Journal Article

Antitumor activity of <i>Z</i>-ajoene, a natural compound purified from garlic: antimitotic and microtubule-interaction properties

Min Li, Jing-Rong Ciu, Ying Ye, Ji-Mei Min, Li-He Zhang, Kui Wang, Michèle Gares, Jean Cros, Michel Wright and Jeanne Leung-Tack

in Carcinogenesis

Volume 23, issue 4, pages 573-579
Published in print April 2002 | ISSN: 0143-3334
Published online April 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.4.573
Antitumor activity of Z-ajoene, a natural compound purified from garlic: antimitotic and microtubule-interaction properties

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Ajoene, a garlic stable oil-soluble sulfur rich compound was generally isolated as a mixture of two isomers [(E, Z)-4,5,9-trithiadodeca-1,6,11-triene-9-oxide]. It has been described essentially as a potent inhibitor of platelet aggregation in vitro and in vivo. The antiproliferative effects of ajoene and experiments using a single isomer had received little attention. The present study aims at defining the antitumor activities of cis-Z-ajoene in vitro and in vivo. Antiproliferative activity of Z-ajoene was demonstrated against a panel of human tumor cell lines with IC50 values varying from 5.2 mM to 26.1 mM and at a lower extent in normal marsupial kidney cells (PtK2). Meanwhile, Z-ajoene arrested HL60 cells in G2/M phase of cell cycle in a dose and time-dependent way. In PtK2 cells, exposure to 20 μM Z-ajoene for 6 h induced a complete disassembly of the microtubule network, that was associated with an increased number of cells blocked in early mitotic stages. An IC50 for microtubule disassembly of 1 μM was determined by a fully automated microplate-based multi-detection reader. In vitro, a reversible inhibition of the microtubule protein assembly was observed with an IC50 of 25 μM Z-ajoene. In vivo, Z-ajoene inhibited tumor growth by 38% and 42% in mice grafted with sarcoma 180 and hepatocarcinoma 22, respectively. For the first time, Z-ajoene was shown to be a potent inhibitor of tumor cell growth both in vitro and in vivo. The microtubule cytoskeleton appeared to be one of the Z-ajoene targets, but the mechanisms by which Z-ajoene interacted with microtubule appeared different from those of other microtubule poisons such as those of the Vinca alkaloids family. The ability of Z-ajoene to preferentially suppress the growth of neoplastic cells could provide a new approach in tumor therapy.

Keywords: DAPI, 4',6-diamidino-2-phenylindole dihydrochloride; DMSO, dimethylsulfoxide; EDTA, ethylenediaminetetraacetic acid; EGTA, ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid; FBS, fetal bovine serum; GTP, guanosine triphosphate; IC50, 50% inhibitory concentration; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; PBS, phosphate-buffered saline; PEG 6000, polyethylene glycol 6000; PEM, (PIPES, EGTA, MgCl2); PI, propidium iodide; PIPES, piperazine-N,N′-bis (2-ethanesulfonic acid)

Journal Article.  5040 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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