
42. Robey RB, Hay N. Is Akt the "Warburg kinase"?-Akt-energy metabolisminteractions and oncogenesis. Semin Cancer Biol 2009;19:25-31.
43. Bouillon R, Eelen G, Verlinden L, Mathieu C, Carmeliet G, Verstuyf A.Vitamin D and cancer. J Steroid Biochem Mol Biol 2006;102:156-62.
44. Chiang KC, Chen TC. Vitamin D for the prevention and treatment ofpancreatic cancer. World J Gastroenterol 2009;15:3349-54.
45. Kawa S, Nikaido T, Aoki Y, Zhai Y, Kumagai T, Furihata K, Fujii S,Kiyosawa K. Vitamin D analogues up-regulate p21 and p27 during growthinhibition of pancreatic cancer cell lines. Br J Cancer 1997;76:884-9.
46. Chiang KC, Yeh CN, Hsu JT, Jan YY, Chen LW, Kuo SF, Takano M,Kittaka A, Chen TC, Chen WT, et al. The vitamin D analog, MART-10, represses metastasis potential via downregulation of epithelialmesenchymaltransition in pancreatic cancer cells. Cancer Lett 2014;354:235-44.
47. Schwartz GG, Eads D, Rao A, Cramer SD, Willingham MC, Chen TC,Jamieson DP, Wang L, Burnstein KL, Holick MF, et al. Pancreatic cancercells express 25-hydroxyvitamin D-1 a-hydroxylase and their proliferationis inhibited by the prohormone 25-hydroxyvitamin D3.Carcinogenesis 2004;25:1015-26.
48. Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao PJ. Thenuclear factor-kappa B RelA transcription factor is constitutively activatedin human pancreatic adenocarcinoma cells. Clin Cancer Res1999;5:119-27.
49. Husain K, Francois RA, Yamauchi T, Perez M, Sebti SM, Malafa MP.Vitamin E d-tocotrienol augments the antitumor activity of gemcitabineand suppresses constitutive NF-kB activation in pancreatic cancer.Mol Cancer Ther 2011;10:2363-72.
50. Evans TR, Colston KW, Lofts FJ, Cunningham D, Anthoney DA,Gogas H, de Bono JS, Hamberg KJ, Skov T, Mansi JL. A phase II trialof the vitamin D analogue Seocalcitol (EB1089) in patients with inoperablepancreatic cancer. Br J Cancer 2002;86:680-5.
51. Arlt A, Gehrz A, Muerkoster S, Vorndamm J, Kruse ML, Folsch UR,Schafer H. Role of NF-kB and Akt/PI3K in the resistance of pancreaticcarcinoma cell lines against gemcitabine-induced cell death. Oncogene2003;22:3243-51.
52. Kong R, Sun B, Jiang H, Pan S, Chen H, Wang S, Krissansen GW, SunX. Downregulation of nuclear factor-kB p65 subunit by small interferingRNA synergizes with gemcitabine to inhibit the growth of pancreaticcancer. Cancer Lett 2010;291:90-8.
53. Kong R, Sun B, Wang SJ, Pan SH, Wang G, Chen H, Xue DB, JiangHC. [An experimental study of gemcitabine inducing pancreatic cancercell apoptosis potentiated by nuclear factor-kappa B P65 siRNA]Zhonghua Wai Ke Za Zhi 2010;48:128-33.
54. Pan X, Arumugam T, Yamamoto T, Levin PA, Ramachandran V, Ji B,Lopez-Berestein G, Vivas-Mejia PE, Sood AK, McConkey DJ, et al.Nuclear factor-kappaB p65/relA silencing induces apoptosis and increasesgemcitabine effectiveness in a subset of pancreatic cancer cells.Clin Cancer Res 2008;14:8143-51.
55. Boucher MJ, Morisset J, Vachon PH, Reed JC, Laine J, Rivard N.MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells.J Cell Biochem 2000;79:355-69.
56. Shin-Kang S, Ramsauer VP, Lightner J, Chakraborty K, StoneW, CampbellS, Reddy SA, Krishnan K. Tocotrienols inhibit AKT and ERK activationand suppress pancreatic cancer cell proliferation by suppressingthe ErbB2 pathway. Free Radic Biol Med 2011;51:1164-74.
