Rationale for possible targeting of histone deacetylase signaling in cancer diseases with a special reference to pancreatic cancer

Journal of Biomedicine and Biotechnology

Volumn 2011, Issue , 2011, Pages

  Ouassi, Mehdi ^a,b,c   Giger, Urs ^d   Sielezneff, Igor ^a,b   Pirr, Nicolas ^a,b   Sastre, Bernard ^a,b,c   Ouaissi, Ali ^e,f  

^a TIMONE HOSPITAL   (France)

^b AIX MARSEILLE UNIVERSITY   (France)

^c University of the Mediterranean Aix Marseille II   (France)

^d Kantonsspital Liestal   (Switzerland)

^e UNIVERSITÉ DE MONTPELLIER   (France)

^f UNIVERSITY OF PORTO   (Portugal)

Author keywords

[No Author keywords available]

Indexed keywords

BEVACIZUMAB; BORTEZOMIB; BUTYRIC ACID; CETUXIMAB; ERLOTINIB; FLUOROURACIL; GEMCITABINE; HISTONE DEACETYLASE; HISTONE DEACETYLASE 1; HISTONE DEACETYLASE 2; HISTONE DEACETYLASE 3; HISTONE DEACETYLASE 5; HISTONE DEACETYLASE INHIBITOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; OXYGEN RADICAL; TRICHOSTATIN A; VORINOSTAT; ANTINEOPLASTIC AGENT;

ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CANCER CELL; CANCER RESISTANCE; CANCER THERAPY; CELL DIFFERENTIATION; CYTOKINE PRODUCTION; CYTOSTASIS; DRUG POTENTIATION; HUMAN; IMMUNOMODULATION; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; PANCREAS CANCER; PROTEIN EXPRESSION; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; TUMOR CELL; TUMOR IMMUNITY; ANIMAL; DRUG EFFECT; ENZYMOLOGY; IMMUNOLOGY; METABOLISM; PANCREAS TUMOR; VASCULARIZATION;

ANIMALS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CELL DIFFERENTIATION; HISTONE DEACETYLASE INHIBITORS; HISTONE DEACETYLASES; HUMANS; PANCREATIC NEOPLASMS; SIGNAL TRANSDUCTION;

EID: 78650723028     PISSN: 11107243     EISSN: 11107251     Source Type: Journal    
DOI: 10.1155/2011/315939     Document Type: Review

References (76)

