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Saussurea Lappa Radix-induced cytotoxicity via ROS generation in A549 lung cancer cells  

Lee, Young-Joon (Department of Preventive Medicine, College of Korean Medicine, Daegu Haany University)
Ku, Sae-Kwang (Medical Research Center for Globalization of Herbal Formulation, Daegu Haany University)
Kang, Su-Jin (Department of Preventive Medicine, College of Korean Medicine, Daegu Haany University)
Publication Information
Journal of Society of Preventive Korean Medicine / v.17, no.2, 2013 , pp. 169-178 More about this Journal
Abstract
Objectives : Many cancers acquired resistance to chemotherapy, thus limiting its anticancer efficacy. It is known that Glutathione (GSH) is related to the development of drug resistance. The expression of GSH synthesizing glutamylcysteine ligase (GCL) was controlled by nuclear factor-E2-related factor(Nrf2). Previous studies showed that pharmacological depletion of GSH results in ROS increase, apoptotic response, and sensitization to oxidizing stimuli. In the current study, we examined Saussurea Lappa (SL) have the inhibitory effect on Nrf2 activity using human lung cancer A549 cells overexpressing Nrf2. Methods : Cell viability of A549 cells on SL treatment was determined by MTT assay. To detect the apeptosis in SL-treated A549 cells, sub-G1 population was measured by flow cytometry analysis (FACS). The level ROS was determined by FACS and fluorescence microscopy. To investigate whether SL have effect the suppression on Nrf2, we performed western blotting analysis. The GSH content was measured since GSH plays an important role in response to oxidative stress and was regulated by Nrf2. Results : A549 cells treated with an SL extract showed a substantial decrease in cell viability, along with a concomitant increase in apoptosis compared to untreated cells. Treatment of the SL extract led to increased Reactive oxygen species (ROS) production and a suppression of Nrf2. In addition, the antioxidant NAC attenuated SL-induced ROS generation, Nrf2 inhibition, and apoptosis. Taken together, these data show that the SL extract induced the production of ROS, and the inhibition of Nrf2, consequently resulting in A549 cell death. Conclusions : These results suggest that SL might be an effective agent to enhance anticancer drug sensitivity via Nrf2 inhibition.
Keywords
Saussurea Lappa Radix; Nrf2; ROS; GSH; A549;
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1 Kartalou M, Essigmann JM. Mechanisms of resistance to cisplatin. Mutation Research/ Fundamental and Molecular Mechanisms of Mutagenesis. 2001;478(1):23-43.   DOI   ScienceOn
2 Fojo T, Bates S. Strategies for reversing drug resistance. Oncogene. 2003;22(47):7512- 7523.   DOI   ScienceOn
3 Kobayashi M, Yamamoto M. Molecular mechanisms activating the Nrf2- Keap1 pathway of antioxidant gene regulation. Antioxidants & redox signaling. 2005;7(3-4):385-394.   DOI   ScienceOn
4 Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007;47:89-116.   DOI   ScienceOn
5 Kwak M-K, Wakabayashi N, Kensler TW. Chemoprevention through the Keap1?Nrf2 signaling pathway by phase 2 enzyme inducers. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 2004;555(1):133-148.   DOI   ScienceOn
6 ChoH-Y, Reddy SP, Kleeberger SR. Nrf2 defends the lung from oxidative stress. Antioxidants & redox signaling. 2006;8(1-2): 76-87.   DOI   ScienceOn
7 Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, Herman JG, Baylin SB, Sidransky D, Gabrielson E. DysfunctionalKEAP1?NRF2 interaction in non-small-celllungcancer. PLoS medicine. 2006;3(10):e420.   DOI
8 Padmanabhan B, Tong KI, Ohta T, Nakamura Y, Scharlock M, Ohtsuji M, Kang M-I, Kobayashi A, Yokoyama S, Yamamoto M. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Molecular cell. 2006;21(5): 689-700.   DOI   ScienceOn
9 본초학교수 전한. 本草學. 서울: 영림사; 1992. 353-354 p.
10 Lee M-G, Lee K-T, Chi S-G, Park J-H. Constunolide Induces Apoptosis by ROS-mediated Mitochondrial Permeability Transition and Cytochrome C Release. Biological and Pharmaceutical Bulletin. 2001;24(3):303-306.   DOI   ScienceOn
11 Bensky D, Gamble A. Chinese herbal medicine: materia medica: Eastland Press Seattle; 1986.339-340p.
12 Matsuda H, Kageura T, Inoue Y, Morikawa T, Yoshikawa M. Absolute Stereostructures and Syntheses of Saussureamines A, B, C, D and E, Amino Acid? Sesquiterpene Conjugates with Gastroprotective Effect, from the Roots of Saussurea lappa. Tetrahedron. 2000;56(39): 7763-7777.   DOI   ScienceOn
13 obles M, Aregullin M, West J, Rodriguez E. Recent Studies on the Zoopharmacognosy, Pharmacology and Neurotoxicology of Sesquiterpene Lactones. Planta medica.1995; 61(03):199-203.   DOI   ScienceOn
14 Ohta T, Iijima K, Miyamoto M, Nakahara I, Tanaka H, Ohtsuji M, Suzuki T, Kobayashi A, Yokota J, Sakiyama T. Loss of Keap1 function activates Nrf2 and provides advantages forlung cancer cell growth. Cancer research. 2008;68(5):1303-1309.   DOI   ScienceOn
15 hnishi M, Yoshimi N, Kawamori T, Ino N, Hirose Y, Tanaka T, Yamahara J, Miyata H, Mori H. Inhibitory Effects of Dietary Protocatechuic Acid and Costunolide on 7, 12?Dimethylbenz [a] anthracene?induced Hamster Cheek Pouch Carcinogenesis. Cancer Science. 1997;88(2):111-119.   DOI
16 atsuda H, ToguchidaI, Ninomiya K, Kageura T, Morikawa T, Yoshikawa M. Effects of sesquiterpenes and aminoacid-sesquiterpene conjugates from the roots of Saussurea lappaon inducible nitric oxide synthase and heat shock protein in lipopolysaccharide- activated macrophages. Bioorganic & medicinal chemistry. 2003;11(5):709-715.   DOI   ScienceOn
17 Ko SG, Kim H-P, Jin D-H, BaeH-S, Kim SH, Park C-H, Lee JW. Saussurea lappa induces G2-growth arrest and apoptosisin AGS gastric cancer cells. Cancer letters. 2005;220(1):11-19.   DOI   ScienceOn
18 May JM, QuZ-C, Whitesell RR, Cobb CE. Ascorbate recycling in human erythrocytes: role of GSH in reducing dehydroascorbate. Free radical biology and medicine.1996; 20(4):543-551.   DOI   ScienceOn
19 Anderson MF, Nilsson M, Eriksson PS, Sims NR. Glutathione monoethyl ester provides neuroprotection in a rat model of stroke. Neuroscience letters. 2004;354(2): 163-165.   DOI   ScienceOn
20 Habib GM, Shi Z-Z, Lieberman MW. Glutathione protects cells against arseniteinduced toxicity. Free radical biology and medicine. 2007;42(2):191-201.   DOI   ScienceOn
21 Rahman I, Biswas SK, Jimenez LA, Torres M, Forman HJ. Glutathione, stress responses, and redox signaling in lung inflammation. Antioxidants & redox signaling. 2005;7 (1-2):42-59.   DOI   ScienceOn