57. Hussein D, Mo H. d-d-Tocotrienol-mediated suppression of the proliferationof human PANC-1, MIA PaCa-2, and BxPC-3 pancreaticcarcinoma cells. Pancreas 2009;38:e124-36.
58. Hodul PJ, Dong Y, Husain K, Pimiento JM, Chen J, Zhang A, Francois R,PledgerWJ, Coppola D, Sebti SM, et al. Vitamin E d-tocotrienol inducesp27(Kip1)-dependent cell-cycle arrest in pancreatic cancer cellsvia an E2F-1-dependent mechanism. PLoS One 2013;8:e52526.
59. Chu IM, Hengst L, Slingerland JM. The Cdk inhibitor p27 in humancancer: prognostic potential and relevance to anticancer therapy. NatRev Cancer 2008;8:253-67.
60. Patacsil D, Osayi S, Tran AT, Saenz F, Yimer L, Shajahan AN, GokhalePC, Verma M, Clarke R, Chauhan SC, et al. Vitamin E succinate inhibitssurvivin and induces apoptosis in pancreatic cancer cells. GenesNutr 2012;7:83-9.
61. Green DR, Kroemer G. The pathophysiology of mitochondrial celldeath. Science 2004;305:626-9.
62. Newmeyer DD, Ferguson-Miller S. Mitochondria: releasing power for lifeand unleashing the machineries of death. Cell 2003;112:481-90.
63. Greco E, Basso D, Fadi E, Padoan A, Fogar P, Zambon CF, Navaglia F,Bozzato D, Moz S, Pedrazzoli S, et al. Analogs of vitamin E epitomizedby a-tocopheryl succinate for pancreatic cancer treatment: in vitroresults induce caution for in vivo applications. Pancreas 2010;39:662-8.
64. Wei G, Wang M, Carr BI. Sorafenib combined vitamin K induces apoptosisin human pancreatic cancer cell lines through RAF/MEK/ERKand c-Jun NH2-terminal kinase pathways. J Cell Physiol 2010;224:112-9.
65. Shibayama-Imazu T, Sakairi S, Watanabe A, Aiuchi T, Nakajo S,Nakaya K. Vitamin K(2) selectively induced apoptosis in ovarianTYK-nu and pancreatic MIA PaCa-2 cells out of eight solid tumorcell lines through a mechanism different from geranylgeraniol. J CancerRes Clin Oncol 2003;129:1-11.
66. Sata N, Klonowski-Stumpe H, Han B, Haussinger D, Niederau C.Menadione induces both necrosis and apoptosis in rat pancreatic acinarAR4-2J cells. Free Radic Biol Med 1997;23:844-50.
67. Kraemer C. Vitamin K [Internet]. [cited 2015 Jun 27]. Available from:http://emedicine.medscape.com/article/2088738-overview.
68. Chen Q, Espey MG, Sun AY, Pooput C, Kirk KL, Krishna MC, KhoshDB, Drisko J, Levine M. Pharmacologic doses of ascorbate act as aprooxidant and decrease growth of aggressive tumor xenografts inmice. Proc Natl Acad Sci USA 2008;105:11105-9.
69. Espey MG, Chen P, Chalmers B, Drisko J, Sun AY, Levine M, Chen Q.Pharmacologic ascorbate synergizes with gemcitabine in preclinicalmodels of pancreatic cancer. Free Radic Biol Med 2011;50:1610-9.
70. Chiang KC, Yeh CN, Hsu JT, Yeh TS, Jan YY,Wu CT, Chen HY, Jwo SC,Takano M, Kittaka A, et al. Evaluation of the potential therapeutic roleof a new generation of vitamin D analog, MART-10, in human pancreaticcancer cells in vitro and in vivo. Cell Cycle 2013;12:1316-25.
71. Husain K, Francois RA, Hutchinson SZ, Neuger AM, Lush R, CoppolaD, Sebti S, Malafa MP. Vitamin E d-tocotrienol levels in tumor andpancreatic tissue of mice after oral administration. Pharmacology2009;83:157-63.
