Recent advances in pancreatic cancer: Biology, treatment, and prevention

Biochimica et Biophysica Acta - Reviews on Cancer

Volumn 1856, Issue 1, 2015, Pages 13-27

  Singh, Divya ^a   Upadhyay, Ghanshyam ^a   Srivastava, Rakesh K ^b   Shankar, Sharmila ^b,c  

^a CITY COLLEGE OF NEW YORK   (United States)

^b VETERANS AFFAIRS MEDICAL CENTER   (United States)

^c UNIVERSITY OF MISSOURI KANSAS CITY SCHOOL OF MEDICINE   (United States)

Author keywords

Cancer prevention; Cancer stem cell; Natural Product; Pancreatic cancer; Signaling pathways

Indexed keywords

ANTINEOPLASTIC AGENT; BENZYL ISOTHIOCYANATE; CURCUMIN; EPIGALLOCATECHIN GALLATE; GEMCITABINE; GENISTEIN; HERBACEOUS AGENT; NOTCH RECEPTOR; PACLITAXEL; PHOSPHATIDYLINOSITOL 3 KINASE; PIPERLONGUMINE; PROTEIN KINASE B; RESVERATROL; SMAD PROTEIN; SONIC HEDGEHOG PROTEIN; STAT3 PROTEIN; SULFORAPHANE; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; WNT PROTEIN;

CANCER CHEMOTHERAPY; CANCER PREVENTION; CANCER RADIOTHERAPY; CANCER STEM CELL; CANCER SURVIVAL; CLINICAL TRIAL (TOPIC); DRUG MECHANISM; GARLIC; HERBAL MEDICINE; HUMAN; NONHUMAN; PANCREAS CANCER; PRIORITY JOURNAL; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; METABOLISM; PANCREATIC NEOPLASMS;

HUMANS; PANCREATIC NEOPLASMS;

EID: 84930204780     PISSN: 0304419X     EISSN: 18792561     Source Type: Journal    
DOI: 10.1016/j.bbcan.2015.04.003     Document Type: Review

References (235)