1. Jemal A., Siegel R., Ward E., Murray T., Xu J., Thun M. J., Cancer statistics, 2007 Ca-A Cancer Journal for Clinicians 2007 57 1 43 66
2. Fidler I. J., The pathogenesis of cancer metastasis: the seed and soil hypothesis revisited Nature Reviews Cancer 2003 3 6 453 458
3. Rosenberg L., Pancreatic cancer: a review of emerging therapies Drugs 2000 59 5 1071 1089
4. Kuo M.-H., Allis C. D., Roles of histone acetyltransferases and deacetylases in gene regulation BioEssays 1998 20 8 615 626
5. Bolden J. E., Peart M. J., Johnstone R. W., Anticancer activities of histone deacetylase inhibitors Nature Reviews Drug Discovery 2006 5 9 769 784
6. Frye R. A., Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins Biochemical and Biophysical Research Communications 2000 273 2 793 798
7. De Nigris F., Cerutti J., Morelli C., Califano D., Chiariotti L., Viglietto G., Santelli G., Fusco A., Isolation of a SIR-like gene, SIR-T8, that is overexpressed in thyroid carcinoma cell lines and tissues British Journal of Cancer 2002 86 6 917 923
8. De Ruijter A. J. M., Van Gennip A. H., Caron H. N., Kemp S., Van Kuilenburg A. B. P., Histone deacetylases (HDACs): characterization of the classical HDAC family Biochemical Journal 2003 370 3 737 749
9. Bradner J. E., West N., Grachan M. L., Greenberg E. F., Haggarty S. J., Warnow T., Mazitschek R., Chemical phylogenetics of histone deacetylases Nature Chemical Biology 2010 6 3 238 243
10. Grozinger C. M., Chao E. D., Blackwell H. E., Moazed D., Schreiber S. L., Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening Journal of Biological Chemistry 2001 276 42 38837 38843
11. Bedalov A., Gatbonton T., Irvine W. P., Gottschling D. E., Simon J. A., Identification of a small molecule inhibitor of Sir2p Proceedings of the National Academy of Sciences of the United States of America 2001 98 26 15113 15118
12. Choi J.-H., Kwon H. J., Yoon B.-I., Kim J.-H., Han S. U., Joo H. J., Kim D.-Y., Expression profile of histone deacetylase 1 in gastric cancer tissues Japanese Journal of Cancer Research 2001 92 12 1300 1304
13. Zhu P., Martin E., Mengwasser J., Schlag P., Janssen K.-P., Gttlicher M., Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis Cancer Cell 2004 5 5 455 463
14. Wilson A. J., Byun D.-S., Popova N., Murray L. B., L'Italien K., Sowa Y., Arango D., Velcich A., Augenlicht L. H., Mariadason J. M., Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer Journal of Biological Chemistry 2006 281 19 13548 13558
15. Scanlan M. J., Welt S., Gordon C. M., Chen Y.-T., Gure A. O., Stockert E., Jungbluth A. A., Ritter G., Jger D., Jger E., Knuth A., Old L. J., Cancer-related serological recognition of human colon cancer: identification of potential diagnostic and immunotherapeutic targets Cancer Research 2002 62 14 4041 4047
16. De Nigris F., Cerutti J., Morelli C., Califano D., Chiariotti L., Viglietto G., Santelli G., Fusco A., Isolation of a SIR-like gene, SIR-T8, that is overexpressed in thyroid carcinoma cell lines and tissues British Journal of Cancer 2002 86 6 917 923
17. Hiratsuka M., Inoue T., Toda T., Kimura N., Shirayoshi Y., Kamitani H., Watanabe T., Ohama E., Tahimic C. G. T., Kurimasa A., Oshimura M., Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene Biochemical and Biophysical Research Communications 2003 309 3 558 566
18. Kim D. W., Sovak M. A., Zanieski G., Nonet G., Romieu-Mourez R., Lau A. W., Hafer L. J., Yaswen P., Stampfer M., Rogers A. E., Russo J., Sonenshein G. E., Activation of NF- B/Rel occurs early during neoplastic transformation of mammary cells Carcinogenesis 2000 21 5 871 879
19. Weichert W., Boehm M., Gekeler V., Bahra M., Langrehr J., Neuhaus P., Denkert C., Imre G., Weller C., Hofmann H.-P., Niesporek S., Jacob J., Dietel M., Scheidereit C., Kristiansen G., High expression of RelA/p65 is associated with activation of nuclear factor- B-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis British Journal of Cancer 2007 97 4 523 530
20. Mori N., Fujii M., Ikeda S., Yamada Y., Tomonaga M., Ballard D. W., Yamamoto N., Constitutive activation of NF- B in primary adult T-cell leukemia cells Blood 1999 93 7 2360 2368
