Pharmacokinetics and pharmacodynamics of orally administered acetylenic tricyclic bis(cyanoenone), a highly potent Nrf2 activator with a reversible covalent mode of action

Biochemical and Biophysical Research Communications

Volumn 465, Issue 3, 2015, Pages 402-407

  Kostov, Rumen V ^a   Knatko, Elena V ^a   McLaughlin, Lesley A ^a   Henderson, Colin J ^a   Zheng, Suqing ^b   Huang, Jeffrey T J ^a   Honda, Tadashi ^b   Dinkova Kostova, Albena T ^a,c  

^a UNIVERSITY OF DUNDEE   (United Kingdom)

^b STONY BROOK UNIVERSITY   (United States)

^c JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Cysteine targeting; Keap1; NQO1; Nrf2; Reversible covalent drug

Indexed keywords

ACETYLENIC TRICYCLIC BIS (CYANOENONE); ALKENE DERIVATIVE; AZATHIOPRINE; CYSTEINE; NAD(P)H QUINONE OXIDOREDUCTASE 1; OXIDOREDUCTASE; TRANSCRIPTION FACTOR NRF2; UNCLASSIFIED DRUG; NFE2L2 PROTEIN, HUMAN; PHENANTHRENE DERIVATIVE; TBE 31;

ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; CARCINOGENESIS; CELL PROTECTION; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG POTENCY; DRUG SAFETY; DRUG STRUCTURE; ENZYME ACTIVITY; FEMALE; HEART; IMMUNOSUPPRESSIVE TREATMENT; IN VIVO STUDY; LIQUID CHROMATOGRAPHY; LIVER; LIVER CARCINOGENESIS; LONG TERM CARE; MASS SPECTROMETRY; MOUSE; NONHUMAN; PLASMA CONCENTRATION-TIME CURVE; PRIORITY JOURNAL; QUANTITATIVE ANALYSIS; SINGLE DRUG DOSE; SKIN CARCINOGENESIS; TREATMENT DURATION; AGONISTS; ANIMAL; ANTIBODY SPECIFICITY; C57BL MOUSE; DOSE RESPONSE; METABOLIC CLEARANCE RATE; ORAL DRUG ADMINISTRATION; SURVIVAL RATE; TISSUE DISTRIBUTION;

ADMINISTRATION, ORAL; ANIMALS; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; METABOLIC CLEARANCE RATE; MICE; MICE, INBRED C57BL; NF-E2-RELATED FACTOR 2; ORGAN SPECIFICITY; PHENANTHRENES; SURVIVAL RATE; TISSUE DISTRIBUTION;

EID: 84940676575     PISSN: 0006291X     EISSN: 10902104     Source Type: Journal    
DOI: 10.1016/j.bbrc.2015.08.016     Document Type: Article

References (36)

