Synergistic Cytotoxic Effect of the Microtubule Inhibitor Marchantin A from Marchantia polymorpha and the Aurora Kinase Inhibitor MLN8237 on Breast Cancer Cells In Vitro

Abstract

Macrocyclic bisbibenzyls are a class of characteristic compounds, exclusively produced by liverworts. They are attracting increasing attention due to their wide range of biological activities, including antibacterial, antifungal, and antioxidative properties as well as cytotoxicity. Marchantin A is a cyclic bisbibenzyl that has previously been isolated from Marchantia polymorpha and other liverwort species and has been shown to exert cytotoxic effects. In the present study we found that the Icelandic M. polymorpha species produces marchantin A and through an in vitro cell growth inhibition assay, marchantin A was shown to induce a reduction in cell viability of breast cancer cell lines A256 (IC₅₀ = 5.5 µM), MCF7 (IC₅₀ = 11.5 µM), and T47D (IC₅₀ = 15.3 µM). The effect was considerably increased in all cell lines in a synergistic manner when the Aurora-A kinase inhibitor MLN8237 was added simultaneously. Fluorescence microscopy confirmed the antimicrotubular effect of marchantin A, and cell cycle analysis indicated enhanced cell division failure when combining this mitotic-spindle inhibitor with the checkpoint modulator.

Key words

marchantin A - Marchantia polymorpha - Marchantiaceae - Aurora-A kinase inhibitor - breast cancer cells - synergism

References

• 1 Huang W J, Wu C L, Lin C W, Chi L L, Chen P Y, Chiu C J, Huang C Y, Chen C N. Marchantin A, a cyclic bis(bibenzyl ether), isolated from the liverwort Marchantia emarginata subsp. tosana induces apoptosis in human MCF-7 breast cancer cells.  Cancer Lett. 2010;  291 108-119
• 2 Asakawa Y, Ludwiczuk A, Nagashima F, Toyota M, Hashimoto T, Tori M, Fukuyama Y, Harinantenaina L. Bryophytes: Bio- and chemical diversity, bioactivity and chemosystematics.  Heterocycles. 2009;  77 99-150
• 3 Asakawa Y. Recent advances in phytochemistry of bryophytes-acetogenins, terpenoids and bis(bibenzyl)s from selected Japanese, Taiwanese, New Zealand, Argentinean and European liverworts.  Phytochemistry. 2001;  56 297-312
• 4 Keseru G M, Nógrádi M. The biological activity of cyclic bis(bibenzyls): a rational approach.  Bioorg Med Chem. 1995;  3 1511-1517
• 5 Gao J, Li X, Lv B B, Sun B, Zhu C J, Lou H X. LC-DAD/MS/MS detection of macrocyclic bisbibenzyls from the liverwort Reboulia hemisphaerica and the cell-based screening of their microtubule inhibitory effects.  Chin J Nat Med. 2009;  7 123-128
• 6 Iwai Y, Murakami K, Gomi Y, Hashimoto T, Asakawa Y, Okuno Y, Ishikawa T, Hatakeyama D, Echigo N, Kuzuhara T. Anti-influenza activity of marchantins, macrocyclic bisbibenzyls contained in liverworts.  PLoS One. 2011;  6 11
• 7 Asakawa Y. Liverworts – potential source of medicinal compounds.  Curr Pharm Design. 2008;  14 3067-3088
• 8 Johannsson B. Íslenskir mosar. Refilmosabálkur og stjörnumosabálkur. Reykjavik: The Icelandic Institute of Natural History; 2002: 51-54
• 9 Keser G M, Nogradi M. The chemistry of macrocyclic bis(bibenzyls).  Nat Prod Rep. 1995;  12 69-75
• 10 Yue Q X, Liu X A, Guo D A. Microtubule – binding natural products for cancer therapy.  Planta Med. 2010;  76 1037-1043
• 11 Mollinedo F, Gajate C. Microtubules, microtubule-interfering agents and apoptosis.  Apoptosis. 2003;  8 413-450
• 12 Bolanos-Garcia V M. Aurora kinases.  Int J Biochem Cell Biol. 2005;  37 1572-1577
• 13 Keen N, Taylor S. Aurora-kinase inhibitors as anticancer agents.  Nat Rev Cancer. 2004;  4 927-936
• 14 Kitzen J, de Jonge M J A, Verweij J. Aurora kinase inhibitors.  Crit Rev Oncol Hematol. 2010;  73 99-110
• 15 Gorgun G, Calabrese E, Hideshima T, Ecsedy J, Perrone G, Mani M, Ikeda H, Bianchi G, Hu Y G, Cirstea D, Santo L, Tai Y T, Nahar S, Zheng M, Bandi M, Carrasco R D, Raje N, Munshi N, Richardson P, Anderson K C. A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma.  Blood. 2010;  115 5202-5213
• 16 Vidarsdottir L, Steingrimsdottir G, Bodvarsdottir S, Ogmundsdottir H, Eyfjord J. Sensitivity of BRCA2 mutated human cell lines to Aurora kinase inhibition.  Invest New Drugs. advance online publication 2010;  DOI: 10.1007/s10637-010-9566-4
• 17 Lok W, Klein R Q, Saif M W. Aurora kinase inhibitors as anti-cancer therapy.  Anticancer Drugs. 2010;  21 339-350
• 18 Chou T C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies.  Pharmacol Rev. 2006;  58 621-681
• 19 Fridriksdottir A J R, Gudjonsson T, Halldorsson T, Johannes B, Steinarsdottir M, Johannsson O T, Ogmundsdottir H M. Establishment of three human breast epithelial cell lines derived from carriers of the 999del5 BRCA2 Icelandic founder mutation.  In Vitro Cell Dev Biol Anim. 2005;  41 337-342
• 20 Odlo K, Klaveness J, Rongved P, Hansen T V. Synthesis of combretastatins A-1 and B-1.  Tetrahedron Lett. 2006;  47 1101-1103
• 21 Asakawa Y, Toyota M, Tori M, Hashimoto T. Chemical structures of macrocyclic bis(bibenzyls) isolated from liverworts (Hepaticae).  Spectroscopy. 2000;  14 149
• 22 Kodama M, Shiobara Y, Sumitomo H, Matsumura K, Tsukamoto M, Harada C. Total syntheses of marchantin A and riccardin B, cytotoxic bis(bibenzyls) from liverworts.  J Org Chem. 1988;  53 72-77
• 23 Tori M, Toyota M, Harrison L J, Takikawa K, Asakawa Y. Total assignment of H-1 and C-13 NMR-spectra of marchantins isolated from liverworts and its application to structure determination of 2 new macrocyclic bis(bibenzyls) from Plagiochasma intermedium and Riccardia multifida.  Tetrahedron Lett. 1985;  26 4735-4738
• 24 Shi Y Q, Zhu C J, Yuan H Q, Li B Q, Gao J, Qu X J, Sun B, Cheng Y N, Li S, Li X, Lou H X. Marchantin C, a novel microtubule inhibitor from liverwort with anti-tumor activity both in vivo and in vitro.  Cancer Lett. 2009;  276 160-170
• 25 Qi W, Cooke L S, Liu X, Rimsza L, Roe D J, Persky A M D O, Miller T P, Mahadevan D. Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma.  Biochem Pharmacol. 2011;  81 881-890
• 26 Al-Rubeai M, Fussenegger M. Apoptosis. Cell engineering. Volume 4 Dordrecht, London: Kluwer Academic; 2004: 281-307
• 27 DiPaola R S. To arrest or not to G(2)-M cell-cycle arrest.  Clin Cancer Res. 2002;  8 3311-3314