1. Maitra A., Ashfaq R., Gunn C.R., Rahman A., Yeo C.J., Sohn T.A., Cameron J.L., Hruban R.H., Wilentz R.E. Cyclooxygenase 2 expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia: an immunohistochemical analysis with automated cellular imaging. Am. J. Clin. Pathol. 2002, 118:194-201.
2. Furukawa T., Fujisaki R., Yoshida Y., Kanai N., Sunamura M., Abe T., Takeda K., Matsuno S., Horii A. Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas. Mod. Pathol. 2005, 18:1034-1042.
3. Tao Y., Lin F., Li T., Xie J., Shen C., Zhu Z. Epigenetically modified pancreatic carcinoma PANC-1 cells Can Act as cancer vaccine to enhance antitumor immune response in mice. Oncol. Res. 2013, 21:307-316.
4. Conrath S.M. The use of epidemiology, scientific data, and regulatory authority to determine risk factors in cancers of some organs of the digestive system. 6. Pancreatic cancer. Regul. Toxicol. Pharmacol. 1986, 6:193-210.
5. Lillemoe K.D., Yeo C.J., Cameron J.L. Pancreatic cancer: state-of-the-art care. CA: a cancer journal for clinicians 2000, 50:241-268.
6. Pierantoni C., Pagliacci A., Scartozzi M., Berardi R., Bianconi M., Cascinu S. Pancreatic cancer: progress in cancer therapy. Crit. Rev. Oncol. Hematol. 2008, 67:27-38.
7. Neesse A., Krug S., Gress T.M., Tuveson D.A., Michl P. Emerging concepts in pancreatic cancer medicine: targeting the tumor stroma. Onco Targets Ther. 2013, 7:33-43.
8. Bardou M., Le Ray I. Treatment of pancreatic cancer: A narrative review of cost-effectiveness studies. Best practice & research. Clin. Gastroenterol. 2013, 27:881-892.
9. Kolodecik T., Shugrue C., Ashat M., Thrower E.C. Risk factors for pancreatic cancer: underlying mechanisms and potential targets. Front. Physiol. 2013, 4:415.
10. Shankar S., Nall D., Tang S.N., Meeker D., Passarini J., Sharma J., Srivastava R.K. Resveratrol inhibits pancreatic cancer stem cell characteristics in human and KrasG12D transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition. PLoS One 2011, 6:e16530.
11. Kapil U., Srivastav M., Nayar D. Vitamin 'A' and oesophageal cancer. Trop. Gastroenterol. 1993, 14:87-90.
12. Kim E.S., Khuri F.R. Chemoprevention of lung cancer. Curr. Oncol. Rep. 2002, 4:341-346.
13. Halvorsen B.L., Holte K., Myhrstad M.C., Barikmo I., Hvattum E., Remberg S.F., Wold A.B., Haffner K., Baugerod H., Andersen L.F., Moskaug O., Jacobs D.R., Blomhoff R. A systematic screening of total antioxidants in dietary plants. J. Nutr. 2002, 132:461-471.
14. Gupta S., Mukhtar H. Chemoprevention of skin cancer: current status and future prospects. Cancer Metastasis Rev. 2002, 21:363-380.
15. Gupta S. Prostate cancer chemoprevention: current status and future prospects. Toxicol. Appl. Pharmacol. 2007, 224:369-376.
16. Pietta P.G. Flavonoids as antioxidants. J. Nat. Prod. 2000, 63:1035-1042.
17. Halliwell B., Gutteridge J.M. Biologically relevant metal ion-dependent hydroxyl radical generation. An update. FEBS Lett. 1992, 307:108-112.
18. Silva A.R., Menezes P.F., Martinello T., Novakovich G.F., Praes C.E., Feferman I.H. Antioxidant kinetics of plant-derived substances and extracts. Int. J. Cosmet. Sci. 2010, 32:73-80.
19. Hidalgo M. Pancreatic cancer. N. Engl. J. Med. 2010, 362:1605-1617.
20. Hockel M., Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J. Natl. Cancer Inst. 2001, 93:266-276.
21. Shweiki D., Itin A., Soffer D., Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992, 359:843-845.
22. Abel E.V., Simeone D.M. Biology and clinical applications of pancreatic cancer stem cells. Gastroenterology 2013, 144:1241-1248.
23. Li C., Heidt D.G., Dalerba P., Burant C.F., Zhang L., Adsay V., Wicha M., Clarke M.F., Simeone D.M. Identification of pancreatic cancer stem cells. Cancer Res. 2007, 67:1030-1037.
24. Lee C.J., Dosch J., Simeone D.M. Pancreatic cancer stem cells. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2008, 26:2806-2812.
25. Herreros-Villanueva M., Zubia-Olascoaga A., Bujanda L. c-Met in pancreatic cancer stem cells: therapeutic implications. World J. Gastroenterol. 2012, 18:5321-5323.
26. Hermann P.C., Huber S.L., Herrler T., Aicher A., Ellwart J.W., Guba M., Bruns C.J., Heeschen C. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007, 1:313-323.
27. Fredebohm J., Boettcher M., Eisen C., Gaida M.M., Heller A., Keleg S., Tost J., Greulich-Bode K.M., Hotz-Wagenblatt A., Lathrop M., Giese N.A., Hoheisel J.D. Establishment and characterization of a highly tumourigenic and cancer stem cell enriched pancreatic cancer cell line as a well defined model system. PLoS One 2012, 7:e48503.
28. Avan A., Quint K., Nicolini F., Funel N., Frampton A.E., Maftouh M., Pelliccioni S., Schuurhuis G.J., Peters G.J., Giovannetti E. Enhancement of the antiproliferative activity of gemcitabine by modulation of c-Met pathway in pancreatic cancer. Curr. Pharm. Des. 2013, 19:940-950.
29. Luo G., Long J., Cui X., Xiao Z., Liu Z., Shi S., Liu L., Liu C., Xu J., Li M., Yu X. Highly lymphatic metastatic pancreatic cancer cells possess stem cell-like properties. Int. J. Oncol. 2013, 42:979-984.
30. Van den Broeck A., Vankelecom H., Van Delm W., Gremeaux L., Wouters J., Allemeersch J., Govaere O., Roskams T., Topal B. Human pancreatic cancer contains a side population expressing cancer stem cell-associated and prognostic genes. PLoS One 2013, 8:e73968.
31. Tanase C.P., Neagu A.I., Necula L.G., Mambet C., Enciu A.M., Calenic B., Cruceru M.L., Albulescu R. Cancer stem cells: involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics. World J. Gastroenterol. 2014, 20:10790-10801.
32. Amsterdam A., Raanan C., Polin N., Melzer E., Givol D., Schreiber L. Modulation of c-kit expression in pancreatic adenocarcinoma: a novel stem cell marker responsible for the progression of the disease. Acta Histochem. 2014, 116:197-203.
33. Castellanos J.A., Merchant N.B., Nagathihalli N.S. Emerging targets in pancreatic cancer: epithelial-mesenchymal transition and cancer stem cells. Onco Targets Ther. 2013, 6:1261-1267.
34. Lu Y., Zhu H., Shan H., Lu J., Chang X., Li X., Lu J., Fan X., Zhu S., Wang Y., Guo Q., Wang L., Huang Y., Zhu M., Wang Z. Knockdown of Oct4 and Nanog expression inhibits the stemness of pancreatic cancer cells. Cancer Lett. 2013, 340:113-123.
35. Yabuuchi S., Pai S.G., Campbell N.R., de Wilde R.F., De Oliveira E., Korangath P., Streppel M.M., Rasheed Z.A., Hidalgo M., Maitra A., Rajeshkumar N.V. Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer. Cancer Lett. 2013, 335:41-51.
36. Maisonneuve P., Marshall B.C., Lowenfels A.B. Risk of pancreatic cancer in patients with cystic fibrosis. Gut 2007, 56:1327-1328.
37. Yu H., Pardoll D., Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 2009, 9:798-809.
38. Maitra A., Hruban R.H. Pancreatic cancer. Annu. Rev. Pathol. 2008, 3:157-188.
39. di Magliano M.P., Logsdon C.D. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology 2013, 144:1220-1229.
40. Rozenblum E., Schutte M., Goggins M., Hahn S.A., Panzer S., Zahurak M., Goodman S.N., Sohn T.A., Hruban R.H., Yeo C.J., Kern S.E. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res. 1997, 57:1731-1734.
