Antiproliferative Activity of Artemisia asiatica Extract and Its Constituents on Human Tumor Cell Lines

Abstract

The extract of Artemisia asiatica herb with antiproliferative activity against four human tumor cell lines (A2780, A431, HeLa, and MCF7) was analyzed by the MTT assay, and bioassay-directed fractionation was carried out in order to identify the compounds responsible for the cytotoxic activity. Guaianolide (1–4), seco-guianolide (5), germacranolide (6) and eudesmanolide sesquiterpenes (7), monoterpenes (8, 9), including the new compound artemisia alcohol glucoside (8), and flavonoids (10–16) were isolated as a result of a multistep chromatographic procedure (CC, CPC, PLC, and gel filtration). The compounds were identified by means of UV, MS, and NMR spectroscopy, including ¹H-and ¹³C-NMR, ¹H-¹H COSY, NOESY, HSQC, and HMBC experiments. The isolated compounds 1–16 were evaluated for their tumor cell growth-inhibitory activities on a panel of four adherent cancer cell lines, and different types of secondary metabolites were found to be responsible for the cytotoxic effects of the extract. Especially cirsilineol (13), 3β-chloro-4α,10α-dihydroxy-1α,2α-epoxy-5α,7αH-guai-11(13)-en-12,6α-olide (3), and iso-seco-tanapartholide 3-O-methyl ester (5) exerted marked cytotoxic effects against the investigated cell lines, while jaceosidin (12), 6-methoxytricin (15), artecanin (2), and 5,7,4′,5′-tetrahydroxy-6,3′-dimethoxyflavone (14) were moderately active. All the sesquiterpenes and monoterpenes are reported here for the first time from this species, and in the case of artecanin (2), 3α-chloro-4β,10α-dihydroxy-1β,2β-epoxy-5α,7αH-guai-11(13)-en-12,6α-olide (4), ridentin (6), and ridentin B (7), previously unreported NMR spectroscopic data were determined.

Key words

Artemisia asiatica - Asteraceae - antiproliferative activity - sesquiterpene lactones - monoterpenes - flavonoids