72. Kunnumakkara AB, Sung B, Ravindran J, Diagaradjane P, DeorukhkarA, Dey S, Koca C, Yadav VR, Tong Z, Gelovani JG, et al. g-Tocotrienolinhibits pancreatic tumors and sensitizes them to gemcitabine treatmentby modulating the inflammatory microenvironment. CancerRes 2010;70:8695-705.
73. Husain K, Centeno BA, Chen DT, Fulp WJ, Perez M, Zhang Lee G,Luetteke N, Hingorani SR, Sebti SM, Malafa MP. Prolonged survivaland delayed progression of pancreatic intraepithelial neoplasia in LSLKrasG12D/+;Pdx-1-Cre mice by vitamin E d-tocotrienol. Carcinogenesis2013;34:858-63.
74. Husain K, Centeno BA, Chen DT, Hingorani SR, Sebti SM,Malafa MP. Vitamin E d-tocotrienol prolongs survival in the LSLKrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) transgenic mousemodel of pancreatic cancer. Cancer Prev Res (Phila) 2013;6:1074-83.
75. Heisler T, Towfigh S, Simon N, Liu C, McFadden DW. Peptide YYaugmentsgross inhibition by vitamin E succinate of human pancreaticcancer cell growth. J Surg Res 2000;88:23-5.
76. Ohlsson B, Albrechtsson E, Axelson J. Vitamins A and D but not Eand K decreased the cell number in human pancreatic cancer celllines. Scand J Gastroenterol 2004;39:882-5.
77. Osada S, Tomita H, Tanaka Y, Tokuyama Y, Tanaka H, Sakashita F,Takahashi T. The utility of vitamin K3 (menadione) against pancreaticcancer. Anticancer Res 2008;28:1A:45-50.
78. Showalter SL, Wang Z, Costantino CL, Witkiewicz AK, Yeo CJ, BrodyJR, Carr BI. Naturally occurring K vitamins inhibit pancreatic cancercell survival through a caspase-dependent pathway. J GastroenterolHepatol 2010;25:738-44.
79. Monti DA, Mitchell E, Bazzan AJ, Littman S, Zabrecky G, Yeo CJ,Pillai MV, Newberg AB, Deshmukh S, Levine M. Phase I evaluation ofintravenous ascorbic acid in combination with gemcitabine and erlotinibin patients with metastatic pancreatic cancer. PLoS One 2012;7:e29794.
80. Welsh JL, Wagner BA, van't Erve TJ, Zehr PS, Berg DJ, HalfdanarsonTR, Yee NS, Bodeker KL, Du J, Roberts, 2nd LJ, et al. Pharmacologicalascorbate with gemcitabine for the control of metastatic and nodepositivepancreatic cancer (PACMAN): results from a phase I clinicaltrial. Cancer Chemother Pharmacol 2013;71:765-75.
81. Blanke CD, Beer TM, Todd K, Mori M, Stone M, Lopez C. Phase IIstudy of calcitriol-enhanced docetaxel in patients with previously untreatedmetastatic or locally advanced pancreatic cancer. Invest NewDrugs 2009;27:374-8.
82. Springett GM, Neuger AM, Centeno BA, Hutchinson T, Jump H,Malafa MP. A phase I dose escalation study of the safety, PK, and PDof vitamin E d-tocotrienol administered to subjects with resectable pancreaticexocrine neoplasia. (Abstract) Cancer Res 2011;71:1299.
83. Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, WesleyRA, Levine M. Vitamin C pharmacokinetics: implications for oral andintravenous use. Ann Intern Med 2004;140:533-7.
84. Ohtani S, Iwamaru A, Deng W, Ueda K, Wu G, Jayachandran G,Kondo S, Atkinson EN, Minna JD, Roth JA, et al. Tumor suppressor101F6 and ascorbate synergistically and selectively inhibit non-smallcell lung cancer growth by caspase-independent apoptosis and autophagy.Cancer Res 2007;67:6293-303.
85. Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB. Oxidativestress induces autophagic cell death independent of apoptosis in transformedand cancer cells. Cell Death Differ 2008;15:171-82.