41. Feldmann G., Beaty R., Hruban R.H., Maitra A. Molecular genetics of pancreatic intraepithelial neoplasia. J. Hepatobiliary Pancreat. Surg. 2007, 14:224-232.
42. Shain A.H., Pollack J.R. The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PLoS One 2013, 8:e55119.
43. Jones S., Zhang X., Parsons D.W., Lin J.C., Leary R.J., Angenendt P., Mankoo P., Carter H., Kamiyama H., Jimeno A., Hong S.M., Fu B., Lin M.T., Calhoun E.S., Kamiyama M., Walter K., Nikolskaya T., Nikolsky Y., Hartigan J., Smith D.R., Hidalgo M., Leach S.D., Klein A.P., Jaffee E.M., Goggins M., Maitra A., Iacobuzio-Donahue C., Eshleman J.R., Kern S.E., Hruban R.H., Karchin R., Papadopoulos N., Parmigiani G., Vogelstein B., Velculescu V.E., Kinzler K.W. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008, 321:1801-1806.
44. Sharma N.K., Shankar S., Srivastava R.K. STAT3 as an emerging molecular target in pancreatic cancer. Gastrointestinal Cancer: Targets and Therapy 2014, 2014(4):115-122.
45. Bar-Natan M., Nelson E.A., Xiang M., Frank D.A. STAT signaling in the pathogenesis and treatment of myeloid malignancies. JAKSTAT 2012, 1:55-64.
46. Yue P., Turkson J. Targeting STAT3 in cancer: how successful are we?. Expert Opin. Investig. Drugs 2009, 18:45-56.
47. Schindler C., Levy D.E., Decker T. JAK-STAT signaling: from interferons to cytokines. J. Biol. Chem. 2007, 282:20059-20063.
48. Bar-Natan M., Nelson E.A., Xiang M., Frank D.A. STAT signaling in the pathogenesis and treatment of myeloid malignancies. JAKSTAT 2012, 1:55-64.
49. Yue P., Turkson J. Targeting STAT3 in cancer: how successful are we?. Expert Opin. Investig. Drugs 2009, 18:45-56.
50. Mankan A.K., Greten F.R. Inhibiting signal transducer and activator of transcription 3: rationality and rationale design of inhibitors. Expert Opin. Investig. Drugs 2011, 20:1263-1275.
51. Chang M.S., Lee H.S., Lee B.L., Kim Y.T., Lee J.S., Kim W.H. Differential protein expression between esophageal squamous cell carcinoma and dysplasia, and prognostic significance of protein markers. Pathol. Res. Pract. 2005, 201:417-425.
52. Scholz A., Heinze S., Detjen K.M., Peters M., Welzel M., Hauff P., Schirner M., Wiedenmann B., Rosewicz S. Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer. Gastroenterology 2003, 125:891-905.
53. Toyonaga T., Nakano K., Nagano M., Zhao G., Yamaguchi K., Kuroki S., Eguchi T., Chijiiwa K., Tsuneyoshi M., Tanaka M. Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer. Cancer Lett. 2003, 201:107-116.
54. Miyatsuka T., Kaneto H., Shiraiwa T., Matsuoka T.A., Yamamoto K., Kato K., Nakamura Y., Akira S., Takeda K., Kajimoto Y., Yamasaki Y., Sandgren E.P., Kawaguchi Y., Wright C.V., Fujitani Y. Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation. Genes Dev. 2006, 20:1435-1440.
55. Wei D., Le X., Zheng L., Wang L., Frey J.A., Gao A.C., Peng Z., Huang S., Xiong H.Q., Abbruzzese J.L., Xie K. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 2003, 22:319-329.
56. Lesina M., Kurkowski M.U., Ludes K., Rose-John S., Treiber M., Kloppel G., Yoshimura A., Reindl W., Sipos B., Akira S., Schmid R.M., Algul H. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 2011, 19:456-469.
57. Chen Y.G., Meng A.M. Negative regulation of TGF-beta signaling in development. Cell Res. 2004, 14:441-449.
58. Shi Y., Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003, 113:685-700.
59. Jonson T., Albrechtsson E., Axelson J., Heidenblad M., Gorunova L., Johansson B., Hoglund M. Altered expression of TGFB receptors and mitogenic effects of TGFB in pancreatic carcinomas. Int. J. Oncol. 2001, 19:71-81.
60. Jonson T., Heidenblad M., Hakansson P., Gorunova L., Johansson B., Fioretos T., Hoglund M. Pancreatic carcinoma cell lines with SMAD4 inactivation show distinct expression responses to TGFB1. Genes Chromosom. Cancer 2003, 36:340-352.
61. Morris J.P.t., Wang S.C., Hebrok M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma, Nature reviews. Cancer 2010, 10:683-695.
62. Brennan K.R., Brown A.M. Wnt proteins in mammary development and cancer. J. Mammary Gland Biol. Neoplasia 2004, 9:119-131.
63. Logan C.Y., Nusse R. The Wnt signaling pathway in development and disease. Annu. Rev. Cell Dev. Biol. 2004, 20:781-810.
64. Al-Aynati M.M., Radulovich N., Riddell R.H., Tsao M.S. Epithelial-cadherin and beta-catenin expression changes in pancreatic intraepithelial neoplasia. Clin. Cancer Res. 2004, 10:1235-1240.
65. Zeng G., Germinaro M., Micsenyi A., Monga N.K., Bell A., Sood A., Malhotra V., Sood N., Midda V., Monga D.K., Kokkinakis D.M., Monga S.P. Aberrant Wnt/beta-catenin signaling in pancreatic adenocarcinoma. Neoplasia 2006, 8:279-289.
66. Pasca di Magliano M., Biankin A.V., Heiser P.W., Cano D.A., Gutierrez P.J., Deramaudt T., Segara D., Dawson A.C., Kench J.G., Henshall S.M., Sutherland R.L., Dlugosz A., Rustgi A.K., Hebrok M. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. PLoS One 2007, 2:e1155.
67. Wang B., Zou Q., Sun M., Chen J., Wang T., Bai Y., Chen Z., Chen B., Zhou M. Reversion of trichostatin A resistance via inhibition of the Wnt signaling pathway in human pancreatic cancer cells. Oncol. Rep. 2014, 32(5):2015-2022.
68. Wang Z., Li Y., Sarkar F.H. Notch signaling proteins: legitimate targets for cancer therapy. Curr. Protein Pept. Sci. 2010, 11:398-408.
69. Wang Z., Li Y., Banerjee S., Sarkar F.H. Exploitation of the Notch signaling pathway as a novel target for cancer therapy. Anticancer Res. 2008, 28:3621-3630.
70. Miele L., Miao H., Nickoloff B.J. NOTCH signaling as a novel cancer therapeutic target. Curr. Cancer Drug Targets 2006, 6:313-323.
71. Fortini M.E. Notch signaling: the core pathway and its posttranslational regulation. Dev. Cell 2009, 16:633-647.
72. Ma J., Xia J., Miele L., Sarkar F.H., Wang Z. Notch signaling pathway in pancreatic cancer progression. Pancreat. Disord. Ther. 2013, 3.
73. Du X., Wang Y.H., Wang Z.Q., Cheng Z., Li Y., Hu J.K., Chen Z.X., Zhou Z.G. Down-regulation of Notch1 by small interfering RNA enhances chemosensitivity to gemcitabine in pancreatic cancer cells through activating apoptosis activity. Zhejiang Da Xue Xue Bao Yi Xue Ban 2014, 43:313-318.
74. Abel E.V., Kim E.J., Wu J., Hynes M., Bednar F., Proctor E., Wang L., Dziubinski M.L., Simeone D.M. The Notch pathway is important in maintaining the cancer stem cell population in pancreatic cancer. PLoS One 2014, 9:e91983.
75. Lee J.Y., Song S.Y., Park J.Y. Notch pathway activation is associated with pancreatic cancer treatment failure. Pancreatology 2014, 14:48-53.
76. Wang Z., Li Y., Kong D., Sarkar F.H. The role of Notch signaling pathway in epithelial-mesenchymal transition (EMT) during development and tumor aggressiveness. Curr. Drug Targets 2010, 11:745-751.
77. De Craene B., Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat. Rev. Cancer 2013, 13:97-110.
