Alkenyl group is responsible for the disruption of microtubule network formation in human colon cancer cell line HT-29 cells

Abstract

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 approximately at 4 h 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 (GSH) or N-acetyl-L-cysteine. Reciprocally, L-buthionine-(S,R)-sulfoximine (500 μM), an inhibitor of GSH synthesis, enhanced the power of DATS in inducing the cell cycle arrest. These results indicate that alk(en)yl 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 toward microtubules. These findings suggest that alkenyl trisulfides and their structurally related compounds may provide novel and effective anticancer agents.

Antibacterial Potential of Garlic-Derived Allicin and Its Cancellation by Sulfhydryl Compounds

“…28) However, our present study is the first to show that SH-compounds cancel the antibiotic properties of garlicderived allicin and authentic allicin, and to discuss the molecular interaction of allicin with intra-and intercellular components.…”

Effect of Dimethyl Sulfides on the Induction of Apoptosis in Human Leukemia Jurkat Cells and HL-60 Cells

“…They have recently demonstrated that DATS-induced microtubule disarrangement and the resulting cell-cycle arrest were completely counteracted by such sulfhydryl reagents as L-cysteine, GSH and NAC, suggesting that exogenous DATS modifies the growth-related proteins at their sulfhydryl groups in the cysteine residues of cellular proteins. 20) The dimethyl trisulfide and tetrasulfide, which also have an -S-S-bond in their structures, may exert a similar effect on the induction of apoptosis to that of DADS and DATS.…”

Diallyl trisulfide induces apoptosis in Jurkat cells by the modification of cysteine residues in thioredoxin

“…[2][3][4] We also reported that DATS induces apoptosis in human colon cell lines by oxidative modification of cysteine residues in β-tubulin into S-allyl cysteine residues; this modification causes cell cycle arrest at M-phase followed by apoptosis. 5,6) On the other hand, we also found that DATS induces apoptosis in human leukemic cells in a cell cycle independent manner; however, the molecular target(s) of DATS remains to be clarified. This study was aimed at clarifying the molecular target of DATS in Jurkat cell by focusing on the oxidative modification of cysteine residue.…”

“…The ASK1 activates JNK to reduce the mitochondrial membrane potential. 9) Because DATS is highly reactive with cysteine residues, 6) we hypothesized that DATS can form disulfide bond between Cys32 and Cys35 of Trx to activate ASK1. To demonstrate this hypothesis, we examined the effect of DATS on the redox state of Trx by urea-polyacryl amide gel electrophoresis (PAGE) and Western blotting.…”