86. ClinicalTrials.gov [Internet]. [cited 2015 Jun 29]. Available from:https://clinicaltrials.gov/ct2/home.
87. McCollum EV, Simmonds N, Becker JE, Shipley PG. (1922) Studieson experimental rickets. XXI. An experimental demonstration of the existenceof a vitamin which promotes calcium deposition. J. Biol Chem53:293-312.
88. Huldshinsky K. Healing of rickets by artificially high sun. Deut MedWochenschr 1919;45:712-3.
89. Holick MF. Sunlight and vitamin D for bone health and prevention ofautoimmune diseases, cancers, and cardiovascular disease. Am J ClinNutr 2004; 80(6, Suppl)1678S-88S.
90. National Institutes of Health, Office of Dietary SupplementsVitaminD [Internet]. [cited 2015 Jun 29]. Available from: http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/.
91. Colston KW, James SY, Ofori-Kuragu EA, Binderup L, Grant AG.Vitamin D receptors and anti-proliferative effects of vitamin D derivativesin human pancreatic carcinoma cells in vivo and in vitro. Br JCancer 1997;76:1017-20.
92. Kawa S, Yoshizawa K, Tokoo M, Imai H, Oguchi H, Kiyosawa K,Homma T, Nikaido T, Furihata K. Inhibitory effect of 220-oxa-1,25-dihydroxyvitamin D3 on the proliferation of pancreatic cancer celllines. Gastroenterology 1996;110:1605-13.
93. Pettersson F, Colston KW, Dalgleish AG. Differential and antagonisticeffects of 9-cis-retinoic acid and vitamin D analogues on pancreaticcancer cells in vitro. Br J Cancer 2000;83:239-45.
94. Zugmaier G, Jager R, Grage B, Gottardis MM, Havemann K, KnabbeC. Growth-inhibitory effects of vitamin D analogues and retinoids onhuman pancreatic cancer cells. Br J Cancer 1996;73:1341-6.
95. Chiang KC, Yeh CN, Chen TC. Vitamin d and pancreatic cancer-anupdate. Cancers (Basel) 2011;3:213-26.
96. Lehmann B, Meurer M. Vitamin D metabolism. Dermatol Ther 2010;23(1):2-12.
97. Chen TC, Holick MF. Vitamin D and prostate cancer prevention andtreatment. Trends Endocrinol Metab 2003;14:423-30.
98. Colston K, Hirt M, Feldman D. Organ distribution of the cytoplasmic1,25-dihydroxycholecalciferol receptor in various mouse tissues. Endocrinology1980;107:1916-22.
99. Skowronski RJ, Peehl DM, Feldman D. Vitamin D and prostate cancer:1,25 dihydroxyvitamin D3 receptors and actions in human prostatecancer cell lines. Endocrinology 1993;132:1952-60.
100. Corton JM, Gillespie JG, Hawley SA, Hardie DG. 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMPactivatedprotein kinase in intact cells? Eur J Biochem 1995;229:558-65.
101. Matsubara S, Ding Q, Miyazaki Y, Kuwahata T, Tsukasa K, Takao S.mTOR plays critical roles in pancreatic cancer stem cells through specificand stemness-related functions. Sci Rep 2013;3:3230.
102. Kim JB, Islam S, Kim YJ, Prudoff RS, Sass KM, Wheelock MJ, JohnsonKR. N-Cadherin extracellular repeat 4 mediates epithelial to mesenchymaltransition and increased motility. J Cell Biol 2000;151:1193-206.
103. Hugh TJ, Dillon SA, Taylor BA, Pignatelli M, Poston GJ, Kinsella AR.Cadherin-catenin expression in primary colorectal cancer: a survivalanalysis. Br J Cancer 1999;80:1046-51.
104. Jawhari A, Jordan S, Poole S, Browne P, Pignatelli M, Farthing MJ. Abnormalimmunoreactivity of the E-cadherin-catenin complex in gastriccarcinoma: relationship with patient survival. Gastroenterology1997;112:46-54.
105. Joo YE, Rew JS, Park CS, Kim SJ. Expression of E-cadherin, a- andb-catenins in patients with pancreatic adenocarcinoma. Pancreatology2002;2:129-37.
106. Karatzas G, Karayiannakis AJ, Syrigos KN, Chatzigianni E, Papanikolaou S,Riza F, Papanikolaou D. E-cadherin expression correlates with tumordifferentiation in colorectal cancer. Hepatogastroenterology 1999;46:232-5.