78. Rhim A.D., Mirek E.T., Aiello N.M., Maitra A., Bailey J.M., McAllister F., Reichert M., Beatty G.L., Rustgi A.K., Vonderheide R.H., Leach S.D., Stanger B.Z. EMT and dissemination precede pancreatic tumor formation. Cell 2012, 148:349-361.
79. Roy S.K., Srivastava R.K., Shankar S. Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer. J. Mol. Signal. 2010, 5:10.
80. Osterlund T., Kogerman P. Hedgehog signalling: how to get from Smo to Ci and Gli. Trends Cell Biol. 2006, 16:176-180.
81. Varjosalo M., Taipale J. Hedgehog: functions and mechanisms. Genes Dev. 2008, 22:2454-2472.
82. Beachy P.A., Karhadkar S.S., Berman D.M. Tissue repair and stem cell renewal in carcinogenesis. Nature 2004, 432:324-331.
83. Feldmann G., Habbe N., Dhara S., Bisht S., Alvarez H., Fendrich V., Beaty R., Mullendore M., Karikari C., Bardeesy N., Ouellette M.M., Yu W., Maitra A. Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer. Gut 2008, 57:1420-1430.
84. Rodova M., Fu J., Watkins D.N., Srivastava R.K., Shankar S. Sonic hedgehog signaling inhibition provides opportunities for targeted therapy by sulforaphane in regulating pancreatic cancer stem cell self-renewal. PLoS One 2012, 7:e46083.
85. Li S.H., Fu J., Watkins D.N., Srivastava R.K., Shankar S. Sulforaphane regulates self-renewal of pancreatic cancer stem cells through the modulation of Sonic hedgehog-GLI pathway. Mol. Cell. Biochem. 2013, 373:217-227.
86. Burris H.A., Moore M.J., Andersen J., Green M.R., Rothenberg M.L., Modiano M.R., Cripps M.C., Portenoy R.K., Storniolo A.M., Tarassoff P., Nelson R., Dorr F.A., Stephens C.D., Von Hoff D.D. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 1997, 15:2403-2413.
87. Fukushima M. [Antitumor activity and function of S-1, a new oral tegafur-based formulation], Gan to kagaku ryoho. Cancer Chemother. 2006, 33(Suppl. 1):19-26.
88. Abou-Alfa G., Letourneau R., Harker G., Modiano M., Hurwitz H., Tchekmedyian N., Feit K., Ackerman J., De Jager R., Eckhardt S., O'Reilly E. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2006, 24:4441-4447.
89. Berlin J., Catalano P., Thomas J., Kugler J., Haller D., Benson A. E.C.O.G.T. E, Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2002, 20:3270-3275.
90. Bramhall S., Schulz J., Nemunaitis J., Brown P., Baillet M., Buckels J. A double-blind placebo-controlled, randomised study comparing gemcitabine and Marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br. J. Cancer 2002, 87:161-167.
91. Colucci G., Labianca R., Di Costanzo F., Labianca R., Di Costanzo F., Gebbia V., Carteni G., Massidda B., Dapretto E., Manzione L., Piazza E., Sannicolo M., Ciaparrone M., Cavanna L., Giuliani F., Maiello E., Testa A., Pederzoli P., Falconi M., Gallo C., Di Maio M., Perrone F. Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2010, 28:1645-1651.
92. Cunningham D., Chau I., Stocken D., Valle J., Smith D., Steward W., Harper P., Dunn J., Tudur-Smith C., West J., Falk S., Crellin A., Adab F., Thompson J., Leonard P., Ostrowski J., Eatock M., Scheithauer W., Herrmann R., Neoptolemos J. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2009, 27:5513-5518.
93. Heinemann V., Quietzsch D., Gieseler F., Gonnermann M., Schonekas H., Rost A., Neuhaus H., Haag C., Clemens M., Heinrich B., Vehling-Kaiser U., Fuchs M., Fleckenstein D., Gesierich W., Uthgenannt D., Einsele H., Holstege A., Hinke A., Schalhorn A., Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2006, 24:3946-3952.
94. Heinemann V., Ursula V.-K., Dirk W., Kettner E., Marten A., Winkelmann C., Klein S., Kojouharoff G., Gauler T., von Weikersthal L., Clemens M., Geissler M., Greten T., Hegewisch-Becker S., Rubanov O., Baake G., Hohler T., Ko Y., Jung A., Neugebauer S., Boeck S. Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the 'Arbeitsgemeinschaft Internistische Onkologie' (AIO-PK0104). Gut 2012, 62:751-759.
95. Herrmann R., Bodoky G., Ruhstaller T., Glimelius B., Bajetta E., Schuller J., Saletti P., Bauer J., Figer A., Pestalozzi B., Kohne C., Mingrone W., Stemmer S., Tamas K., Kornek G., Koeberle D., Cina S., Bernhard J., Dietrich D., Scheithauer W. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the swiss group for clinical cancer Res and the central european cooperative oncology group. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2007, 25:2212-2217.
96. Kindler H., Ioka T., Richel D., Bennouna J., Letourneau R., Okusaka T., Funakoshi A., Furuse J., Park Y., Ohkawa S., Springett G., Wasan H., Trask P., Bycott P., Ricart A., Kim S., Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011, 12:25.
97. Louvet C., Labianca R., Hammel P., Lledo G., Zampino M., Andre T., Zaniboni A., Ducreux M., Aitini E., Taieb J., Faroux R., Lepere C., de Gramont A. GERCOR, GISCAD, Gemcitabine in combination with Oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2005, 23:3509-3516.
98. Moore M., Goldstein D., Hamm J., Figer A., Hecht J., Gallinger S., Au H., Murawa P., Walde D., Wolff R., Campos D., Lim R., Ding K., Clark G., Voskoglou-Nomikos T., Ptasynski M., Parulekar W. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2007, 25:1960-1966.
99. Oettle H., Richards D., Ramanathan R., van Laethem J., Peeters M., Fuchs M., Zimmermann A., John W., Von Hoff D., Arning M., Kindler H. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann. Oncol. 2005, 16:1639-1645.
100. Philip P., Benedetti J., Corless C., Wong R., O'Reilly E., Flynn P., Rowland K., Atkins J., Mirtsching B., Rivkin S., Khorana A., Goldman B., Fenoglio-Preiser C., Abbruzzese J., Blanke C. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group- directed intergroup trial S0205. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2010, 28:3605-3610.
101. Poplin E., Levy D., Berlin J., Ochster H., Mitchell E., Alberts S., O'Dwyer P., Haller D., Catalano P., Cella D., Benson A. Phase III trial of gemcitabine (30-minute infusion) versus gemcitabine (fixed-dose-rate infusion [FDR]) versus gemcitabine oxaliplatin (GEMOX) in patients with advanced pancreatic cancer (E6201). J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2006, 24:933S.
102. Reni M., Cereda S., Passoni P., Rognone A., Mazza E., Nicoletti R., Arcidiacono P., Zerbi A., Balzano G., Di Carlo V. A randomized phase II trial of PEXG (cisplatin, epirubicin, capecitabine, gemcitabine) or PDXG (docetaxel) regimen in advanced pancreatic adenocarcinoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2007, 25:A4628.
103. Reni M., Cordio S., Milandri C., Passoni P., Passoni P., Bonetto E., Oliani C., Luppi G., Nicoletti R., Galli L., Bordonaro R., Passardi A., Zerbi A., Balzano G., Aldrighetti L., Staudacher C., Villa E., Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005, 6:369-376.
104. Riess H., Helm A., Niedergethmann M., Schmidt-Wolf I., Moik M., Hammer C., Zippel K., Weigang-Kohler K., Stauch M., Oettle H. A randomised, prospective, multicenter, phase III trial of gemcitabine, 5-fluorouracil (5- FU), folinic acid vs. gemcitabine alone in patients with advanced pancreatic cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2005, 23:4009.
