Caffeic acid, morin hydrate and quercetin partially attenuate sulfur mustard-induced cell death by inhibiting the lipoxygenase pathway

Kim,Shin; Jeong,Kwang‑Joon; Cho,Sung  Kweon; Park,Joo‑Won; Park,Woo‑Jae

doi:10.3892/mmr.2016.5766

Caffeic acid, morin hydrate and quercetin partially attenuate sulfur mustard-induced cell death by inhibiting the lipoxygenase pathway

Authors:
- Shin Kim
- Kwang‑Joon Jeong
- Sung Kweon Cho
- Joo‑Won Park
- Woo‑Jae Park
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Affiliations: Department of Immunology, School of Medicine, Keimyung University, Daegu 406‑799, Republic of Korea, Department of Research, The Armed Forces Medical Research Institute, Daejeon 305‑878, Republic of Korea, Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158‑710, Republic of Korea
Published online on: September 23, 2016 https://doi.org/10.3892/mmr.2016.5766
Pages: 4454-4460

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Abstract

Sulfur mustard (SM) is an alkylating agent, which has been used as in chemical warfare in a number of conflicts. As the generation of reactive oxygen species (ROS), and adducts in DNA and proteins have been suggested as the mechanism underlying SM‑induced cytotoxicity, the present study screened several antioxidant candidates, including tannic acid, deferoxamine mesylate, trolox, vitamin C, ellagic acid and caffeic acid (CA) to assess their potential as therapeutic agents for SM‑induced cell death. Among several antioxidants, CA partially alleviated SM‑induced cell death in a dose‑dependent manner. Although CA treatment decreased the phosphorylation of p38 mitogen‑activated protein (MAP) kinase and p53, p38 MAP kinase inhibition by SB203580 did not affect SM‑induced cell death. As CA has also been reported as a 15‑lipoxygenase (15‑LOX) inhibitor, the role of 15‑LOX in SM‑induced cytotoxicity was also examined. Similar to the results observed with CA, treatment with PD146176, a specific 15‑LOX inhibitor, decreased SM‑induced cytotoxicity, accompanied by decreases in the production of tumor necrosis factor‑α and 15‑hydroxyeicosatetraenoic acid. Furthermore, the present study investigated the protective effects of two natural 15‑LOX inhibitors, morin hydrate and quercetin, in SM‑induced cytotoxicity. As expected, these inhibitors had similar protective effects against SM‑induced cytotoxicity. These antioxidants also reduced the generation of ROS and nitrate/nitrite. Therefore, the results of the present study indicated that the natural products, CA, quercetin and morin hydrate, offer potential as adjuvant therapeutic agents for SM‑induced toxicity, not only by reducing inflammation mediated by the p38 and LOX signaling pathways, but also by decreasing the generation of ROS and nitrate/nitrite.