107. Karayiannakis AJ, Syrigos KN, Polychronidis A, Simopoulos C. Expressionpatterns of a-, b- and g-catenin in pancreatic cancer: correlationwith E-cadherin expression, pathological features and prognosis. AnticancerRes 2001;21: 6A:4127-34.
108. Richmond PJ, Karayiannakis AJ, Nagafuchi A, Kaisary AV, PignatelliM. Aberrant E-cadherin and a-catenin expression in prostate cancer:correlation with patient survival. Cancer Res 1997;57:3189-93.
109. Hazan RB, Phillips GR, Qiao RF, Norton L, Aaronson SA. Exogenousexpression of N-cadherin in breast cancer cells induces cell migration,invasion, and metastasis. J Cell Biol 2000;148:779-90.
110. Nakajima S, Doi R, Toyoda E, Tsuji S, Wada M, Koizumi M, TulachanSS, Ito D, Kami K, Mori T, et al. N-cadherin expression and epithelialmesenchymaltransition in pancreatic carcinoma. Clin Cancer Res2004;10:4125-33.
111. Miller GJ. Vitamin D and prostate cancer: biologic interactions andclinical potentials. Cancer Metastasis Rev 1998;17:353-60.
112. Apperly FL. The relation of solar radiation to cancer mortality inNorth American. Cancer Res 1941;1:191-5.
113. Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK,Gorham ED. Serum 25-hydroxyvitamin D and colon cancer: eightyearprospective study. Lancet 1989;2:1176-8.
114. Grant WB. An ecologic study of the role of solar UV-B radiation inreducing the risk of cancer using cancer mortality data, dietary supplydata and latitude for European countries. Edition ed. In: Holick MF,ed. Biologic Effects of Light 2001. Boston, MA: Kluwer AcademicPublishing, 2002:267-76.
115. Stolzenberg-Solomon RZ, Jacobs EJ, Arslan AA, Qi D, Patel AV,Helzlsouer KJ, Weinstein SJ, McCullough ML, Purdue MP, Shu XO,et al. Circulating 25-hydroxyvitamin D and risk of pancreatic cancer:Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. AmJ Epidemiol 2010;172:81-93.
116. Wolpin BM, Ng K, Bao Y, Kraft P, Stampfer MJ, Michaud DS, Ma J,Buring JE, Sesso HD, Lee IM, et al. Plasma 25-hydroxyvitamin Dand risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev2012;21:82-91.
117. Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. Therole of vitamin D in reducing cancer risk and progression. Nat RevCancer 2014;14:342-57.
118. Kostner K, Denzer N, Muller CS, Klein R, Tilgen W, Reichrath J. Therelevance of vitamin D receptor (VDR) gene polymorphisms for cancer:a review of the literature. Anticancer Res 2009;29:3511-36.
119. Anderson LN, Cotterchio M, Knight JA, Borgida A, Gallinger S,Cleary SP. Genetic variants in vitamin d pathway genes and risk ofpancreas cancer; results from a population-based case-control studyin ontario, Canada. PLoS One 2013;8:e66768.
120. Sylvester PW, Shah SJ. Mechanisms mediating the antiproliferativeand apoptotic effects of vitamin E in mammary cancer cells. Front Biosci2005;10:699-709.
121. Wada S, Satomi Y, Murakoshi M, Noguchi N, Yoshikawa T, NishinoH. Tumor suppressive effects of tocotrienol in vivo and in vitro. CancerLett 2005;229:181-91.
122. Xu WL, Liu JR, Liu HK, Qi GY, Sun XR, Sun WG, Chen BQ. Inhibitionof proliferation and induction of apoptosis by g-tocotrienol inhuman colon carcinoma HT-29 cells. Nutrition 2009;25:555-66.
123. Charbek E, Staros EB. Vitamin E [Internet]. [cited 2015 Jun 29]. Availablefrom: http://emedicine.medscape.com/article/2088716-overview.
124. Barnett KT, Fokum FD, Malafa MP. Vitamin E succinate inhibits coloncancer liver metastases. J Surg Res 2002;106:292-8.