105. Rocha Lima C., Green M., Rotche R., Miller W., Jeffrey G., Cisar L., Morganti A., Orlando N., Gruia G., Miller L. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2004, 22:3776-3783.
106. Scheithauer W., Schull B., Ulrich-Pur H., Schmid K., Raderer M., Haider K., Kwasny W., Depisch D., Schneeweiss B., Lang F., Kornek G. Biweekly high- dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial. Ann. Oncol. 2003, 14:97-104.
107. Stathopoulos G., Syrigos K., Aravantinos G., Polyzos A., Papakotoulas P., Fountzilas G., Potamianou A., Ziras N., Boukovinas J., Varthalitis J., Androulakis N., Kotsakis A., Samonis G., Georgoulias V. A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. Br. J. Cancer 2006, 95:587-592.
108. Ueno H., Kosuge T., Matsuyama Y., Yamamoto J., Yamamoto J., Nakao A., Egawa S., Doi R., Monden M., Hatori T., Tanaka M., Shimada M., Kanemitsu K. A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer. Br. J. Cancer 2009, 101:908-915.
109. Van Cutsem E., van de Velde H., Karasek P., Vervenne W., Szawlowski A., Schoffski P., Post S., Verslype C., Neumann H., Safran H., Humblet Y., Perez Ruixo J., Ma Y., Von Hoff D. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2004, 22:1430-1438.
110. Conroy T., Desseigne F., Ychou M., Bouche O., Guimbaud R., Becouarn Y., Adenis A., Raoul J.L., Gourgou-Bourgade S., de la Fouchardiere C., Bennouna J., Bachet J.B., Khemissa-Akouz F., Pere-Verge D., Delbaldo C., Assenat E., Chauffert B., Michel P., Montoto-Grillot C., Ducreux M. U. Groupe Tumeurs Digestives of, P. Intergroup, FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 2011, 364:1817-1825.
111. Papadatos-Pastos D., Thillai K., Rabbie R., Ross P., Sarker D. FOLFIRINOX - a new paradigm in the treatment of pancreatic cancer. Expert. Rev. Anticancer. Ther. 2014, 14:1115-1125.
112. Von Hoff D.D., Ervin T., Arena F.P., Chiorean E.G., Infante J., Moore M., Seay T., Tjulandin S.A., Ma W.W., Saleh M.N., Harris M., Reni M., Dowden S., Laheru D., Bahary N., Ramanathan R.K., Tabernero J., Hidalgo M., Goldstein D., Van Cutsem E., Wei X., Iglesias J., Renschler M.F. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 2013, 369:1691-1703.
113. Yu E., Saif M.W., Huber K. Phase 1 trials in pancreatic cancer. J. Pancreas 2014, 15:326-328.
114. Ramos S. Effects of dietary flavonoids on apoptotic pathways related to cancer chemoprevention. J. Nutr. Biochem. 2007, 18:427-442.
115. Goldbohm R.A., Hertog M.G., Brants H.A., van Poppel G., van den Brandt P.A. Consumption of black tea and cancer risk: a prospective cohort study. J. Natl. Cancer Inst. 1996, 88:93-100.
116. Tsubono Y., Nishino Y., Komatsu S., Hsieh C.C., Kanemura S., Tsuji I., Nakatsuka H., Fukao A., Satoh H., Hisamichi S. Green tea and the risk of gastric cancer in Japan. N. Engl. J. Med. 2001, 344:632-636.
117. Garcia R., Gonzalez C.A., Agudo A., Riboli E. High intake of specific carotenoids and flavonoids does not reduce the risk of bladder cancer. Nutr. Cancer 1999, 35:212-214.
118. Arts I.C., Hollman P.C., Bueno De Mesquita H.B., Feskens E.J., Kromhout D. Dietary catechins and epithelial cancer incidence: the Zutphen elderly study. Int. J. Cancer 2001, 92:298-302.
119. Garcia-Closas R., Agudo A., Gonzalez C.A., Riboli E. Intake of specific carotenoids and flavonoids and the risk of lung cancer in women in Barcelona, Spain. Nutr. Cancer 1998, 32:154-158.
120. De Stefani E., Deneo-Pellegrini H., Mendilaharsu M., Ronco A. Diet and risk of cancer of the upper aerodigestive tract-I, Foods. Oral Oncol. 1999, 35:17-21.
121. Imai K., Suga K., Nakachi K. Cancer-preventive effects of drinking green tea among a Japanese population. Prev. Med. 1997, 26:769-775.
122. Key T.J., Sharp G.B., Appleby P.N., Beral V., Goodman M.T., Soda M., Mabuchi K. Soya foods and breast cancer risk: a prospective study in Hiroshima and Nagasaki, Japan. Br. J. Cancer 1999, 81:1248-1256.
123. Donnelly L.E., Newton R., Kennedy G.E., Fenwick P.S., Leung R.H., Ito K., Russell R.E., Barnes P.J. Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms. Am. J. Physiol. Lung Cell. Mol. Physiol. 2004, 287:L774-L783.
124. Aggarwal B.B., Bhardwaj A., Aggarwal R.S., Seeram N.P., Shishodia S., Takada Y. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res. 2004, 24:2783-2840.
125. Hung L.M., Chen J.K., Huang S.S., Lee R.S., Su M.J. Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc. Res. 2000, 47:549-555.
126. Sun Z.J., Pan C.E., Liu H.S., Wang G.J. Anti-hepatoma activity of resveratrol in vitro. World J. Gastroenterol. 2002, 8:79-81.
127. Potter G.A., Patterson L.H., Wanogho E., Perry P.J., Butler P.C., Ijaz T., Ruparelia K.C., Lamb J.H., Farmer P.B., Stanley L.A., Burke M.D. The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYP1B1. Br. J. Cancer 2002, 86:774-778.
128. Piver B., Fer M., Vitrac X., Merillon J.M., Dreano Y., Berthou F., Lucas D. Involvement of cytochrome P450 1A2 in the biotransformation of trans-resveratrol in human liver microsomes. Biochem. Pharmacol. 2004, 68:773-782.
129. Lu J., Ho C.H., Ghai G., Chen K.Y. Resveratrol analog, 3,4,5,4'-tetrahydroxystilbene, differentially induces pro-apoptotic p53/Bax gene expression and inhibits the growth of transformed cells but not their normal counterparts. Carcinogenesis 2001, 22:321-328.
130. Piver B., Berthou F., Dreano Y., Lucas D. Differential inhibition of human cytochrome P450 enzymes by epsilon-viniferin, the dimer of resveratrol: comparison with resveratrol and polyphenols from alcoholized beverages. Life Sci. 2003, 73:1199-1213.
131. Piver B., Berthou F., Dreano Y., Lucas D. Inhibition of CYP3A, CYP1A and CYP2E1 activities by resveratrol and other non volatile red wine components. Toxicol. Lett. 2001, 125:83-91.
132. Lin M.T., Yen M.L., Lin C.Y., Kuo M.L. Inhibition of vascular endothelial growth factor-induced angiogenesis by resveratrol through interruption of Src-dependent vascular endothelial cadherin tyrosine phosphorylation. Mol. Pharmacol. 2003, 64:1029-1036.
133. Upadhyay G., Singh A.K., Kumar A., Prakash O., Singh M.P. Resveratrol modulates pyrogallol-induced changes in hepatic toxicity markers, xenobiotic metabolizing enzymes and oxidative stress. Eur. J. Pharmacol. 2008, 596:146-152.
134. Yu C., Shin Y.G., Kosmeder J.W., Pezzuto J.M., van Breemen R.B. Liquid chromatography/tandem mass spectrometric determination of inhibition of human cytochrome P450 isozymes by resveratrol and resveratrol-3-sulfate. Rapid Commun. Mass Spectrom. 2003, 17:307-313.
135. Ciolino H.P., Daschner P.J., Yeh G.C. Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor. Cancer Res. 1998, 58:5707-5712.
136. Chang T.K., Chen J., Lee W.B. Differential inhibition and inactivation of human CYP1 enzymes by trans-resveratrol: evidence for mechanism-based inactivation of CYP1A2. J. Pharmacol. Exp. Ther. 2001, 299:874-882.
137. Szaefer H., Cichocki M., Brauze D., Baer-Dubowska W. Alteration in phase I and II enzyme activities and polycyclic aromatic hydrocarbons-DNA adduct formation by plant phenolics in mouse epidermis. Nutr. Cancer 2004, 48:70-77.
