DOI QR코드

DOI QR Code

Inhibitory Effect of Acetylshikonin from Roots of Lithospermum erythrorhizon on LDL Oxidation and FPTase Activity

지치뿌리로부터 분리한 Acetylshikonin의 LDL 산화 저해활성과 FPTase 저해활성

  • Kim, Geum-Soog (Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, RDA) ;
  • Jeong, Tae-Sook (Korea Research Institute of Bioscience & Biotechnology) ;
  • Kwon, Byoung-Mok (Korea Research Institute of Bioscience & Biotechnology) ;
  • Kim, Young-Ok (Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, RDA) ;
  • Cha, Seon-Woo (Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, RDA) ;
  • Song, Kyung-Sik (College of Agriculture and Life Sciences, Kyungpook National University) ;
  • Bek, Nam-In (Graduate School of Biotechnology, Kyung Hee University)
  • 김금숙 (농촌진흥청 국립원예특작과학원 인삼특작부) ;
  • 정태숙 (한국생명공학연구원) ;
  • 권병목 (한국생명공학연구원) ;
  • 김영옥 (농촌진흥청 국립원예특작과학원 인삼특작부) ;
  • 차선우 (농촌진흥청 국립원예특작과학원 인삼특작부) ;
  • 송경식 (경북대학교 농업생명과학대학) ;
  • 백남인 (경희대학교 생명공학원)
  • Published : 2009.12.31

Abstract

Lithospermum erythrorhizon has been known well as one of traditional medicine for fever reduction, detoxication, and blood circulation improvement. This study was carried out to isolate biological active compounds from roots of Lithospermum erythrorhizon and to investigate their low density lipoprotein (LDL) antioxidant and anticancer activities. The hexane extract of Lithospermi Radix has been separated on silica gel chromatography and a naphthoquinone pigment compound 1 has been isolated. The structure of the compound 1 has been identified by spectroscopic technique, including MS and NMR, as acetylshikonin (1). Acetylshikonin showed significantly inhibitory activity on $Cu^{2+}$-induced human LDL oxidation with $IC_{50}$ value of $8.8\;{\mu}M$ and obvious anticancer effect by inhibiting farnesyl:protein transferase (FPTase) activity with $IC_{50}$ value of $23\;{\mu}M$, which suggested that acetylshikonin might be useful for the treatment of atherosclerosis and cancer.