125. Malafa MP, Fokum FD, Andoh J, Neitzel LT, Bandyopadhyay S, ZhanR, Iiizumi M, Furuta E, Horvath E, Watabe K. Vitamin E succinatesuppresses prostate tumor growth by inducing apoptosis. Int J Cancer2006;118:2441-7.
126. Malafa MP, Fokum FD, Mowlavi A, Abusief M, King M. Vitamin Einhibits melanoma growth in mice. Surgery 2002;131:85-91.
127. Malafa MP, Neitzel LT. Vitamin E succinate promotes breast cancertumor dormancy. J Surg Res 2000;93:163-70.
128. Neuzil J. Vitamin E succinate and cancer treatment: a vitamin Eprototype for selective antitumour activity. Br J Cancer 2003;89:1822-6.
129. Quin J, Engle D, Litwiller A, Peralta E, Grasch A, Boley T, Hazelrigg S.Vitamin E succinate decreases lung cancer tumor growth in mice.J Surg Res 2005;127:139-43.
130. Bollrath J, Greten FR. IKK/NF-kappaB and STAT3 pathways: centralsignalling hubs in inflammation-mediated tumour promotion andmetastasis. EMBO Rep 2009;10:1314-9.
131. Wang C, Hou X, Mohapatra S, Ma Y, Cress WD, Pledger WJ, Chen J.Activation of p27Kip1 Expression by E2F1. A negative feedback mechanism.J Biol Chem 2005;280:12339-43.
132. Alleva R, Benassi MS, Pazzaglia L, Tomasetti M, Gellert N, Borghi B,Neuzil J, Picci P. a-Tocopheryl succinate alters cell cycle distributionsensitising human osteosarcoma cells to methotrexate-induced apoptosis.Cancer Lett 2006;232:226-35.
133. Qian M, Sanders BG, Kline K. RRR-a-Tocopheryl succinate inducesapoptosis in avian retrovirus-transformed lymphoid cells. Nutr Cancer1996;25:9-26.
134. Yu W, Sanders BG, Kline K. RRR-a-Tocopheryl succinate induction ofDNA synthesis arrest of human MDA-MB-435 cells involves TGFb-independent activation of p21Waf1/Cip1. Nutr Cancer 2002;43:227-36.
135. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activatedprotein kinase cascade for the treatment of cancer. Oncogene 2007;26:3291-310.
136. Green DR, Evan GI. A matter of life and death. Cancer Cell 2002;1:19-30.
137. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70.
138. Riedl SJ, Shi Y. Molecular mechanisms of caspase regulation duringapoptosis. Nat Rev Mol Cell Biol 2004;5:897-907.
139. Thompson CB. Apoptosis in the pathogenesis and treatment of disease.Science 1995;267(5203):1456-62.
140. Vaux DL, Flavell RA. Apoptosis genes and autoimmunity. Curr OpinImmunol 2000;12:719-24.
141. Yuan J, Yankner BA. Apoptosis in the nervous system. Nature 2000;407:802-9.
142. Ha TY, Hwang S, Hong HN, Choi YI, Yoon SY, Won YJ, Song GW,Kim N, Tak E, Ryoo BY. Synergistic effect of sorafenib and vitaminK on suppression of hepatocellular carcinoma cell migration and metastasis.Anticancer Res 2015;35:1985-95.
143. Yamamoto T, Nakamura H, Liu W, Cao K, Yoshikawa S, Enomoto H,Iwata Y, Koh N, Saito M, Imanishi H, et al. Involvement of hepatomaderivedgrowth factor in the growth inhibition of hepatocellular carcinomacells by vitamin K(2). J Gastroenterol 2009;44:228-35.
144. Iwamoto J. Vitamin K(2) therapy for postmenopausal osteoporosis.Nutrients 2014;6:1971-80.
145. Pumiglia KM, Decker SJ. Cell cycle arrest mediated by the MEK/mitogenactivatedprotein kinase pathway. Proc Natl Acad Sci USA 1997;94:448-52.
146. Cui J, Zhang M, Zhang YQ, Xu ZH. JNK pathway: diseases and therapeuticpotential. Acta Pharmacol Sin 2007;28:601-8.