21. Cogswell P. C., Guttridge D. C., Funkhouser W. K., Baldwin A. S. Jr., Selective activation of NF- B subunits in human breast cancer: potential roles for NF- B2/p52 and for Bcl-3 Oncogene 2000 19 9 1123 1131
22. Ashburner B. P., Westerheide S. D., Baldwin A. S. Jr., The p65 (RelA) subunit of NF- B interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression Molecular and Cellular Biology 2001 21 20 7065 7077
23. Chen L.-F., Fischle W., Verdin E., Greene W. C., Duration of nuclear NF- B action regulated by reversible acetylation Science 2001 293 5535 1653 1657
24. Yeung F., Hoberg J. E., Ramsey C. S., Keller M. D., Jones D. R., Frye R. A., Mayo M. W., Modulation of NF- B-dependent transcription and cell survival by the SIRT1 deacetylase EMBO Journal 2004 23 12 2369 2380
25. Yoshida M., Kijima M., Akita M., Beppu T., Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A Journal of Biological Chemistry 1990 265 28 17174 17179
26. Finnin M. S., Donigian J. R., Cohen A., Richon V. M., Rifkind R. A., Marks P. A., Breslow R., Pavletich N. P., Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors Nature 1999 401 6749 188 193
27. Bolden J. E., Peart M. J., Johnstone R. W., Anticancer activities of histone deacetylase inhibitors Nature Reviews Drug Discovery 2006 5 9 769 784
28. Xu W., Ngo L., Perez G., Dokmanovic M., Marks P. A., Intrinsic apoptotic and thioredoxin pathways in human prostate cancer cell response to histone deacetylase inhibitor Proceedings of the National Academy of Sciences of the United States of America 2006 103 42 15540 15545
29. Nebbioso A., Clarke N., Voltz E., Germain E., Ambrosino C., Bontempo P., Alvarez R., Schiavone E. M., Ferrara F., Bresciani F., Weisz A., De Lera A. R., Gronemeyer H., Altucci L., Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells Nature Medicine 2005 11 1 77 84
30. Insinga A., Monestiroli S., Ronzoni S., Gelmetti V., Marchesi F., Viale A., Altucci L., Nervi C., Minucci S., Pelicci P. G., Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway Nature Medicine 2005 11 1 71 76
31. Ruefli A. A., Ausserlechner M. J., Bernhard D., Sutton V. R., Tainton K. M., Kofler R., Smyth M. J., Johnstone R. W., The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species Proceedings of the National Academy of Sciences of the United States of America 2001 98 19 10833 10838
32. Peart M. J., Tainton K. M., Ruefli A. A., Dear A. E., Sedelies K. A., O'Reilly L. A., Waterhouse N. J., Trapani J. A., Johnstone R. W., Novel mechanisms of apoptosis induced by histone deacetylase inhibitors Cancer Research 2003 63 15 4460 4471
33. Mitsiades C. S., Mitsiades N. S., McMullan C. J., Poulaki V., Shringarpure R., Hideshima T., Akiyama M., Chauhan D., Munshi N., Gu X., Bailey C., Joseph M., Libermann T. A., Richon V. M., Marks P. A., Anderson K. C., Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications Proceedings of the National Academy of Sciences of the United States of America 2004 101 2 540 545
34. Zhao Y., Tan J., Zhuang L., Jiang X., Liu E. T., Yu Q., Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim Proceedings of the National Academy of Sciences of the United States of America 2005 102 44 16090 16095
35. Zhang Y., Adachi M., Kawamura R., Imai K., Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis Cell Death and Differentiation 2006 13 1 129 140
36. Rosato R. R., Almenara J. A., Grant S., The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 Cancer Research 2003 63 13 3637 3645
37. Garca-Morales P., Gmez-Martnez A., Carrato A., Martnez-Lacaci I., Barber V. M., Soto J. L., Carrasco-Garca E., Menndez-Gutierrez M. P., Castro-Galache M. D., Ferragut J. A., Saceda M., Histone deacetylase inhibitors induced caspase-independent apoptosis in human pancreatic adenocarcinoma cell lines Molecular Cancer Therapeutics 2005 4 8 1222 1230
38. Kim M. S., Kwon H. J., Lee Y. M., Baek J. H., Jang J.-E., Lee S.-W., Moon E.-J., Kim H.-S., Lee S.-K., Chung H. Y., Kim C. W., Kim K.-W., Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes Nature Medicine 2001 7 4 437 443
39. Qian D. Z., Kato Y., Shabbeer S., Wei Y., Verheul H. M. W., Salumbides B., Sanni T., Atadja P., Pili R., Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589 Clinical Cancer Research 2006 12 2 634 642