1. S. Zheng, Y.R.S. Laxmi, E. David, A.T. Dinkova-Kostova, K.H. Shiavoni, Y. Ren, Y. Zheng, I. Trevino, R. Bumeister, I. Ojima, W.C. Wigley, J.B. Bliska, D.F. Mierke, and T. Honda Synthesis, chemical reactivity as Michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents J. Med. Chem. 55 2012 4837 4846
2. R.M. Miller, V.O. Paavilainen, S. Krishnan, I.M. Serafimova, and J. Taunton Electrophilic fragment-based design of reversible covalent kinase inhibitors J. Am. Chem. Soc. 135 2013 5298 5301
3. A.T. Dinkova-Kostova, W.D. Holtzclaw, R.N. Cole, K. Itoh, N. Wakabayashi, Y. Katoh, M. Yamamoto, and P. Talalay Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants Proc. Natl. Acad. Sci. U. S. A. 99 2002 11908 11913
4. K. Itoh, N. Wakabayashi, Y. Katoh, T. Ishii, K. Igarashi, J.D. Engel, and M. Yamamoto Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain Genes Dev. 13 1999 76 86
5. K. Itoh, T. Chiba, S. Takahashi, T. Ishii, K. Igarashi, Y. Katoh, T. Oyake, N. Hayashi, K. Satoh, I. Hatayama, M. Yamamoto, and Y. Nabeshima An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements Biochem. Biophys. Res. Commun. 236 1997 313 322
6. A. Kobayashi, M.I. Kang, H. Okawa, M. Ohtsuji, Y. Zenke, T. Chiba, K. Igarashi, and M. Yamamoto Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2 Mol. Cell. Biol. 24 2004 7130 7139
7. S.B. Cullinan, J.D. Gordan, J. Jin, J.W. Harper, and J.A. Diehl The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase Mol. Cell. Biol. 24 2004 8477 8486
8. D.D. Zhang, S.C. Lo, J.V. Cross, D.J. Templeton, and M. Hannink Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex Mol. Cell. Biol. 24 2004 10941 10953
9. L. Baird, D. Lleres, S. Swift, and A.T. Dinkova-Kostova Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex Proc. Natl. Acad. Sci. U. S. A. 110 2013 15259 15264
10. M. McMahon, N. Thomas, K. Itoh, M. Yamamoto, and J.D. Hayes Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a "tethering" mechanism: a two-site interaction model for the Nrf2-Keap1 complex J. Biol. Chem. 281 2006 24756 24768
11. M. McMahon, D.J. Lamont, K.A. Beattie, and J.D. Hayes Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals Proc. Natl. Acad. Sci. U. S. A. 107 2010 18838 18843
12. M. Kobayashi, L. Li, N. Iwamoto, Y. Nakajima-Takagi, H. Kaneko, Y. Nakayama, M. Eguchi, Y. Wada, Y. Kumagai, and M. Yamamoto The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds Mol. Cell. Biol. 29 2009 493 502
13. D.D. Zhang, and M. Hannink Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress Mol. Cell. Biol. 23 2003 8137 8151
14. J.D. Hayes, and A.T. Dinkova-Kostova The Nrf2 regulatory network provides an interface between redox and intermediary metabolism Trends Biochem. Sci. 39 2014 199 218
15. K. Liby, M.M. Yore, B.D. Roebuck, K.J. Baumgartner, T. Honda, C. Sundararajan, H. Yoshizawa, G.W. Gribble, C.R. Williams, R. Risingsong, D.B. Royce, A.T. Dinkova-Kostova, K.K. Stephenson, P.A. Egner, M.S. Yates, J.D. Groopman, T.W. Kensler, and M.B. Sporn A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin Cancer Res. 68 2008 6727 6733
16. A.T. Dinkova-Kostova, P. Talalay, J. Sharkey, Y. Zhang, W.D. Holtzclaw, X.J. Wang, E. David, K.H. Schiavoni, S. Finlayson, D.F. Mierke, and T. Honda An exceptionally potent inducer of cytoprotective enzymes: elucidation of the structural features that determine inducer potency and reactivity with Keap1 J. Biol. Chem. 285 2010 33747 33755
17. T. Honda, H. Yoshizawa, C. Sundararajan, E. David, M.J. Lajoie, F.G. Favaloro Jr., T. Janosik, X. Su, Y. Honda, B.D. Roebuck, and G.W. Gribble Tricyclic compounds containing nonenolizable cyano enones. A novel class of highly potent anti-inflammatory and cytoprotective agents J. Med. Chem. 54 2011 1762 1778
18. S. Kalra, E.V. Knatko, Y. Zhang, T. Honda, M. Yamamoto, and A.T. Dinkova-Kostova Highly potent activation of Nrf2 by topical tricyclic bis(cyano enone): implications for protection against UV radiation during thiopurine therapy Cancer Prev. Res. (Phila.) 5 2012 973 981
