Antitumor activity of Z-ajoene, a natural compound purified from garlic: antimitotic and microtubule-interaction properties.
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 IC(50) 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 G(2)/M phase of cell cycle in a dose and time-dependent way. In PtK2 cells, exposure to 20 microM 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 IC(50) for microtubule disassembly of 1 microM 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 IC(50) of 25 microM 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.
Li
Min
M
National Research Laboratories of Natural and Biomimetic Drugs, Peking University, Beijing ROC.
Ciu
Jing-Rong
JR
Ye
Ying
Y
Min
Ji-Mei
JM
Zhang
Li-He
LH
Wang
Kui
K
Gares
Michèle
M
Cros
Jean
J
Wright
Michel
M
Leung-Tack
Jeanne
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division; D003599:Cytoskeleton / Q000378:metabolism; D004220:Disulfides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D005737:Garlic / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects*; D010936:Plant Extracts / Q000494:pharmacology*; D011485:Protein Binding; D020033:Protein Isoforms; D013454:Sulfoxides; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004220:Disulfides; D004791:Enzyme Inhibitors; D010936:Plant Extracts; D020033:Protein Isoforms; D013454:Sulfoxides; D014404:Tubulin; C048980:ajoene