Keywords

References

  1. Ahn BT, Lee SG, Lee SB, Lee ES, Kim JG, Bok SH, and Jeong TS (2001) Low-density lipoprotein-antioxidant constituents of Saururus chinensis. J Nat Prod 64, 1562-1564 https://doi.org/10.1021/np0006061
  2. Bjorkhem I, Henriksson-Freyschuss A, Breuer O, Diczfalusy U, Berglund L, and Henriksson P (1991) The antioxidant butylated hydroxytoluene protects against atherosclerosis. Arterioscler Thromb 11, 15-22
  3. Buege JA and Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52, 302-310 https://doi.org/10.1016/S0076-6879(78)52032-6
  4. Chang YS, Kuo SC, Weng SH, Jan SC, Ko FN, and Teng CM (1993) Inhibition of platelet aggregation by shikonin derivatives isolated from Arnebia euchromoma. Planta Med 59, 401-404 https://doi.org/10.1055/s-2006-959718
  5. Diaz MN, Frei B, Vita JA, and Jr. Keaney JF (1997) Antioxidants and atherosclerotic heart disease. N Engl J Med 337, 408-416 https://doi.org/10.1056/NEJM199708073370607
  6. Havel RJ, Eder HA, and Bragdon JH (1955) The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest 34, 1345-1353 https://doi.org/10.1172/JCI103182
  7. Hsu MF, Chang LC, Huang LJ, Kuo SC, Lee HY, Lu MC, and Wang JP (2009) The influence of acetylshikonin, a natural naphthoquinone, on the production of leukotriene B-4 and thromboxane A(2) in rat neutrophils. Eur J Pharmacol 607, 234-243 https://doi.org/10.1016/j.ejphar.2009.02.005
  8. Hwang SY, Hwang BY, Kang SS, Kim CM, Park JH, Bae KH, Son KH, Lee SH, Chang SY, Kan SJ, Ro JS, and Lee KS (2000) Isolation and quantitative analysis of acetylshikonin from Lithospermi Radix. Kor J Pharmacogn 31, 295-299
  9. Jeong TS, Kim JR, Kim KS, Cho KH, Bae KH, and Lee WS (2004) Inhibiatory effects of multi-substituted benzylidenethiazolidine-2,4-diones on LDL oxidation. Bioorg Med Chem 12, 4017-4023 https://doi.org/10.1016/j.bmc.2004.06.001
  10. Jeong TS, Ryu YB, Kim HY, Curtis-Long MJ, An SJ, Lee JH, Lee WS, and Park KH (2008) Low density lipoprotein (LDL)-antioxidant flavonoids from roots of Sophora flavescens. Biol Pharm Bull 31, 2097-2102 https://doi.org/10.1248/bpb.31.2097
  11. Kwon BM, Kim SH, Baek NI, Lee SI, Kim EJ, Yang JH, Chae BS, Lee JH, Park HW, Park JS, and Kim DK (2009) Farnesyl protein transferase inhibitory components of Polygonum multiflorum. Arch Pharm Res 32, 495-499 https://doi.org/10.1007/s12272-009-1403-y
  12. Lee HJ, Lee HJ, Magesh V, Nam DW, Lee EO, Ahn KS, Jung MH, Ahn KS, Kim DK, Kim JY, and Kim SH (2008) Shikonin, acetylshikonin, and isobutyroylshikonin inhibit VEGF-induced angiogenesis and suppress tumor growth in Lewis lung carcinoma-bearing mice Yakugaku Zasshi 128, 1681-1688 https://doi.org/10.1248/yakushi.128.1681
  13. Lee SH, Kim HK, Seo JM, Kang HM, Kim JH, Son KH, Lee HS, and Kwon BM (2002) Arteminolides B, C, and D, new inhibitors of farnesyl protein transferase from Artemisia argyi. J Org Chem 67, 7670-7675 https://doi.org/10.1021/jo020299z
  14. Lee KS, Ahn DK, Shin MK, Kim CM et al. (1998) In The Encyclopedia of Oriental Herbal Medicine, pp. 4657-4663, Jungdam Pubishing Co., Seoul, Korea
  15. Leonard DM (1997) Ras farnesyltransferase: A new therapeutic target. J Med Chem 40, 2971-2990 https://doi.org/10.1021/jm970226l
  16. Mashima R, Witting PK, and Stecker R (2001) Oxidants and antioxidants in atherosclerosis. Curr Opin Lipidol 12, 411-418 https://doi.org/10.1097/00041433-200108000-00007
  17. Nagnao Y, Nakamura T, Matsuzawa Y, Cho M, Ueda Y, and Kita T (1992) Probucol and atherosclerosis in the Watanabe heritable hyperlipidemic rabbit:long-term antiatherogenic effect and effects on established plaques. Atherosclerosis 92, 131-140 https://doi.org/10.1016/0021-9150(92)90272-I