138. Signorelli P., Ghidoni R. Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J. Nutr. Biochem. 2005, 16:449-466.
139. Roman V., Billard C., Kern C., Ferry-Dumazet H., Izard J.C., Mohammad R., Mossalayi D.M., Kolb J.P. Analysis of resveratrol-induced apoptosis in human B-cell chronic leukaemia. Br. J. Haematol. 2002, 117:842-851.
140. Jang M., Cai L., Udeani G.O., Slowing K.V., Thomas C.F., Beecher C.W., Fong H.H., Farnsworth N.R., Kinghorn A.D., Mehta R.G., Moon R.C., Pezzuto J.M. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997, 275:218-220.
141. Mgbonyebi O.P., Russo J., Russo I.H. Antiproliferative effect of synthetic resveratrol on human breast epithelial cells. Int. J. Oncol. 1998, 12:865-869.
142. Mitchell S.H., Zhu W., Young C.Y. Resveratrol inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Cancer Res. 1999, 59:5892-5895.
143. Schneider Y., Vincent F., Duranton B., Badolo L., Gosse F., Bergmann C., Seiler N., Raul F. Anti-proliferative effect of resveratrol, a natural component of grapes and wine, on human colonic cancer cells. Cancer Lett. 2000, 158:85-91.
144. Zhou J.H., Cheng H.Y., Yu Z.Q., He D.W., Pan Z., Yang D.T. Resveratrol induces apoptosis in pancreatic cancer cells. Chin. Med. J. (Engl.) 2011, 124:1695-1699.
145. Cui X., Jin Y., Hofseth A.B., Pena E., Habiger J., Chumanevich A., Poudyal D., Nagarkatti M., Nagarkatti P.S., Singh U.P., Hofseth L.J. Resveratrol suppresses colitis and colon cancer associated with colitis. Cancer Prev. Res. (Phila.) 2010, 3:549-559.
146. Oi N., Jeong C.H., Nadas J., Cho Y.Y., Pugliese A., Bode A.M., Dong Z. Resveratrol, a red wine polyphenol, suppresses pancreatic cancer by inhibiting leukotriene Ahydrolase. Cancer Res. 2010, 70:9755-9764.
147. Chen X., Wang S., Wu N., Yang C.S. Leukotriene A4 hydrolase as a target for cancer prevention and therapy. Curr. Cancer Drug Targets 2004, 4:267-283.
148. Shehzad A., Wahid F., Lee Y.S. Curcumin in cancer chemoprevention: molecular targets, pharmacokinetics, bioavailability, and clinical trials. Arch. Pharm. (Weinheim, Ger.) 2010, 343:489-499.
149. Veeraraghavan J., Natarajan M., Lagisetty P., Awasthi V., Herman T.S., Aravindan N. Impact of curcumin, raspberry extract, and neem leaf extract on Rel protein-regulated cell death/radiosensitization in pancreatic cancer cells. Pancreas 2011, 40(7):1107-1119.
150. Aggarwal S., Ndinguri M.W., Solipuram R., Wakamatsu N., Hammer R.P., Ingram D., Hansel W. [DLys(6)]-luteinizing hormone releasing hormone-curcumin conjugate inhibits pancreatic cancer cell growth in vitro and in vivo. Int. J. Cancer 2011, 129:1611-1623.
151. Subramaniam D., Ramalingam S., Linehan D.C., Dieckgraefe B.K., Postier R.G., Houchen C.W., Jensen R.A., Anant S. RNA binding protein CUGBP2/CELF2 mediates curcumin-induced mitotic catastrophe of pancreatic cancer cells. PLoS One 2011, 6:e16958.
152. Glienke W., Maute L., Wicht J., Bergmann L. Wilms' tumour gene 1 (WT1) as a target in curcumin treatment of pancreatic cancer cells. Eur. J. Cancer 2009, 45:874-880.
153. Glienke W., Maute L., Wicht J., Bergmann L. Curcumin inhibits constitutive STAT3 phosphorylation in human pancreatic cancer cell lines and downregulation of survivin/BIRC5 gene expression. Cancer Investig. 2010, 28:166-171.
154. Bar-Sela G., Epelbaum R., Schaffer M. Curcumin as an anti-cancer agent: review of the gap between basic and clinical applications. Curr. Med. Chem. 2010, 17:190-197.
155. Epelbaum R., Schaffer M., Vizel B., Badmaev V., Bar-Sela G. Curcumin and gemcitabine in patients with advanced pancreatic cancer. Nutr. Cancer 2010, 62:1137-1141.
156. Dhillon N., Aggarwal B.B., Newman R.A., Wolff R.A., Kunnumakkara A.B., Abbruzzese J.L., Ng C.S., Badmaev V., Kurzrock R. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin. Cancer Res. 2008, 14:4491-4499.
157. Kurbitz C., Heise D., Redmer T., Goumas F., Arlt A., Lemke J., Rimbach G., Kalthoff H., Trauzold A. Epicatechin gallate and catechin gallate are superior to epigallocatechin gallate in growth suppression and anti-inflammatory activities in pancreatic tumor cells. Cancer Sci. 2011, 102:728-734.
158. Vu H.A., Beppu Y., Chi H.T., Sasaki K., Yamamoto H., Xinh P.T., Tanii T., Hara Y., Watanabe T., Sato Y., Ohdomari I. Green tea epigallocatechin gallate exhibits anticancer effect in human pancreatic carcinoma cells via the inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor. J. Biomed. Biotechnol. 2010, 2010:290516.
159. Barnes S., Sfakianos J., Coward L., Kirk M. Soy isoflavonoids and cancer prevention. Underlying biochemical and pharmacological issues. Adv. Exp. Med. Biol. 1996, 401:87-100.
160. Li Y., Zhang T., Jiang Y., Lee H.F., Schwartz S.J., Sun D. (-)-Epigallocatechin-3-gallate inhibits Hsp90 function by impairing Hsp90 association with cochaperones in pancreatic cancer cell line Mia Paca-2. Mol. Pharm. 2009, 6:1152-1159.
161. Basu A., Haldar S. Combinatorial effect of epigallocatechin-3-gallate and TRAIL on pancreatic cancer cell death. Int. J. Oncol. 2009, 34:281-286.
162. Shankar S., Ganapathy S., Hingorani S.R., Srivastava R.K. EGCG inhibits growth, invasion, angiogenesis and metastasis of pancreatic cancer. Front. Biosci. 2008, 13:440-452.
163. Kaufman P.B., Duke J.A., Brielmann H., Boik J., Hoyt J.E. A comparative survey of leguminous plants as sources of the isoflavones, genistein and daidzein: implications for human nutrition and health. J. Altern. Complement. Med. 1997, 3:7-12.
164. Rao C.V., Tokumo K., Rigotty J., Zang E., Kelloff G., Reddy B.S. Chemoprevention of colon carcinogenesis by dietary administration of piroxicam, alpha-difluoromethylornithine, 16 alpha-fluoro-5-androsten-17-one, and ellagic acid individually and in combination. Cancer Res. 1991, 51:4528-4534.
165. Alves R.C., Almeida I.M., Casal S., Oliveira M.B. Isoflavones in coffee: influence of species, roast degree, and brewing method. J. Agric. Food Chem. 2010, 58:3002-3007.
166. Akiyama T., Ishida J., Nakagawa S., Ogawara H., Watanabe S., Itoh N., Shibuya M., Fukami Y. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J. Biol. Chem. 1987, 262:5592-5595.
167. Dang Z.C., Audinot V., Papapoulos S.E., Boutin J.A., Lowik C.W. Peroxisome proliferator-activated receptor gamma (PPARgamma) as a molecular target for the soy phytoestrogen genistein. J. Biol. Chem. 2003, 278:962-967.
168. Gossner G., Choi M., Tan L., Fogoros S., Griffith K.A., Kuenker M., Liu J.R. Genistein-induced apoptosis and autophagocytosis in ovarian cancer cells. Gynecol. Oncol. 2007, 105:23-30.
169. Kuiper G.G., Lemmen J.G., Carlsson B., Corton J.C., Safe S.H., van der Saag P.T., van der Burg B., Gustafsson J.A. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 1998, 139:4252-4263.
170. Lopez-Lazaro M., Willmore E., Austin C.A. Cells lacking DNA topoisomerase II beta are resistant to genistein. J. Nat. Prod. 2007, 70:763-767.