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1	Kehe K, Balszuweit F, Steinritz D and Thiermann H: Molecular toxicology of sulfur mustard-induced cutaneous inflammation and blistering. Toxicology. 263:12–19. 2009. View Article : Google Scholar : PubMed/NCBI
2	Ries C, Popp T, Egea V, Kehe K and Jochum M: Matrix metalloproteinase-9 expression and release from skin fibroblasts interacting with keratinocytes: Upregulation in response to sulphur mustard. Toxicology. 263:26–31. 2009. View Article : Google Scholar : PubMed/NCBI
3	McClintock SD, Hoesel LM, Das SK, Till GO, Neff T, Kunkel RG, Smith MG and Ward PA: Attenuation of half sulfur mustard gas-induced acute lung injury in rats. J Appl Toxicol. 26:126–131. 2006. View Article : Google Scholar : PubMed/NCBI
4	Kehe K, Raithel K, Kreppel H, Jochum M, Worek F and Thiermann H: Inhibition of poly (ADP-ribose) polymerase (PARP) influences the mode of sulfur mustard (SM)-induced cell death in HaCaT cells. Arch Toxicol. 82:461–470. 2008. View Article : Google Scholar : PubMed/NCBI
5	Simbulan-Rosenthal CM, Ray R, Benton B, Soeda E, Daher A, Anderson D, Smith WJ and Rosenthal DS: Calmodulin mediates sulfur mustard toxicity in human keratinocytes. Toxicology. 227:21–35. 2006. View Article : Google Scholar : PubMed/NCBI
6	Dillman JF III, McGary KL and Schlager JJ: An inhibitor of p38 MAP kinase downregulates cytokine release induced by sulfur mustard exposure in human epidermal keratinocytes. Toxicol In Vitro. 18:593–599. 2004. View Article : Google Scholar : PubMed/NCBI
7	Rebholz B, Kehe K, Ruzicka T and Rupec RA: Role of NF-kappaB/RelA and MAPK pathways in keratinocytes in response to sulfur mustard. J Invest Dermatol. 128:1626–1632. 2008. View Article : Google Scholar : PubMed/NCBI
8	Pal A, Tewari-Singh N, Gu M, Agarwal C, Huang J, Day BJ, White CW and Agarwal R: Sulfur mustard analog induces oxidative stress and activates signaling cascades in the skin of SKH-1 hairless mice. Free Radic Biol Med. 47:1640–1651. 2009. View Article : Google Scholar : PubMed/NCBI
9	Paromov V, Suntres Z, Smith M and Stone WL: Sulfur mustard toxicity following dermal exposure: Role of oxidative stress and antioxidant therapy. J Burns Wounds. 7:e72007.PubMed/NCBI
10	Kumar O, Sugendran K and Vijayaraghavan R: Protective effect of various antioxidants on the toxicity of sulphur mustard administered to mice by inhalation or percutaneous routes. Chem Biol Interact. 134:1–12. 2001. View Article : Google Scholar : PubMed/NCBI
11	Naghii MR: Sulfur mustard intoxication, oxidative stress, and antioxidants. Mil Med. 167:573–575. 2002.PubMed/NCBI
12	Gamaro GD, Suyenaga E, Borsoi M, Lermen J, Pereira P and Ardenghi P: Effect of rosmarinic and caffeic acids on inflammatory and nociception process in rats. ISRN Pharmacol. 2011:4516822011. View Article : Google Scholar : PubMed/NCBI
13	Natarajan K, Singh S, Burke TR Jr, Grunberger D and Aggarwal BB: Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proc Natl Acad Sci USA. 93:9090–9095. 1996. View Article : Google Scholar : PubMed/NCBI
14	Sud'ina GF, Mirzoeva OK, Pushkareva MA, Korshunova GA, Sumbatyan NV and Varfolomeev SD: Caffeic acid phenethyl ester as a lipoxygenase inhibitor with antioxidant properties. FEBS Lett. 329:21–24. 1993. View Article : Google Scholar : PubMed/NCBI
15	Sultana B and Anwar F: Flavonols (kaempeferol, quercetin, myricetin) contents of selected fruits, vegetables and medicinal plants. Food Chem. 108:879–884. 2008. View Article : Google Scholar : PubMed/NCBI
16	Rattanachaikunsopon P and Phumkhachorn P: Bacteriostatic effect of flavonoids isolated from leaves of Psidium guajava on fish pathogens. Fitoterapia. 78:434–436. 2007. View Article : Google Scholar : PubMed/NCBI
17	Brash AR: Lipoxygenases: Occurrence, functions, catalysis, and acquisition of substrate. J Biol Chem. 274:23679–23682. 1999. View Article : Google Scholar : PubMed/NCBI
18	Minsavage GD and Dillman JF III: Bifunctional alkylating agent-induced p53 and nonclassical nuclear factor kappaB responses and cell death are altered by caffeic acid phenethyl ester: A potential role for antioxidant/electrophilic response-element signaling. J Pharmacol Exp Ther. 321:202–212. 2007. View Article : Google Scholar : PubMed/NCBI
