E.-H. Chew et al. / Free Radical Biology & Medicine 48 (2010) 98–111
111
[17] Rushmore, T. H.; Morton, M. R.; Pickett, C. B. The antioxidant responsive element:
activation by oxidative stress and identification of the DNA consensus sequence
required for functional activity. J. Biol. Chem. 266:11632–11639; 1991.
[18] Ramos-Gomez, M.; Kwak, M. K.; Dolan, P. M.; Itoh, K.; Yamamoto, M.; Talalay, P.;
Kensler, T. W. Sensitivity to carcinogenesis is increased and chemoprotective
efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc.
Natl. Acad. Sci. USA 98:3410–3415; 2001.
mechanism of thioredoxin reductase from human placenta is similar to the
mechanisms of lipoamide dehydrogenase and glutathione reductase and is dis-
tinct from the mechanism of thioredoxin reductase from Escherichia coli. Proc.
Natl. Acad. Sci. USA 94:3621–3626; 1997.
[36] Hintze, K. J.; Wald, K. A.; Zeng, H.; Jeffery, E. H.; Finley, J. W. Thioredoxin
reductase in human hepatoma cells is transcriptionally regulated by sulfor-
aphane and other electrophiles via an antioxidant response element. J. Nutr. 133:
2721–2727; 2003.
[19] Zhang, D. D. Mechanistic studies of the Nrf2–Keap1 signaling pathway. Drug
Metab. Rev. 38:769–789; 2006.
[20] Li, W.; Kong, A. N. Molecular mechanisms of Nrf2-mediated antioxidant response.
Mol. Carcinog. 48:91–104; 2009.
[37] Chen, Z. H.; Saito, Y.; Yoshida, Y.; Sekine, A.; Noguchi, N.; Niki, E. 4-
Hydroxynonenal induces adaptive response and enhances PC12 cell tolerance
primarily through induction of thioredoxin reductase 1 via activation of Nrf2.
J. Biol. Chem. 280:41921–41927; 2005.
[38] Liao, B. C.; Hsieh, C. W.; Liu, Y. C.; Tzeng, T. T.; Sun, Y. W.; Wung, B. S.
Cinnamaldehyde inhibits the tumor necrosis factor-alpha-induced expression of
cell adhesion molecules in endothelial cells by suppressing NF-kappaB activation:
effects upon IkappaB and Nrf2. Toxicol. Appl. Pharmacol. 229:161–171; 2008.
[39] Wondrak, G. T.; Cabello, C. M.; Villeneuve, N. F.; Zhang, S.; Ley, S.; Li, Y.; Sun, Z.;
Zhang, D. D. Cinnamoyl-based Nrf2-activators targeting human skin cell photo-
oxidative stress. Free Radic. Biol. Med. 45:385–395; 2008.
[40] Masutani, H.; Otsuki, R.; Yamaguchi, Y.; Takenaka, M.; Kanoh, N.; Takatera, K.;
Kunimoto, Y.; Yodoi, J. Fragrant unsaturated aldehydes elicit activation of the
Keap1/Nrf2 System leading to the up-regulation of thioredoxin expression and
protection against oxidative stress. Antioxid. Redox. Signaling 11:949–962;
2009.
[41] Ka, H.; Park, H. J.; Jung, H. J.; Choi, J. W.; Cho, K. S.; Ha, J.; Lee, K. T.
Cinnamaldehyde induces apoptosis by ROS-mediated mitochondrial permeabil-
ity transition in human promyelocytic leukemia HL-60 cells. Cancer Lett. 196:
143–152; 2003.
[42] Lee, C. W.; Hong, D. H.; Han, S. B.; Park, S. H.; Kim, H. K.; Kwon, B. M.; Kim, H. M.
Inhibition of human tumor growth by 2′-hydroxy- and 2′-benzoyloxycinnamal-
dehydes. Planta. Med. 65:263–266; 1999.
[43] Kwon, B. M.; Cho, Y. K.; Lee, S. H.; Nam, J. Y.; Bok, S. H.; Chun, S. K.; Kim, J. A.; Lee,
I. R. 2′-Hydroxycinnamaldehyde from stem bark of Cinnamomum cassia. Planta.
Med. 62:183–184; 1996.
[44] Kwon, B. M.; Lee, S. H.; Cho, Y. K.; Bok, S. H.; So, S. H.; Youn, M. R.; Chang, S. I.
Synthesis and biological activity of cinnamaldehydes as angiogenesis inhibitors.
Bioorg. Med. Chem. Lett. 7:2473–2476; 1997.
[45] Moon, E. Y.; Lee, M. R.; Wang, A. G.; Lee, J. H.; Kim, H. C.; Kim, H. M.; Kim, J. M.;
Kwon, B. M.; Yu, D. Y. Delayed occurrence of H-ras12V-induced hepatocellular
carcinoma with long-term treatment with cinnamaldehydes. Eur. J. Pharmacol.
530:270–275; 2006.
[21] Dinkova-Kostova, A. T.; Holtzclaw, W. D.; Kensler, T. W. The role of Keap1 in
cellular protective responses. Chem. Res. Toxicol. 18:1779–1791; 2005.
[22] Fang, J.; Lu, J.; Holmgren, A. Thioredoxin reductase is irreversibly modified by
curcumin: a novel molecular mechanism for its anticancer activity. J. Biol. Chem.
280:25284–25290; 2005.
[23] Lu, J.; Papp, L. V.; Fang, J.; Rodriguez-Nieto, S.; Zhivotovsky, B.; Holmgren, A.