171. Mann G.E., Bonacasa B., Ishii T., Siow R.C. Targeting the redox sensitive Nrf2-Keap1 defense pathway in cardiovascular disease: protection afforded by dietary isoflavones. Curr. Opin. Pharmacol. 2009, 9:139-145.
172. Markovits J., Linassier C., Fosse P., Couprie J., Pierre J., Jacquemin-Sablon A., Saucier J.M., Le Pecq J.B., Larsen A.K. Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase II. Cancer Res. 1989, 49:5111-5117.
173. Nakamura Y., Yogosawa S., Izutani Y., Watanabe H., Otsuji E., Sakai T. A combination of indol-3-carbinol and genistein synergistically induces apoptosis in human colon cancer HT-29 cells by inhibiting Akt phosphorylation and progression of autophagy. Mol. Cancer 2009, 8:100.
174. Vera J.C., Reyes A.M., Carcamo J.G., Velasquez F.V., Rivas C.I., Zhang R.H., Strobel P., Iribarren R., Scher H.I., Slebe J.C., et al. Genistein is a natural inhibitor of hexose and dehydroascorbic acid transport through the glucose transporter, GLUT1. J. Biol. Chem. 1996, 271:8719-8724.
175. Constantinou A., Kiguchi K., Huberman E. Induction of differentiation and DNA strand breakage in human HL-60 and K-562 leukemia cells by genistein. Cancer Res. 1990, 50:2618-2624.
176. Fotsis T., Pepper M., Adlercreutz H., Fleischmann G., Hase T., Montesano R., Schweigerer L. Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc. Natl. Acad. Sci. U. S. A. 1993, 90:2690-2694.
177. Gorczyca W., Gong J., Ardelt B., Traganos F., Darzynkiewicz Z. The cell cycle related differences in susceptibility of HL-60 cells to apoptosis induced by various antitumor agents. Cancer Res. 1993, 53:3186-3192.
178. Kuriu A., Ikeda H., Kanakura Y., Griffin J.D., Druker B., Yagura H., Kitayama H., Ishikawa J., Nishiura T., Kanayama Y., et al. Proliferation of human myeloid leukemia cell line associated with the tyrosine-phosphorylation and activation of the proto-oncogene c-kit product. Blood 1991, 78:2834-2840.
179. Li B.Q., Subleski M., Shalloway D., Kung H.F., Kamata T. Mitogenic activation of the Ras guanine nucleotide exchange factor in NIH 3T3 cells involves protein tyrosine phosphorylation. Proc. Natl. Acad. Sci. U. S. A. 1993, 90:8504-8508.
180. Linassier C., Pierre M., Le Pecq J.B., Pierre J. Mechanisms of action in NIH-3T3 cells of genistein, an inhibitor of EGF receptor tyrosine kinase activity. Biochem. Pharmacol. 1990, 39:187-193.
181. Linnekin D., Park L.S., Farrar W.L. Dissociation of human cytokine receptor expression and signal transduction. Blood 1992, 80:1896-1904.
182. Matsukawa Y., Marui N., Sakai T., Satomi Y., Yoshida M., Matsumoto K., Nishino H., Aoike A. Genistein arrests cell cycle progression at G2-M. Cancer Res. 1993, 53:1328-1331.
183. Okura A., Arakawa H., Oka H., Yoshinari T., Monden Y. Effect of genistein on topoisomerase activity and on the growth of [Val 12]Ha-ras-transformed NIH 3T3 cells. Biochem. Biophys. Res. Commun. 1988, 157:183-189.
184. Traganos F., Ardelt B., Halko N., Bruno S., Darzynkiewicz Z. Effects of genistein on the growth and cell cycle progression of normal human lymphocytes and human leukemic MOLT-4 and HL-60 cells. Cancer Res. 1992, 52:6200-6208.
185. Bao B., Wang Z., Ali S., Kong D., Banerjee S., Ahmad A., Li Y., Azmi A.S., Miele L., Sarkar F.H. Over-expression of FoxM1 leads to epithelial-mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells. J. Cell. Biochem. 2011, 112:2296-2306.
186. Wang Z., Ahmad A., Banerjee S., Azmi A., Kong D., Li Y., Sarkar F.H. FoxM1 is a novel target of a natural agent in pancreatic cancer. Pharm. Res. 2010, 27:1159-1168.
187. Fahey J.W., Zhang Y., Talalay P. Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc. Natl. Acad. Sci. U. S. A. 1997, 94:10367-10372.
188. Zhang Y., Kensler T.W., Cho C.G., Posner G.H., Talalay P. Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proc. Natl. Acad. Sci. U. S. A. 1994, 91:3147-3150.
189. Chung F.L., Conaway C.C., Rao C.V., Reddy B.S. Chemoprevention of colonic aberrant crypt foci in Fischer rats by sulforaphane and phenethyl isothiocyanate. Carcinogenesis 2000, 21:2287-2291.
190. Shen G., Khor T.O., Hu R., Yu S., Nair S., Ho C.T., Reddy B.S., Huang M.T., Newmark H.L., Kong A.N. Chemoprevention of familial adenomatous polyposis by natural dietary compounds sulforaphane and dibenzoylmethane alone and in combination in ApcMin/+ mouse. Cancer Res. 2007, 67:9937-9944.
191. Chaudhuri D., Orsulic S., Ashok B.T. Antiproliferative activity of sulforaphane in Akt-overexpressing ovarian cancer cells. Mol. Cancer Ther. 2007, 6:334-345.
192. Park S.Y., Kim G.Y., Bae S.J., Yoo Y.H., Choi Y.H. Induction of apoptosis by isothiocyanate sulforaphane in human cervical carcinoma HeLa and hepatocarcinoma HepG2 cells through activation of caspase-3. Oncol. Rep. 2007, 18:181-187.
193. Li Y., Zhang T., Korkaya H., Liu S., Lee H.F., Newman B., Yu Y., Clouthier S.G., Schwartz S.J., Wicha M.S., Sun D. Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin. Cancer Res. 2010, 16:2580-2590.
194. Li Y., Zhang T., Schwartz S.J., Sun D. Sulforaphane potentiates the efficacy of 17-allylamino 17-demethoxygeldanamycin against pancreatic cancer through enhanced abrogation of Hsp90 chaperone function. Nutr. Cancer 2011, 63:1151-1159.
195. Srivastava R.K., Tang S.N., Zhu W., Meeker D., Shankar S. Sulforaphane synergizes with quercetin to inhibit self-renewal capacity of pancreatic cancer stem cells. Front. Biosci. 2011, 3:515-528.
196. Kallifatidis G., Rausch V., Baumann B., Apel A., Beckermann B.M., Groth A., Mattern J., Li Z., Kolb A., Moldenhauer G., Altevogt P., Wirth T., Werner J., Schemmer P., Buchler M.W., Salnikov A.V., Herr I. Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling. Gut 2009, 58:949-963.
197. Shukla Y., Kalra N. Cancer chemoprevention with garlic and its constituents. Cancer Lett. 2007, 247:167-181.
198. Rao C.V. Benzyl isothiocyanate: double trouble for breast cancer cells. Cancer Prev. Res. (Phila.) 2013, 6:760-763.
199. Hecht S.S. Chemoprevention of cancer by isothiocyanates, modifiers of carcinogen metabolism. J. Nutr. 1999, 129:768S-774S.
200. Hecht S.S. Inhibition of carcinogenesis by isothiocyanates. Drug Metab. Rev. 2000, 32:395-411.
201. Wattenberg L.W. Inhibition of carcinogenic effects of polycyclic hydrocarbons by benzyl isothiocyanate and related compounds. J. Natl. Cancer Inst. 1977, 58:395-398.
202. Wattenberg L.W. Inhibition of carcinogen-induced neoplasia by sodium cyanate, tert-butyl isocyanate, and benzyl isothiocyanate administered subsequent to carcinogen exposure. Cancer Res. 1981, 41:2991-2994.
203. Zhang Y., Talalay P., Cho C.G., Posner G.H. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc. Natl. Acad. Sci. U. S. A. 1992, 89:2399-2403.
204. Batra S., Sahu R.P., Kandala P.K., Srivastava S.K. Benzyl isothiocyanate-mediated inhibition of histone deacetylase leads to NF-kappaB turnoff in human pancreatic carcinoma cells. Mol. Cancer Ther. 2010, 9:1596-1608.
205. Sahu R.P., Srivastava S.K. The role of STAT-3 in the induction of apoptosis in pancreatic cancer cells by benzyl isothiocyanate. J. Natl. Cancer Inst. 2009, 101:176-193.
