Embelin Derivatives and Their Anticancer Activity through Microtubule Disassembly

Abstract

Biological activities of the 1,4-benzoquinone derivatives 5-O-ethylembelin (1) and 5-O-methylembelin (2) were investigated. Both of them showed antiproliferative activity against a panel of human tumor cell lines upon comparison to normal marsupial kidney cells (PtK2). They arrested HL-60 cells in the G₀/G₁ phase of the cell cycle in a dose- and time-dependent manner. In HeLa cells, exposure to 100 μM of 1 or 2 for 6 h induced a complete disassembly of the microtubule network and an increased number of cells blocked in mitotic stages. Treatment with 10 μM of 1 and 2 for 24 h induced apoptosis in HL-60 cells. This evidence suggests that both 1 and 2 are promising novel antimitotic and anticancer molecules targeting microtubular proteins.

Abbreviations

DMSO:dimethyl sulfoxide

MTT:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazo-lium bromide

Pet. ether:petroleum ether

SRB:sulphorhodamine B

Key words

Aegiceras corniculatum - Aegicerataceae - anticancer - cell cycle - microtubules - apoptosis

References

• 1 Li M, Lee S. Mangroves of China: a brief review.  Forest Ecol Management. 1997;  96 241-59
• 2 Harris G H. An Indian remedy for tapeworm.  Lancet. 1887;  2 199
• 3 Lin P, Fu Q. Environmental ecology and economic utilization of mangroves. Beijing, China; Higher Education Press 1995: pp 1-95
• 4 Gomez E, Cruz-Giron O. Toxicants from mangrove plants, V. isolation of the piscicide, 2-hydroxy-5-methoxy-3-undecyl-1,4-benzuoquinone (5-O-methylembelin) from Aegiceras corniculatum .  J Nat Prod. 1989;  52 649-51
• 5 Prakash A. Antifertility investigations on embelin - an oral contraceptive of plant origin.  J Med Plant Res. 1981;  41 259-66
• 6 Bøgh H, Andreassen J, Lemmich J. Anthelmintic usage of extracts of Embelia schimperi from Tanzania.  J Ethnopharmacol. 1996;  50 35-42
• 7 Atal C K, Siddiqui M A, Zutshi U SHA, Amla V, Johri R K, RAO P G. et al . Non-narcotic orally effective centrally acting analgesic from an Ayurvedic drug.  J Ethnopharmacol. 1984;  2 309-17
• 8 Chitra M, Sukumar E, Suja V, Devi C. Antibacterial activity of embelin.  Fitoterapia. 2003;  74 401-3
• 9 Kinoshita K, Morikawa K, Fujita M, Natori S. Inhibitory effects of plant secondary metabolites on cytotoxic activity of polymorphonuclear leucocytes.  Planta Med. 1992;  58 137-45
• 10 Chitra M, Sukumar E, Devi C S. [³H]-thymidine uptake and lipid peroxidation by tumor cells on embelin treatment: an in vitro study.  Oncology. 1995;  52 66-8
• 11 Chitra M, Sukumar E, Suja V, Devi C. Antitumor, anti-inflammatory and analgesic property of embelin, a plant product.  Med Sci Res. 1994;  22 877-8
• 12 Xu M, Deng Z, Li M, Li J, Fu H, Proksch P ,. et al . Chemical constituents from the mangrove plant, Aegiceras corniculatum .  J Nat Prod. 2004;  67 762-6
• 13 Nogales E. Structural insight into microtubule function.  Annu Rev Biophys Biomol Struct. 2001;  30 397-420
• 14 Yvon A M, Wadsworth P, Jordan M A. Taxol suppresses dynamics of individual microtubules in living human tumor cells.  Mol Biol Cell. 1999;  10 947-59
• 15 Jordan M A, Wilson L. Microtubules and actin filaments: dynamic targets for cancer chemotherapy.  Curr Opin Cell Biol. 1998;  10 123-30
• 16 Fanara P, Turner S, Busch R, Killion S, Awada M, Turner H. et al . In vivo measurement of microtubule dynamics using stable isotope labeling with heavy water. Effect of taxanes.  J Biol Chem. 2004;  279 49 940-7
• 17 Jordan M A, Wilson L. Microtubules as a target for anticancer drugs.  Nat Rev Cancer. 2004;  4 253-65
• 18 Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays.  J Immunol Methods. 1983;  65 55-63
• 19 Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D. et al . New colorimetric cytotoxicity assay for anticancer-drug screening.  J Natl Cancer Inst. 1990;  82 1107-12
• 20 Li M, Cui J R, Ye Y, Min J M, Zhang L H, Wang K. et al . J. Antitumor activity of Z-ajoene, a natural compound purified from garlic: antimitotic and microtubule-interaction properties.  Carcinogenesis. 2002;  23 573-9
• 21 Islam M N, Iskander M N. Microtubulin binding sites as target for developing anticancer agents.  Mini Rev Med Chem. 2004;  4 077-104
• 22 Himes R H, Kersey R N, Heller-Bettinger I, Samson F E. Action of the vinca alkaloids vincristine, vinblastine, and desacetyl vinblastine amide on microtubules in vitro .  Cancer Res. 1976;  36 3798-802
• 23 Nikolovska-Coleska Z, Xu L, Hu Z, Tomita Y, Li P, Roller P P. et al . Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database.  J Med Chem. 2004;  47 2430-40