Pharmacokinetics of the Garlic Compound<i>S</i>-Allylcysteine

Nagae, Shinji; Ushijima, Mitsuyasu; Hatono, S.; Imai, Jun; Kasuga, Shigeo; Matsuura, Hiromichi; Itakura, Y.; Higashi, Yasuhiko

doi:10.1055/s-2006-959461

Cited by 156 publications

(109 citation statements)

References 3 publications

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“…The maximum plasma concentration of SAC has also been reported to be >200 Amol/L after p.o. administration of a 50 mg/kg dose to rats (35). Therefore, the organosulfur compound concentrations we used in our cell culture studies are comparable with those seen in the serum of animals and to those used in previous cell culture assays (36).…”

Section: Discussionsupporting

confidence: 59%

Effects of a series of organosulfur compounds on mitotic arrest and induction of apoptosis in colon cancer cells

Xiao

Pinto²,

Gundersen³

et al. 2005

Molecular Cancer Therapeutics

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We previously reported that the garlic-derived compound S-allylmercaptocysteine (SAMC) causes growth inhibition, mitotic arrest, and induction of apoptosis in SW480 human colon cancer cells by inducing microtubule depolymerization and c-Jun NH 2 terminus kinase-1 activation. In the present study, we compared the aforementioned effects of SAMC to those of a series of garlic-derived and other organosulfur compounds. Among the 10 compounds tested, only SAMC, diallyl disulfide (DADS), and S-trityl-Lcysteine (trityl-cys) cause significant inhibition of cell growth with IC 50 values of 150, 56, and 0.9 Mmol/L, respectively. These three compounds also induce G 2 -M cell cycle arrest and apoptosis. Further studies reveal that, like SAMC, the garlic-derived compound DADS exerts antiproliferative effects by binding directly to tubulin and disrupting the microtubule assembly, thus arresting cells in mitosis and triggering mitochondriamediated signaling pathways that lead to apoptosis. However, the synthetic compound trityl-cys exerts its effect on M-phase arrest and growth inhibition by mechanisms that involve spindle impairment but do not involve disruption of microtubule structure or dynamics. Furthermore, trityl-cys does not induce marked loss of mitochondrial membrane potential or release of cytochrome c, but it does induce caspase-3 activation and poly(ADP-ribose) polymerase cleavage. Structure-function analysis suggests that both the allyl and the disulfide moieties are important features for the antiproliferative effects of SAMC and DADS. These findings may be useful in the identification, synthesis, and development of organosulfur compounds that have anticancer activity. [Mol Cancer Ther 2005;4(9):1388 -98]

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Section: Discussionsupporting

confidence: 59%

Effects of a series of organosulfur compounds on mitotic arrest and induction of apoptosis in colon cancer cells

Xiao

Pinto²,

Gundersen³

et al. 2005

Molecular Cancer Therapeutics

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“…It is unclear if such concentrations of DATS are achievable in humans because of lack of pharmacokinetic data on this agent. However, the pharmacokinetics of S-allylcysteine, a water soluble OSC analog, has been studied in rodents and dogs (Nagae et al, 1994). This study showed that S-allylcysteine was absorbed rapidly, and reached peak plasma concentration within 0.5-1 h. The plasma concentrations following oral administration of 12.5, 25 and 50 mg S-allylcysteine/kg body weight were about 50, 112 and 227 mM, respectively (Nagae et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…However, the pharmacokinetics of S-allylcysteine, a water soluble OSC analog, has been studied in rodents and dogs (Nagae et al, 1994). This study showed that S-allylcysteine was absorbed rapidly, and reached peak plasma concentration within 0.5-1 h. The plasma concentrations following oral administration of 12.5, 25 and 50 mg S-allylcysteine/kg body weight were about 50, 112 and 227 mM, respectively (Nagae et al, 1994). Thus, it is possible that the concentrations of DATS required to inhibit cell proliferation and cause cell cycle arrest and apoptosis may be achievable in humans.…”

Section: Discussionmentioning

confidence: 99%

Diallyl trisulfide-induced G2–M phase cell cycle arrest in human prostate cancer cells is caused by reactive oxygen species-dependent destruction and hyperphosphorylation of Cdc25C

Xiao

Herman-Antosiewicz²,

Antosiewicz³

et al. 2005

Oncogene

179

195

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Molecular mechanism of cell cycle arrest caused by diallyl trisulfide (DATS), a garlic-derived cancer chemopreventive agent, has been investigated using PC-3 and DU145 human prostate cancer cells as a model. Treatment of PC-3 and DU145 cells, but not a normal prostate epithelial cell line (PrEC), with growth suppressive concentrations of DATS caused enrichment of the G 2 -M fraction. The DATS-induced cell cycle arrest in PC-3 cells was associated with increased Tyr 15 phosphorylation of cyclin-dependent kinase 1 (Cdk1) and inhibition of Cdk1/cyclinB1 kinase activity. The DATStreated PC-3 and DU145 cells also exhibited a decrease in the protein level of Cdc25C and an increase in its Ser 216 phosphorylation. The DATS-mediated decrease in protein level and Ser 216 phosphorylation of Cdc25C as well as G 2 -M phase cell cycle arrest were significantly attenuated in the presence of N-acetylcysteine implicating reactive oxygen species (ROS) in cell cycle arrest caused by DATS. ROS generation was observed in DATS-treated PC-3 and DU145 cells. DATS treatment also caused an increase in the protein level of Cdk inhibitor p21, but DATS-induced G 2 -M phase arrest was not affected by antisense-mediated suppression of p21 protein level. In conclusion, the results of the present study indicate that DATS-induced G 2 -M phase cell cycle arrest in human prostate cancer cells is caused by ROS-mediated destruction and hyperphosphorylation of Cdc25C.

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“…Pharmacokinetic studies demonstrate fast absorption and distribution phases followed by a slow elimination phase for oral administration, as well as fast distribution and slow elimination phases for i.v. administration (Nagae et al, 1994;Yan & Zeng, 2005). Pharmacokinetics of S-allylcysteine in humans by oral garlic administration revealed a half-life of 10 h and clearance time of 30 h (Kodera et al, 2002), suggesting a high bioavailability.…”

Section: Presumable Protective Effect Of Garlic Compounds In Cerebralmentioning

confidence: 98%

Nrf2 Activation, an Innovative Therapeutic Alternative in Cerebral Ischemia

Silva-Islas¹,

Santana-Martínez²,

Colín-González³

et al. 2012

Advances in the Preclinical Study of Ischemic Stroke

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Pharmacokinetics of the Garlic CompoundS-Allylcysteine

Cited by 156 publications

References 3 publications

Effects of a series of organosulfur compounds on mitotic arrest and induction of apoptosis in colon cancer cells

Effects of a series of organosulfur compounds on mitotic arrest and induction of apoptosis in colon cancer cells

Diallyl trisulfide-induced G2–M phase cell cycle arrest in human prostate cancer cells is caused by reactive oxygen species-dependent destruction and hyperphosphorylation of Cdc25C

Nrf2 Activation, an Innovative Therapeutic Alternative in Cerebral Ischemia

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