Specific reaction of α,β‐unsaturated carbonyl compounds such as 6‐shogaol with sulfhydryl groups in tubulin leading to microtubule damage

Ishiguro, Kazuhiro; Ando, Takafumi; Watanabe, Osamu; Goto, Hidemi

doi:10.1016/j.febslet.2008.09.027

Cited by 39 publications

(25 citation statements)

References 30 publications

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“…The analyses in (a) and (b) were performed three times with similar results and a representative image is shown abrogation of cell cycle checkpoint proteins and spindle assembly checkpoint proteins. Together with results reported by a previous study indicating that 6-shogaol caused microtubule damage through specific reaction with sulfhydryl groups in tubulin [19], we propose here that shogaols induce aberrant mitosis through at least two mechanisms: (1) direct targeting of microtubules, and (2) indirect perturbation of the proper functioning of the mitotic spindle through interference of cell cycle and spindle assembly checkpoint proteins. While it is acknowledged that further work needs to be performed to fully elucidate the exact molecular target(s) of shogaols, this study has thrown light on the structure-activity relationship of naturally-occurring shogaols, where 4-and 6-shogaol possessing short carbon chain lengths were found to exhibit in vitro cytotoxicity in submicromolar concentrations.…”

Section: Discussionsupporting

confidence: 88%

“…For example, studies investigating the shogaols' mechanism of apoptosis have reported that 6-and 8-shogaol induce caspase-dependent apoptosis through reactive oxygen species production and disruption of mitochondrial transmembrane potential [16][17][18]. A previous study by Ishiguro et al [19] has provided evidence that 6-shogaol impairs tubulin polymerization through direct targeting of the cysteine residues in b-tubulin. While the findings support G 2 /M arrest as a cellular outcome, we postulate that there may be additional upstream cellular events at work that cause the halt at G 2 /M stage and subsequently induce apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Shogaols at proapoptotic concentrations induce G2/M arrest and aberrant mitotic cell death associated with tubulin aggregation

et al. 2011

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Shogaols have been previously reported to induce cancer cell death via multiple mechanisms, among which one analog 6-shogaol has been reported to cause microtubule damage through specific reaction with sulfhydryl groups in tubulin. In this study, a series of shogaols with different side chain lengths (4-, 6-, 8- and 10-shogaol) was synthesized and evaluated for antiproliferative activity in HCT 116 colon carcinoma and SH-SY5Y neuroblastoma cells. 4- and 6-shogaol were identified as lead compounds possessing the strongest antiproliferative activity. In the soft agar assay, the lead shogaols displayed dose-dependent inhibition on cancer cell colony formation under anchorage-independent conditions. Using HCT 116 as the selected cancer cell line, the molecular events linking shogaols-induced G(2)/M cell cycle arrest to apoptosis characterized by caspase 3 and PARP cleavage were investigated. At sublethal concentrations, the halt at G(2)/M phase was alleviated along time and cells survived. Conversely, proapoptotic concentrations of 4- and 6-shogaol induced irreversible G(2)/M arrest that was at least in part associated with down-regulation of cell cycle checkpoint proteins cdk1, cyclin B and cdc25C, as well as spindle assembly checkpoint proteins mad2, cdc20 and survivin. A dose- and time-dependent accumulation of insoluble tubulin in the insoluble fractions of cell lysates provided evidence that G(2) checkpoint failure led to disruption of microtubule turnover. In summary, our results conclude that shogaols cause apoptosis by inducing aberrant mitosis at least through the attenuation of cell cycle and spindle assembly checkpoint proteins.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Shogaols at proapoptotic concentrations induce G2/M arrest and aberrant mitotic cell death associated with tubulin aggregation

et al. 2011

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“…60 In fact, 6S can easily react with cysteine as a Michael reaction acceptor. 24 Cysteine residues of tubulin 61 and TRPA1, 62 and even serine residues of eIF2α 63 and Akt1, 64 are modified by 6S. Further study is warranted to pinpoint the sensor cysteines in Keap1 modified by 6S and the structure–activity relationship of shogaols in Keap1 modification.…”

Section: Discussionmentioning

confidence: 99%

Ginger Compound [6]-Shogaol and Its Cysteine-Conjugated Metabolite (M2) Activate Nrf2 in Colon Epithelial Cells in Vitro and in Vivo

Chen

et al. 2014

Chem. Res. Toxicol.