40. Maeda T., Towatari M., Kosugi H., Saito H., Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells Blood 2000 96 12 3847 3856
41. Magner W. J., Kazim A. L., Stewart C., Romano M. A., Catalano G., Grande C., Keiser N., Santaniello F., Tomasi T. B., Activation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitors Journal of Immunology 2000 165 12 7017 7024
42. Zhao S., Venkatasubbarao K., Li S., Freeman J. W., Requirement of a specific Sp1 site for histone deacetylase-mediated repression of transforming growth factor type II receptor expression in human pancreatic cancer cells Cancer Research 2003 63 10 2624 2630
43. Reddy P., Maeda Y., Hotary K., Liu C., Reznikov L. L., Dinarello C. A., Ferrara J. L. M., Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect Proceedings of the National Academy of Sciences of the United States of America 2004 101 11 3921 3926
44. Nusinzon I., Horvath C. M., Interferon-stimulated transcription and innate antiviral immunity require deacetylase activity and histone deacetylase 1 Proceedings of the National Academy of Sciences of the United States of America 2003 100 25 14742 14747
45. Yuan Z.-L., Guan Y.-J., Chatterjee D., Chin Y. E., Stat3 dimerization regulated by reversible acetylation of a single lysine residue Science 2005 307 5707 269 273
46. Moldenhauer A., Frank R. C., Pinilla-Ibarz J., Holland G., Boccuni P., Scheinberg D. A., Salama A., Seeger K., Moore M. A. S., Nimer S. D., Histone deacetylase inhibition improves dendritic cell differentiation of leukemic blasts with AML1-containing fusion proteins Journal of Leukocyte Biology 2004 76 3 623 633
47. Yu C., Rahmani M., Conrad D., Subler M., Dent P., Grant S., The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571 Blood 2003 102 10 3765 3774
48. Nawrocki S. T., Carew J. S., Pino M. S., Highshaw R. A., Andtbacka R. H. I., Dunner K. Jr., Pal A., Bornmann W. G., Chiao P. J., Huang P., Xiong H., Abbruzzese J. L., McConkey D. J., Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells Cancer Research 2006 66 7 3773 3781
49. Maggio S. C., Rosato R. R., Kramer L. B., Dai Y., Rahmani M., Paik D. S., Czarnik A. C., Payne S. G., Spiegel S., Grant S., The histone deacetylase inhibitor MS-275 interacts synergistically with fludarabine to induce apoptosis in human leukemia cells Cancer Research 2004 64 7 2590 2600
50. Jemal A., Murray T., Ward E., Samuels A., Tiwari R. C., Ghafoor A., Feuer E. J., Thun M. J., Cancer statistics, 2005 Ca-A Cancer Journal for Clinicians 2005 55 1 10 30
51. Burris H. A. III, 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 Journal of Clinical Oncology 1997 15 6 2403 2413
52. Moore M. J., Goldstein D., Hamm J., Figer A., Hecht J. R., Gallinger S., Au H. J., Murawa P., Walde D., Wolff R. A., 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 Journal of Clinical Oncology 2007 25 15 1960 1966
53. Kindler H. L., Niedzwiecki D., Hollis D., A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): a preliminary analysis of Cancer and Leukemia Group B (CALGB) Journal of Clinical Oncology 2007 25 18S, article 4508
54. Philip P. A., Benedetti J., Fenoglio-Preiser C., Phase III study of gemcitabine plus cetuximab versus gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma: SWOG S0205 study Journal of Clinical Oncology 2007 25, article LBA4509
55. Rowinsky E. K., Windle J. J., Von Hoff D. D., Ras protein farnesyltransferase: a strategic target for anticancer therapeutic development Journal of Clinical Oncology 1999 17 11 3631 3652
56. Van Cutsem E., Van De Velde H., Karasek P., Oettle H., Vervenne W. L., 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 Journal of Clinical Oncology 2004 22 8 1430 1438
57. Bai J., Sui J., Demirjian A., Vollmer C. M. Jr., Marasco W., Callery M. P., Predominant Bcl-XL knockdown disables antiapoptotic mechanisms: tumor necrosis factor-related apoptosis-inducing ligand-based triple chemotherapy overcomes chemoresistance in pancreatic cancer cells in vitro Cancer Research 2005 65 6 2344 2352
58. Bardeesy N., DePinho R. A., Pancreatic cancer biology and genetics Nature Reviews Cancer 2002 2 12 897 909