• References

• 1 Morrissey C, Gallis B, Solazzi JW, Kim BJ, Gulati R, Vakar-Lopez F, Goodlett DR, Vessella RL, Sasaki T. Effect of artemisinin derivatives on apoptosis and cell cycle in prostate cancer cells. Anticancer Drugs 2010; 21: 423-432
• 2 Hartwell JL. Plants used against cancer. A survey (Review). Lloydia 1968; 31: 71-170
• 3 Baek YH, Lee KN, Jun DW, Yoon BC, Kim JM, Oh TY, Lee OY. Augmenting effect of DA-9601 on ghrelin in an acute gastric injury model. Gut Liver 2011; 5: 52-56
• 4 Seo HJ, Park KK, Han SS, Chung WY, Son MW, Kim WB, Surh YJ. Inhibitory effects of the standardized extract (DA-9601) of Artemisia asiatica Nakai on phorbol ester-induced ornithine decarboxylase activity, papilloma formation, cyclooxygenase-2 expression, inducible nitric oxide synthase expression and nuclear transcription factor kappa B activation in mouse skin. Int J Cancer 2002; 100: 456-462
• 5 Réthy B, Csupor-Löffler B, Zupkó I, Hajdú Z, Máthé I, Hohmann J, Rédei T, Falkay G. Antiproliferative activity of Hungarian Asteraceae species against human cancer cell lines. Part I. Phytother Res 2007; 21: 1200-1208
• 6 Huneck S, Zdero C, Bohlmann F. Seco-guaianolides and other constituents from Artemisia species. Phytochemistry 1986; 25: 883-889
• 7 Marco JA, Sanz-Cervera JF, Manglano E, Sancenon F, Rustaiyan A, Kardar M. Sesquiterpene lactones from iranian Artemisia species. Phytochemistry 1993; 34: 1561-1564
• 8 Trifunović S, Milosavljević S, Vajs V, Macura S, Todorović N. Stereochemistry and conformations of natural 1,2-epoxy-guaianolides based on 1D and 2D NMR data and semiempirical calculations. Magn Reson Chem 2008; 46: 427-431
• 9 Trifunović S, Vajs V, Juranić Z, Žižak Z, Tešević V, Macura S, Milosavljević S. Cytotoxic constituents of Achillea clavennae from Montenegro. Phytochemistry 2006; 67: 887-893
• 10 Trifunovic S, Aljančić I, Vajs V, Macura S, Milosavljević S. Sesquiterpene lactones and flavonoids of Achillea depressa . Biochem Syst Ecol 2005; 33: 317-322
• 11 Tan RX, Jia JZ, Jakupovic J, Bohlmann F, Huneck S. Sesquiterpene lactones from Artemisia rutifolia . Phytochemistry 1991; 30: 3033-3035
• 12 Irwin MA, Lee KH, Simson RF, Geisman TA. Sesquiterpene lactones of Artemisia. Ridentin. Phytochemistry 1969; 8: 2009-2012
• 13 Asaruddin MR, Honda G, Tsubouchi A, Shimada JN, Aoki T, Kiuchi F. Trypanocydal constituents from Michelia alba . Nat Med 2003; 57: 61-65
• 14 Hajdú Z, Martins A, Orbán-Gyapai O, Forgo P, Jedlinszki N, Máthé I, Hohmann J. Xanthine oxidase inhibitory activity and antioxidant properties of extract and flavonoids of Artemisia asiatica . Rec Nat Prod 2014; 8: 299-302
• 15 Kalemba D. Constituents of the essential oil of Artemisia asiatica Nakai. Flavour Frag J 1999; 14: 173-176
• 16 Kalemba D, Kusewicz D, Świąder K. Antimicrobial properties of the essential oil of Artemisia asiatica Nakai. Phytother Res 2002; 16: 288-291
• 17 Oh TY, Shin CY, Sohn YS, Kim DH, Ahn BO, Lee EB, Park CH. Therapeutic effect of DA-9601 on chronic reflux gastritis induced by sodium taurocholate in rats. World J Gastroenterol 2005; 11: 7430-7435
• 18 Park BB, Yoon JS, Kim ES, Choi J, Won YW, Choi JH, Lee YY. Inhibitory effects of eupatilin on tumor invasion of human gastric cancer MKN-1 cells. Tumor Biol 2013; 34: 875-885
• 19 Reddy AM, Lee JY, Seo JH, Kim BH, Chung EY, Ryu SY, Kim YS, Lee CK, Min KR, Kim Y. Artemisolide from Artemisia asiatica, nuclear factor-kappaB inhibitor suppressing prostaglandin E2 and nitric oxide production in macrophages. Arch Pharm Res 2006; 29: 591-597
• 20 Kim JH, Kim H, Jeon SB, Son K, Kim EH, Kang SK, Sung N, Kwon BM. New sesquiterpene-monoterpene lactone, artemisolide, isolated from Artemisia argyi . Tetrahedron Lett 2002; 43: 6205-6208
• 21 Irwin MA, Geismann TA. Ridentin B: an eudesmanolide from Artemisia tripartita ssp. rupicola . Phytochemistry 1973; 12: 871-873
• 22 Csupor-Löffler B, Hajdú Z, Zupkó I, Molnár J, Forgo P, Vasas A, Kele Z, Hohmann J. Antiproliferative constituents of the roots of Conyza canadensis . Planta Med 2011; 77: 1183-1188
• 23 Forgo P, Zupkó I, Molnár J, Vasas A, Dombi G, Hohmann J. Bioactivity-guided isolation of antiproliferative compounds from Centaurea jacea L. Fitoterapia 2012; 83: 921-925