19	Sadik CD, Sies H and Schewe T: Inhibition of 15-lipoxygenases by flavonoids: Structure-activity relations and mode of action. Biochem Pharmacol. 65:773–781. 2003. View Article : Google Scholar : PubMed/NCBI
20	Black AT, Joseph LB, Casillas RP, Heck DE, Gerecke DR, Sinko PJ, Laskin DL and Laskin JD: Role of MAP kinases in regulating expression of antioxidants and inflammatory mediators in mouse keratinocytes following exposure to the half mustard, 2-chloroethyl ethyl sulfide. Toxicol Appl Pharmacol. 245:352–360. 2010. View Article : Google Scholar : PubMed/NCBI
21	Lefkowitz LJ and Smith WJ: Sulfur mustard-induced arachidonic acid release is mediated by phospholipase D in human keratinocytes. Biochem Biophys Res Commun. 295:1062–1067. 2002. View Article : Google Scholar : PubMed/NCBI
22	Gerecke DR, Chen M, Isukapalli SS, Gordon MK, Chang YC, Tong W, Androulakis IP and Georgopoulos PG: Differential gene expression profiling of mouse skin after sulfur mustard exposure: Extended time response and inhibitor effect. Toxicol Appl Pharmacol. 234:156–165. 2009. View Article : Google Scholar : PubMed/NCBI
23	Folco G and Murphy RC: Eicosanoid transcellular biosynthesis: From cell-cell interactions to in vivo tissue responses. Pharmacol Rev. 58:375–388. 2006. View Article : Google Scholar : PubMed/NCBI
24	Seiler A, Schneider M, Förster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E, Rådmark O, Wurst W, et al: Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 8:237–248. 2008. View Article : Google Scholar : PubMed/NCBI
25	Gu J, Liu Y, Wen Y, Natarajan R, Lanting L and Nadler JL: Evidence that increased 12-lipoxygenase activity induces apoptosis in fibroblasts. J Cell Physiol. 186:357–365. 2001. View Article : Google Scholar : PubMed/NCBI
26	Wang H, Li J, Follett PL, Zhang Y, Cotanche DA, Jensen FE, Volpe JJ and Rosenberg PA: 12-Lipoxygenase plays a key role in cell death caused by glutathione depletion and arachidonic acid in rat oligodendrocytes. Eur J Neurosci. 20:2049–2058. 2004. View Article : Google Scholar : PubMed/NCBI
27	Li Y, Maher P and Schubert D: A role for 12-lipoxygenase in nerve cell death caused by glutathione depletion. Neuron. 19:453–463. 1997. View Article : Google Scholar : PubMed/NCBI
28	Martínez-Clemente M, Ferré N, González-Périz A, López-Parra M, Horrillo R, Titos E, Morán-Salvador E, Miquel R, Arroyo V, Funk CD and Clària J: 5-lipoxygenase deficiency reduces hepatic inflammation and tumor necrosis factor alpha-induced hepatocyte damage in hyperlipidemia-prone ApoE-null mice. Hepatology. 51:817–827. 2010. View Article : Google Scholar : PubMed/NCBI
29	Wen Y, Gu J, Chakrabarti SK, Aylor K, Marshall J, Takahashi Y, Yoshimoto T and Nadler JL: The role of 12/15-lipoxygenase in the expression of interleukin-6 and tumor necrosis factor-alpha in macrophages. Endocrinology. 148:1313–1322. 2007. View Article : Google Scholar : PubMed/NCBI
30	Schade UF, Ernst M, Reinke M and Wolter DT: Lipoxygenase inhibitors suppress formation of tumor necrosis factor in vitro and in vivo. Biochem Biophys Res Commun. 159:748–754. 1989. View Article : Google Scholar : PubMed/NCBI
31	Zhang R, Kang KA, Piao MJ, Maeng YH, Lee KH, Chang WY, You HJ, Kim JS, Kang SS and Hyun JW: Cellular protection of morin against the oxidative stress induced by hydrogen peroxide. Chem Biol Interact. 177:21–27. 2009. View Article : Google Scholar : PubMed/NCBI
32	Dugas AJ, Castañeda-Acosta J, Bonin GC, Price KL, Fischer NH and Winston GW: Evaluation of the total peroxyl radical-scavenging capacity of flavonoids: Structure-activity relationships. J Nat Prod. 63:327–331. 2000. View Article : Google Scholar : PubMed/NCBI
33	Chen YJ, Shiao MS and Wang SY: The antioxidant caffeic acid phenethyl ester induces apoptosis associated with selective scavenging of hydrogen peroxide in human leukemic HL-60 cells. Anticancer Drugs. 12:143–149. 2001. View Article : Google Scholar : PubMed/NCBI
34	Choi K and Choi C: Differential regulation of c-Jun N-terminal kinase and NF-kappaB pathway by caffeic acid phenethyl ester in astroglial and monocytic cells. J Neurochem. 105:557–564. 2008. View Article : Google Scholar : PubMed/NCBI