59. Cascall M., Calb J., Capell G., Filiat C., Pastor-Anglada M., Mazo A., Enhancement of gemcitabine-induced apoptosis by restoration of p53 function in human pancreatic tumors Oncology 2005 68 2-3 179 189
60. Garca-Morales P., Gmez-Martnez A., Carrato A., Martnez-Lacaci I., Barber V. M., Soto J. L., Carrasco-Garca E., Menndez-Gutierrez M. P., Castro-Galache M. D., Ferragut J. A., Saceda M., Histone deacetylase inhibitors induced caspase-independent apoptosis in human pancreatic adenocarcinoma cell lines Molecular Cancer Therapeutics 2005 4 8 1222 1230
61. Donadelli M., Costanzo C., Beghelli S., Scupoli M. T., Dandrea M., Bonora A., Piacentini P., Budillon A., Caraglia M., Scarpa A., Palmieri M., Synergistic inhibition of pancreatic adenocarcinoma cell growth by trichostatin A and gemcitabine Biochimica et Biophysica Acta 2007 1773 7 1095 1106
62. Bai J., Demirjian A., Sui J., Marasco W., Callery M. P., Histone deacetylase inhibitor trichostatin A and proteasome inhibitor PS-341 synergistically induce apoptosis in pancreatic cancer cells Biochemical and Biophysical Research Communications 2006 348 4 1245 1253
63. Ouassi M., Cabral S., Tavares J., Cordeiro Da Silva A., Mathieu Daude F., Mas E., Bernard J. P., Sastre B., Lombardo D., Ouaissi A., Histone deacetylase (HDAC) encoding gene expression in pancreatic cancer cell lines and cell sensitivity to HDAC inhibitors Cancer Biology and Therapy 2008 7 4 523 531
64. Ouassi M., Sielezneff I., Silvestre R., Sastre B., Bernard J.-P., Lafontaine J. S., Payan M. J., Dahan L., Pirr N., Seitz J. F., Mas E., Lombardo D., Ouaissi A., High histone deacetylase 7 (HDAC7) expression is significantly associated with adenocarcinomas of the pancreas Annals of Surgical Oncology 2008 15 8 2318 2328
65. Gerdes B., Ramaswamy A., Ziegler A., Lang S. A., Kersting M., Baumann R., Wild A., Moll R., Rothmund M., Bartsch D. K., p16INK4a is a prognostic marker in resected ductal pancreatic cancer: an analysis of p16INK4a, p53, MDM2, an Rb Annals of Surgery 2002 235 1 51 59
66. Mottet D., Bellahcne A., Pirotte S., Waltregny D., Deroanne C., Lamour V., Lidereau R., Castronovo V., Histone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis Circulation Research 2007 101 12 1237 1246
67. Marks P. A., Breslow R., Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug Nature Biotechnology 2007 25 1 84 90
68. Dokmanovic M., Perez G., Xu W., Ngo L., Clarke C., Parmigiani R. B., Marks P. A., Histone deacetylase inhibitors selectively suppress expression of HDAC7 Molecular Cancer Therapeutics 2007 6 9 2525 2534
69. Stimson L., La Thangue N. B., Biomarkers for predicting clinical responses to HDAC inhibitors Cancer Letters 2009 280 2 177 183
70. Manuyakorn A., Paulus R., Farrell J., Dawson N. A., Tze S., Cheung-Lau G., Hines O. J., Reber H., Seligson D. B., Horvath S., Kurdistani S. K., Guha C., Dawson D. W., Cellular histone modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma: results from RTOG 9704 Journal of Clinical Oncology 2010 28 8 1358 1365
71. Dequiedt F., Kasler H., Fischle W., Kiermer V., Weinstein M., Herndier B. G., Verdin E., HDAC7, a thymus-specific class II histone deacetylase, regulates Nur77 transcription and TCR-mediated apoptosis Immunity 2003 18 5 687 698
72. Chen J., Fiskus W., Eaton K., Fernandez P., Wang Y., Rao R., Lee P., Joshi R., Yang Y., Kolhe R., Balusu R., Chappa P., Natarajan K., Jillella A., Atadja P., Bhalla K. N., Cotreatment with BCL-2 antagonist sensitizes cutaneous T-cell lymphoma to lethal action of HDAC7-Nur77-based mechanism Blood 2009 113 17 4038 4048
73. Kao H.-Y., Verdel A., Tsai C.-C., Simon C., Juguilon H., Khochbin S., Mechanism for nucleocytoplasmic shuttling of histone deacetylase 7 Journal of Biological Chemistry 2001 276 50 47496 47507
74. Fischle W., Dequiedt F., Fillion M., Hendzel M. J., Voelter W., Verdin E., Human HDAC7 histone deacetylase activity is associated with HDAC3 in vivo Journal of Biological Chemistry 2001 276 38 35826 35835
75. Baylin S. B., Ohm J. E., Epigenetic gene silencing in cancera mechanism for early oncogenic pathway addiction? Nature Reviews Cancer 2006 6 2 107 116
76. Pandolfi P. P., Histone deacetylases and transcriptional therapy with their inhibitors Cancer Chemotherapy and Pharmacology 2001 48 1 S17 S19