  18. Omer CA, Chen Z, Diehl RE, Conner MW, Chen HY, Trumbauer ME, Gopal-Truter S, Seeburger G, Bhimnathwala H, Abrams MT, Davide JP, Ellis MS, Gibbs JB, Greenberg I, Hamilton K, Koblan KS, Kral AM, Liu D, Lobell RB, Miller PJ, Mosser SD, O'Neill TJ, Rands E, Schaber MD, Senderak ET, Oliff A, and Kohl NE (2000) Mouse mammary tumor virus-Ki-rasB transgenic mice develop mammary carcinomas that can be growth-inhibited by a farnesyl:protein transferase inhibitor. Cancer Res 60, 2680-2688
  19. Pompliano DL, Rands E, Schaber MD, Mosser SD, Anthony NJ, and Gibs JB (1992) Steady-state kinetic mechanism of ras farnesy1:protein transferase. Biochemistry 31, 3800-3807 https://doi.org/10.1021/bi00130a010
  20. Reiss Y, Goldstein JL, Seabra MC, Casey PJ, and Brown MS (1990a) Inhibition of purified $p21^{ras}$ farnesyl:protein transferase by Cys-AAX tetrapeptides. Cell 62, 81-88 https://doi.org/10.1016/0092-8674(90)90242-7
  21. Reiss Y, Seabra MC, Goldstein JL, and Brown MS (1990b) Purification of ras farnesyl:protein transferase. Methods: Companion Methods Enzymol 1, 241-245 https://doi.org/10.1016/S1046-2023(05)80323-8
  22. Sankawa U, Ebizuka Y, Miyazaki T, Isomura Y, and Otsuka H (1977) Antitumor activity of shikonin and its derivatives. Chem Pharm Bull 25, 1392-1395
  23. Sankawa U, Otsuka H, Kataoka Y, Iitaka Y, Hoshi A, and Kuretani K (1981) Antitumor activity of shikonin and its derivatives. II. X-ray analysis of cyclo-alkannin leucoacetate, tautomerism of alkannin and cyclo-alkannin and antitumor activity of alkannin derivatives. Chem Pharm Bull 29, 116-122
  24. Sekine T, Masumizu T, Maitani Y, and Nagai T (1998) Evaluation of superoxide anion radical scavenging activity of shikonin by electron spin resonance. Int J Pharm 174, 133-139 https://doi.org/10.1016/S0378-5173(98)00256-7
  25. Sharma N, Sharma UK, Gupta AP, Devla, Sinha AK, Lal B, and Ahuja PS (2009) Simultaneous densitometric determination of shikonin, acetylshikonin, and beta-acetoxyisovaleryl-shikonin in ultrasonic-assisted extracts of four Arnebia species using reversed-phase thin layer chromatography. J Sep Sci 32, 3239-3245 https://doi.org/10.1002/jssc.200900129
  26. Staniforth V, Wang SY, Shyur LF, and Yang NS (2004) Shikonins, phytocompounds from Lithospermum erythrorhizon, inhibit the transcriptional activation of human tumor necrosis factor $\acute{a}$ promoter in vivo. J Biol Chem 279, 5877-5885 https://doi.org/10.1074/jbc.M309185200
  27. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, and Witztum JL (1989) Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 320, 915-924 https://doi.org/10.1056/NEJM198904063201407
  28. Tabata M, Tsukada M, and Fukui H (1982) Antimicrobial activity of quinone derivatives from Echium lycopsis callus cultures. Planta Med 44, 234-236 https://doi.org/10.1055/s-2007-971456
  29. Tanaka S, Tajima M, Tsukada M, and Tabata M (1986) A comparative study on anti-inflammatory activities of the enantiomers, shikonin and alkannin J Nat Prod 49, 466-469 https://doi.org/10.1021/np50045a014
  30. Weng XC, Xiang GQ, Jiang AL, Liu YP, Wu LL, Dong XW, and Duan S (2000) Antioxidant properties of components extracted from puccoon (Lithospermum erythrorhizon Sieb. et Zucc.). Food Chem 69, 143-146 https://doi.org/10.1016/S0308-8146(99)00236-8

Cited by

  1. 지치의 생육시기 및 재배지역별 시코닌계 색소 함량 및 항산화 활성 vol.19, pp.6, 2009, https://doi.org/10.7783/kjmcs.2011.19.6.435
  2. 지치 육묘시 발생하는 유묘썩음증상 원인균 분리·동정 및 경감 육묘환경에 관한 연구 vol.21, pp.1, 2013, https://doi.org/10.7783/kjmcs.2013.21.1.27
  3. 지치의 초임계추출물, Shikonin 및 Acetylshikonin의 연골세포 및 MIA 유도 관절염 모델에서의 효과 vol.21, pp.6, 2013, https://doi.org/10.7783/kjmcs.2013.21.6.466