Inhibition of mammalian thioredoxin reductase by some flavonoids: implica-
tions for myricetin and quercetin anticancer activity. Cancer Res. 66:4410–4418;
2006.
[24] Talalay, P.; De Long, M. J.; Prochaska, H. J. Identification of a common chemical
signal regulating the induction of enzymes that protect against chemical
carcinogenesis. Proc. Natl. Acad. Sci. USA 85:8261–8265; 1988.
[25] Dinkova-Kostova, A. T.; Massiah, M. A.; Bozak, R. E.; Hicks, R. J.; Talalay, P. Potency
of Michael reaction acceptors as inducers of enzymes that protect against
carcinogenesis depends on their reactivity with sulfhydryl groups. Proc. Natl.
Acad. Sci. USA 98:3404–3409; 2001.
[26] Arnér, E. S. J.; Sarioglu, H.; Lottspeich, F.; Holmgren, A.; Böck, A. High-level
expression in Escherichia coli of selenocysteine-containing rat thioredoxin
reductase utilizing gene fusions with engineered bacterial-type SECIS elements
and co-expression with the selA, selB and selC genes. J. Mol. Biol. 292:1003–1016;
1999.
[27] Jeong, H. W.; Kim, M. R.; Son, K. H.; Han, M. Y.; Ha, J. H.; Garnier, M.; Meijer, L.;
Kwon, B. M. Cinnamaldehydes inhibit cyclin dependent kinase 4/cyclin D1.
Bioorg. Med. Chem. Lett. 10:1819–1822; 2000.
[28] Arner, E. S. J.; Holmgren, A. Measurement of thioredoxin and thioredoxin
reductase. In: Maines, M.D., Costa, L.G., Reed, D.J., Sassa, S., Sipes, I.G. (Eds.),
Current Protocols in Toxicology, Suppl. 5. Wiley, New York, pp. 7.4.1–7.4.14; 2000.
[29] Dhakshinamoorthy, S.; Porter, A. G. Nitric oxide-induced transcriptional up-
regulation of protective genes by Nrf2 via the antioxidant response element
counteracts apoptosis of neuroblastoma cells. J. Biol. Chem. 279:20096–20107;
2004.
[30] Han, D. C.; Lee, M. Y.; Shin, K. D.; Jeon, S. B.; Kim, J. M.; Son, K. H.; Kim, H. C.; Kim,
H. M.; Kwon, B. M. 2′-Benzoyloxycinnamaldehyde induces apoptosis in human
carcinoma via reactive oxygen species. J. Biol. Chem. 279:6911–6920; 2004.
[31] Wu, S. J.; Ng, L. T. MAPK inhibitors and pifithrin-alpha block cinnamaldehyde-
induced apoptosis in human PLC/PRF/5 cells. Food Chem. Toxicol. 45:2446–2453;
2007.
[46] Kwon, B. M.; Lee, S. H.; Choi, S. U.; Park, S. H.; Lee, C. O.; Cho, Y. K.; Sung, N. D.; Bok,
S. H. Synthesis and in vitro cytotoxicity of cinnamaldehydes to human solid tumor
cells. Arch. Pharmacal. Res. 21:147–152; 1998.
[47] Kim, S. Y.; Lee, K. J.; Shin, Y. H.; Lee, C. H. Physicochemical properties of
2′-benzoyloxycinnamaldehyde. Int. J. Pharm. 287:21–26; 2004.
[48] Lee, K.; Kwon, B. M.; Kim, K.; Ryu, J.; Oh, S. J.; Lee, K. S.; Kwon, M. G.; Park, S. K.;
Kang, J. S.; Lee, C. W.; Kim, H. M. Plasma pharmacokinetics and metabolism of the
antitumour drug candidate 2′-benzoyloxycinnamaldehyde in rats. Xenobiotica 39:
255–265; 2009.
[32] Cenas, N.; Nivinskas, H.; Anusevicius, Z.; Sarlauskas, J.; Lederer, F.; Arnér, E. S.
Interactions of quinones with thioredoxin reductase: a challenge to the anti-
oxidant role of the mammalian selenoprotein. J. Biol. Chem. 279:2583–2592; 2004.
[33] Gasdaska, P. Y.; Gasdaska, J. R.; Cochran, S.; Powis, G. Cloning and sequencing of a
human thioredoxin reductase. FEBS Lett. 373:5–9; 1995.
[34] Zhong, L.; Arnér, E. S. J.; Holmgren, A. Structure and mechanism of mammalian
thioredoxin reductase: the active site is a redox-active selenolthiol/selenenyl-
sulfide formed from the conserved cysteine–selenocysteine sequence. Proc. Natl.
Acad. Sci. USA 97:5854–5859; 2000.
[49] Hong, S. H.; Kim, J.; Kim, J. M.; Lee, S. Y.; Shin, D. S.; Son, K. H.; Han, D. C.; Sung,
Y. K.; Kwon, B. M. Apoptosis induction of 2′-hydroxycinnamaldehyde as
a
proteasome inhibitor is associated with ER stress and mitochondrial perturba-
tion in cancer cells. Biochem. Pharmacol. 74:557–565; 2007.
[50] Park, Y. S.; Misonou, Y.; Fujiwara, N.; Takahashi, M.; Miyamoto, Y.; Koh, Y. H.;
Suzuki, K.; Taniguchi, N. Induction of thioredoxin reductase as an adaptive
response to acrolein in human umbilical vein endothelial cells. Biochem. Biophys.
Res. Commun. 327:1058–1065; 2005.
[35] Arscott, L. D.; Gromer, S.; Schirmer, R. H.; Becker, K.; Williams Jr., C. H. The