19. E.V. Knatko, S.H. Ibbotson, Y. Zhang, M. Higgins, J.W. Fahey, P. Talalay, R.S. Dawe, J. Ferguson, J.T. Huang, R. Clarke, S. Zheng, A. Saito, S. Kalra, A.L. Benedict, T. Honda, C.M. Proby, and A.T. Dinkova-Kostova Nrf2 Activation Protects against Solar-Simulated Ultraviolet Radiation in Mice and Humans Cancer Prev. Res. (Phila.) 8 2015 475 486
20. S. Zheng, J.T. Huang, E.V. Knatko, S. Sharp, M. Higgins, I. Ojima, A.T. Dinkova-Kostova, and T. Honda Synthesis of (13) C2 (15) N2 -labeled anti-inflammatory and cytoprotective tricyclic bis(cyanoenone) ([(13) C2 (15) N2 ]-TBE-31) as an internal standard for quantification by stable isotope dilution LC-MS method J. Label. Compd. Radiopharm. 57 2014 606 610
21. H.J. Prochaska, and A.B. Santamaria Direct measurement of NAD(P)H:quinone reductase from cells cultured in microtiter wells: a screening assay for anticarcinogenic enzyme inducers Anal. Biochem. 169 1988 328 336
22. W.H. Habig, and W.B. Jakoby Glutathione S-transferases (rat and human) Methods Enzymol. 77 1981 218 231
23. F. Hong, M.L. Freeman, and D.C. Liebler Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane Chem. Res. Toxicol. 18 2005 1917 1926
24. C. Hu, A.L. Eggler, A.D. Mesecar, and R.B. van Breemen Modification of keap1 cysteine residues by sulforaphane Chem. Res. Toxicol. 24 2011 515 521
25. A.L. Eggler, Y. Luo, R.B. van Breemen, and A.D. Mesecar Identification of the highly reactive cysteine 151 in the chemopreventive agent-sensor Keap1 protein is method-dependent Chem. Res. Toxicol. 20 2007 1878 1884
26. Y. Zhang Molecular mechanism of rapid cellular accumulation of anticarcinogenic isothiocyanates Carcinogenesis 22 2001 425 431
27. L. Ye, and Y. Zhang Total intracellular accumulation levels of dietary isothiocyanates determine their activity in elevation of cellular glutathione and induction of Phase 2 detoxification enzymes Carcinogenesis 22 2001 1987 1992
28. Y. Zhang Role of glutathione in the accumulation of anticarcinogenic isothiocyanates and their glutathione conjugates by murine hepatoma cells Carcinogenesis 21 2000 1175 1182
29. B.S. Cornblatt, L. Ye, A.T. Dinkova-Kostova, M. Erb, J.W. Fahey, N.K. Singh, M.S. Chen, T. Stierer, E. Garrett-Mayer, P. Argani, N.E. Davidson, P. Talalay, T.W. Kensler, and K. Visvanathan Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast Carcinogenesis 28 2007 1485 1490
30. Y. Zhang, Y.H. Ahn, I.J. Benjamin, T. Honda, R.J. Hicks, V. Calabrese, P.A. Cole, and A.T. Dinkova-Kostova HSF1-dependent upregulation of Hsp70 by sulfhydryl-reactive inducers of the KEAP1/NRF2/ARE pathway Chem. Biol. 18 2011 1355 1361
31. T.E. Sussan, J. Jun, R. Thimmulappa, D. Bedja, M. Antero, K.L. Gabrielson, V.Y. Polotsky, and S. Biswal Disruption of Nrf2, a key inducer of antioxidant defenses, attenuates ApoE-mediated atherosclerosis in mice PloS One 3 2008 e3791
32. B. Barajas, N. Che, F. Yin, A. Rowshanrad, L.D. Orozco, K.W. Gong, X. Wang, L.W. Castellani, K. Reue, A.J. Lusis, and J.A. Araujo NF-E2-related factor 2 promotes atherosclerosis by effects on plasma lipoproteins and cholesterol transport that overshadow antioxidant protection Arterioscler. Thromb. Vasc. Biol. 31 2011 58 66
33. N. Harada, K. Ito, T. Hosoya, J. Mimura, A. Maruyama, N. Noguchi, K. Yagami, N. Morito, S. Takahashi, J.M. Maher, M. Yamamoto, and K. Itoh Nrf2 in bone marrow-derived cells positively contributes to the advanced stage of atherosclerotic plaque formation Free Radic. Biol. Med. 53 2012 2256 2262
34. R. Kundu, S. Dasgupta, A. Biswas, S. Bhattacharya, B.C. Pal, P.G. Rao, N.C. Barua, and M. Bordoloi Carlinoside reduces hepatic bilirubin accumulation by stimulating bilirubin-UGT activity through Nrf2 gene expression Biochem. Pharmacol. 82 2011 1186 1197
35. M. Wang, S. Chen, S. Wang, D. Sun, J. Chen, Y. Li, W. Han, X. Yang, and H.Q. Gao Effects of phytochemicals sulforaphane on uridine diphosphate-glucuronosyltransferase expression as well as cell-cycle arrest and apoptosis in human colon cancer Caco-2 cells Chin. J. Physiol. 55 2012 134 144
36. A. Kadakol, S.S. Ghosh, B.S. Sappal, G. Sharma, J.R. Chowdhury, and N.R. Chowdhury Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype Hum. Mutat. 16 2000 297 306