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In this study, we identified Nrf2 as a molecular target of [6]-shogaol (6S), a bioactive compound isolated from ginger, in colon epithelial cells in vitro and in vivo. Following 6S treatment of HCT-116 cells, the intracellular GSH/GSSG ratio was initially diminished but was then elevated above the basal level. Intracellular reactive oxygen species (ROS) correlated inversely with the GSH/GSSG ratio. Further analysis using gene microarray showed that 6S upregulated the expression of Nrf2 target genes (AKR1B10, FTL, GGTLA4, and HMOX1) in HCT-116 cells. Western blotting confirmed upregulation, phosphorylation, and nuclear translocation of Nrf2 protein followed by Keap1 decrease and upregulation of Nrf2 target genes (AKR1B10, FTL, GGTLA4, HMOX1, and MT1) and glutathione synthesis genes (GCLC and GCLM). Pretreatment of cells with a specific inhibitor of p38 (SB202190), PI3K (LY294002), or MEK1 (PD098059) attenuated these effects of 6S. Using ultra-high-performance liquid chromatography–tandem mass spectrometry, we found that 6S modified multiple cysteine residues of Keap1 protein. In vivo 6S treatment induced Nrf2 nuclear translocation and significantly upregulated the expression of MT1, HMOX1, and GCLC in the colon of wild-type mice but not Nrf2–/– mice. Similar to 6S, a cysteine-conjugated metabolite of 6S (M2), which was previously found to be a carrier of 6S in vitro and in vivo, also activated Nrf2. Our data demonstrated that 6S and its cysteine-conjugated metabolite M2 activate Nrf2 in colon epithelial cells in vitro and in vivo through Keap1-dependent and -independent mechanisms.

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“…Ginger, owing to its functional ingredients like [6]-gingerol, [6]-shogaol, [6]paradol, and zerumbone, exhibits anti-inflammatory and antitumorigenic activities (Jeong et al, 2009;Hung et al, 2009). Ginger and its bioactive molecules are effective in controlling the extent of colorectal, gastric, ovarian, liver, skin cancers (Ishiguro et al, 2008;Sung et al, 2008;Brown et al, 2009;Kim et al, 2009;Jeong et al, 2009). Some recent works related to anticancer perspectives have been presented in Table 3.…”

Section: Cancer Insurgence and Gingermentioning

confidence: 99%

Ginger and its Health Claims: Molecular Aspects

Butt

Sultan

2011

Critical Reviews in Food Science and Nutrition

155

106

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Recent research has rejuvenated centuries-old traditional herbs to cure various ailments by using modern tools like diet-based therapy and other regimens. Ginger is one of the classic examples of an herb used for not only culinary preparations but also for unique therapeutic significance owing to its antioxidant, antimicrobial, and anti-inflammatory potential. The pungent fractions of ginger, namely gingerols, shogaols, paradols, and volatile constituents like sesquiterpenes and monoterpenes, are mainly attributed to the health-enhancing perspectives of ginger. This review elucidates the health claims of ginger and the molecular aspects and targets, with special reference to anticancer perspectives, immunonutrition, antioxidant potential, and cardiovascular cure. The molecular targets involved in chemoprevention like the inhibition of NF-κB activation via impairing nuclear translocation, suppresses cIAP1 expression, increases caspase-3/7 activation, arrests cell cycle in G2 + M phases, up-regulates Cytochrome-c, Apaf-1, activates PI3K/Akt/I kappaB kinases IKK, suppresses cell proliferation, and inducts apoptosis and chromatin condensation. Similarly, facts are presented regarding the anti-inflammatory response of ginger components and molecular targets including inhibition of prostaglandin and leukotriene biosynthesis and suppression of 5-lipoxygenase. Furthermore, inhibition of phosphorylation of three mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinase (JNK) are also discussed. The role of ginger in reducing the extent of cardiovascular disorders, diabetes mellitus, and digestive problems has also been described in detail. Although, current review articles summarized the literature pertaining to ginger and its components. However, authors are still of the view that further research should be immediately carried out for meticulousness.

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Specific reaction of α,β‐unsaturated carbonyl compounds such as 6‐shogaol with sulfhydryl groups in tubulin leading to microtubule damage

Cited by 39 publications

References 30 publications

Shogaols at proapoptotic concentrations induce G2/M arrest and aberrant mitotic cell death associated with tubulin aggregation

Shogaols at proapoptotic concentrations induce G2/M arrest and aberrant mitotic cell death associated with tubulin aggregation

Ginger Compound [6]-Shogaol and Its Cysteine-Conjugated Metabolite (M2) Activate Nrf2 in Colon Epithelial Cells in Vitro and in Vivo

Ginger and its Health Claims: Molecular Aspects

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