206. Sahu R.P., Zhang R., Batra S., Shi Y., Srivastava S.K. Benzyl isothiocyanate-mediated generation of reactive oxygen species causes cell cycle arrest and induces apoptosis via activation of MAPK in human pancreatic cancer cells. Carcinogenesis 2009, 30:1744-1753.
207. Zhang R., Loganathan S., Humphreys I., Srivastava S.K. Benzyl isothiocyanate-induced DNA damage causes G2/M cell cycle arrest and apoptosis in human pancreatic cancer cells. J. Nutr. 2006, 136:2728-2734.
208. Boreddy S.R., Sahu R.P., Srivastava S.K. Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF-alpha/VEGF/Rho-GTPases: pivotal role of STAT-3. PLoS One 2011, 6:e25799.
209. Boreddy S.R., Pramanik K.C., Srivastava S.K. Pancreatic tumor suppression by benzyl isothiocyanate is associated with inhibition of PI3K/AKT/FOXO pathway. Clin. Cancer Res. 2011, 17:1784-1795.
210. Raj L., Ide T., Gurkar A.U., Foley M., Schenone M., Li X., Tolliday N.J., Golub T.R., Carr S.A., Shamji A.F., Stern A.M., Mandinova A., Schreiber S.L., Lee S.W. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 2011, 475:231-234.
211. Randhawa H., Kibble K., Zeng H., Moyer M.P., Reindl K.M. Activation of ERK signaling and induction of colon cancer cell death by piperlongumine. Toxicol. In Vitro 2013, 27:1626-1633.
212. Dhillon H., Chikara S., Reindl K.M. Piperlongumine induces pancreatic cancer cell death by enhancing reactive oxygen species and DNA damage. Toxic. Rep. 2014, 1:309-318.
213. Qin Y., Ma Z., Dang X., Li W., Ma Q. Effect of resveratrol on proliferation and apoptosis of human pancreatic cancer MIA PaCa-2 cells may involve inhibition of the Hedgehog signaling pathway. Mol. Med. Rep. 2014, 10:2563-2567.
214. Kumar A., Hu J., LaVoie H.A., Walsh K.B., DiPette D.J., Singh U.S. Conformational changes and translocation of tissue-transglutaminase to the plasma membranes: role in cancer cell migration. BMC Cancer 2014, 14:256.
215. Yang L., Yang L., Tian W., Li J., Liu J., Zhu M., Zhang Y., Yang Y., Liu F., Zhang Q., Liu Q., Shen Y., Qi Z. Resveratrol plays dual roles in pancreatic cancer cells. J. Cancer Res. Clin. Oncol. 2014, 140:749-755.
216. Li W., Ma J., Ma Q., Li B., Han L., Liu J., Xu Q., Duan W., Yu S., Wang F., Wu E. Resveratrol inhibits the epithelial-mesenchymal transition of pancreatic cancer cells via suppression of the PI-3K/Akt/NF-kappaB pathway. Curr. Med. Chem. 2013, 20:4185-4194.
217. Liu P., Liang H., Xia Q., Li P., Kong H., Lei P., Wang S., Tu Z. Resveratrol induces apoptosis of pancreatic cancers cells by inhibiting miR-21 regulation of BCL-2 expression. Clin. Transl. Oncol. 2013, 15:741-746.
218. Mo W., Xu X., Xu L., Wang F., Ke A., Wang X., Guo C. Resveratrol inhibits proliferation and induces apoptosis through the hedgehog signaling pathway in pancreatic cancer cell. Pancreatology 2011, 11:601-609.
219. Roy S.K., Chen Q., Fu J., Shankar S., Srivastava R.K. Resveratrol inhibits growth of orthotopic pancreatic tumors through activation of FOXO transcription factors. PLoS One 2011, 6:e25166.
220. Bimonte S., Barbieri A., Palma G., Luciano A., Rea D., Arra C. Curcumin inhibits tumor growth and angiogenesis in an orthotopic mouse model of human pancreatic cancer. Biomed Res. Int. 2013, 2013:810423.
221. Sarkar S., Dubaybo H., Ali S., Goncalves P., Kollepara S.L., Sethi S., Philip P.A., Li Y. Down-regulation of miR-221 inhibits proliferation of pancreatic cancer cells through up-regulation of PTEN, p27(kip1), p57(kip2), and PUMA. Am. J. Cancer Res. 2013, 3:465-477.
222. Ranjan A.P., Mukerjee A., Helson L., Gupta R., Vishwanatha J.K. Efficacy of liposomal curcumin in a human pancreatic tumor xenograft model: inhibition of tumor growth and angiogenesis. Anticancer Res. 2013, 33:3603-3609.
223. Youns M., Fathy G.M. Upregulation of extrinsic apoptotic pathway in curcumin-mediated antiproliferative effect on human pancreatic carcinogenesis. J. Cell. Biochem. 2013, 114:2654-2665.
224. Sun X.D., Liu X.E., Huang D.S. Curcumin reverses the epithelial-mesenchymal transition of pancreatic cancer cells by inhibiting the Hedgehog signaling pathway. Oncol. Rep. 2013, 29:2401-2407.
225. Bao B., Ali S., Banerjee S., Wang Z., Logna F., Azmi A.S., Kong D., Ahmad A., Li Y., Padhye S., Sarkar F.H. Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer Res. 2012, 72:335-345.
226. Liu S., Wang X.J., Liu Y., Cui Y.F. PI3K/AKT/mTOR signaling is involved in (-)-epigallocatechin-3-gallate-induced apoptosis of human pancreatic carcinoma cells. Am. J. Chin. Med. 2013, 41:629-642.
227. Kim S.O., Kim M.R. (-)-Epigallocatechin 3-gallate inhibits invasion by inducing the expression of Raf kinase inhibitor protein in AsPC1 human pancreatic adenocarcinoma cells through the modulation of histone deacetylase activity. Int. J. Oncol. 2013, 42:349-358.
228. Hardtner C., Multhoff G., Falk W., Radons J. (-)-Epigallocatechin-3-gallate, a green tea-derived catechin, synergizes with celecoxib to inhibit IL-1-induced tumorigenic mediators by human pancreatic adenocarcinoma cells Colo357. Eur. J. Pharmacol. 2012, 684:36-43.
229. Zhu Z., Wang Y., Liu Z., Wang F., Zhao Q. Inhibitory effects of epigallocatechin-3-gallate on cell proliferation and the expression of HIF-1alpha and P-gp in the human pancreatic carcinoma cell line PANC-1. Oncol. Rep. 2012, 27:1567-1572.
230. Tang S.N., Fu J., Shankar S., Srivastava R.K. EGCG enhances the therapeutic potential of gemcitabine and CP690550 by inhibiting STAT3 signaling pathway in human pancreatic cancer. PLoS One 2012, 7:e31067.
231. Tang S.N., Fu J., Nall D., Rodova M., Shankar S., Srivastava R.K. Inhibition of sonic hedgehog pathway and pluripotency maintaining factors regulate human pancreatic cancer stem cell characteristics. Int. J. Cancer 2012, 131:30-40.
232. Forster T., Rausch V., Zhang Y., Isayev O., Heilmann K., Schoensiegel F., Liu L., Nessling M., Richter K., Labsch S., Nwaeburu C.C., Mattern J., Gladkich J., Giese N., Werner J., Schemmer P., Gross W., Gebhard M.M., Gerhauser C., Schaefer M., Herr I. Sulforaphane counteracts aggressiveness of pancreatic cancer driven by dysregulated Cx43-mediated gap junctional intercellular communication. Oncotarget 2014, 5:1621-1634.
233. Thakkar A., Sutaria D., Grandhi B.K., Wang J., Prabhu S. The molecular mechanism of action of aspirin, curcumin and sulforaphane combinations in the chemoprevention of pancreatic cancer. Oncol. Rep. 2013, 29:1671-1677.
234. Li Y., Karagoz G.E., Seo Y.H., Zhang T., Jiang Y., Yu Y., Duarte A.M., Schwartz S.J., Boelens R., Carroll K., Rudiger S.G., Sun D. Sulforaphane inhibits pancreatic cancer through disrupting Hsp90-p50(Cdc37) complex and direct interactions with amino acids residues of Hsp90. J. Nutr. Biochem. 2012, 23:1617-1626.
235. Kallifatidis G., Labsch S., Rausch V., Mattern J., Gladkich J., Moldenhauer G., Buchler M.W., Salnikov A.V., Herr I. Sulforaphane increases drug-mediated cytotoxicity toward cancer stem-like cells of pancreas and prostate. Mol. Ther. 2011, 19:188-195.