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Carcinogenesis Advance Access published online on May 29, 2008
Carcinogenesis, doi:10.1093/carcin/bgn124
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Alkenyl group is responsible for the disruption of microtubule network formation in human colon cancer cell line HT-29 cells

Takashi Hosono1,{dagger}, Tomomi Hosono-Fukao1,{dagger}, Kahoru Inada1, Rie Tanaka1, Haruhisa Yamada1, Yuji Iitsuka1, Taiichiro Seki1,*, Isao Hasegawa2 and Toyohiko Ariga1

1 Department of Applied Life Sciences, Nihon University Graduate School of Bioresource Sciences, Kanagawa 252-8510, Japan
2 Department of Environmental Sciences, Nihon University Graduate School of Bioresource Sciences, Kanagawa 252-8510, Japan

* To whom correspondence should be addressed: Laboratory of Nutrition and Physiology, Dept. of Applied Life Sciences, Nihon University Graduate School of Bioresource Sciences, Kanagawa 252-8510, Japan. Tel./Fax: 81-466-84-3949; E-mail: tseki{at}brs.nihon-u.ac.jp.

Alk(en)yl trisulfides (R-SSS-R’) are organosulfur compounds produced by crushed garlic and other Allium vegetables. We found that these compounds exhibit potent anticancer effects through the reaction with microtubules, causing cell-cycle arrest. Nine alk(en)yl trisulfides including dimethyl trisulfide, diethyl trisulfide, dipropyl trisulfide (DPTS), dibutyl trisulfide, dipentyl trisulfide, diallyl trisulfide (DATS), dibutenyl trisulfide, dipentenyl trisulfide, and allyl methyl trisulfide were synthesized and added to cultures of HT-29 human colon cancer cells at a concentration of 10 µM. The trisulfides with alkenyl groups such as DATS, but not those with alkyl groups, induced rapid microtubule disassembly at 30-60 min as well as cell-cycle arrest during the mitotic phase at approximately at 4 hours after the treatment. Both DATS-induced microtubule disassembly and the cell-cycle arrest were cancelled by the simultaneous treatment of the cancer cells with 2 mM L-cysteine, glutathione, or N-acetyl-L-cysteine. Reciprocally, L-buthionine-(S,R)- sulfoximine (500 µM), an inhibitor of glutathione synthesis, enhanced the power of DATS in inducing the cell-cycle arrest. These results indicate that alk(en)ly trisulfide react with sulfhydryl groups in cysteine residues of cellular proteins such as microtubule proteins. Thus, the present study provides evidence that trisulfides with alkenyl groups have potent anticancer activities, at least in part, directed towards microtubules. These findings suggest that alkenyl trisulfides and their structurally related compounds may provide novel and effective anticancer agents.

{dagger} Present address: Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, 36-3, Morioka, Obu, Aichi 474-8522, Japan.

Received December 5, 2007; revised May 16, 2008; accepted May 16, 2008.


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