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[6]-Gingerol Induces Cell Cycle Arrest and Cell Death of Mutant p53-expressing Pancreatic Cancer Cells

Department of Internal Medicine, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-gu, Seoul 120-752, Korea.
Yonsei Medical Journal (Impact Factor: 1.26). 11/2006; 47(5):688-97. DOI: 10.3349/ymj.2006.47.5.688
Source: PubMed

ABSTRACT [6]-Gingerol, a major phenolic compound derived from ginger, has anti-bacterial, anti-inflammatory and anti-tumor activities. While several molecular mechanisms have been described to underlie its effects on cells in vitro and in vivo, the underlying mechanisms by which [6]-gingerol exerts anti-tumorigenic effects are largely unknown. The purpose of this study was to investigate the action of [6]-gingerol on two human pancreatic cancer cell lines, HPAC expressing wild- type (wt) p53 and BxPC-3 expressing mutated p53. We found that [6]-gingerol inhibited the cell growth through cell cycle arrest at G1 phase in both cell lines. Western blot analyses indicated that [6]-gingerol decreased both Cyclin A and Cyclin-dependent kinase (Cdk) expression. These events led to reduction in Rb phosphorylation followed by blocking of S phase entry. p53 expression was decreased by [6]-gingerol treatment in both cell lines suggesting that the induction of Cyclin-dependent kinase inhibitor, p21cip1, was p53-independent. [6]-Gingerol induced mostly apoptotic death in the mutant p53-expressing cells, while no signs of early apoptosis were detected in wild type p53-expressing cells and this was related to the increased phosphorylation of AKT. These results suggest that [6]-gingerol can circumvent the resistance of mutant p53- expressing cells towards chemotherapy by inducing apoptotic cell death while it exerts cytostatic effect on wild type p53- expressing cells by inducing temporal growth arrest.

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    • "The action of [ 6 ] - gingerol on two human pancreatic cancer cell lines , HPAC expressing wild - type ( wt ) p53 and BxPC - 3 expressing mutated p53 was studied ( Park et al . , 2006 ) and found that [ 6 ] - gingerol can circumvent the resistance of mu - tant p53 - expressing cells towards chemotherapy by inducing apoptotic cell death while it exerts cytostatic effect on wild type p53 - expressing cells by inducing temporal growth ar - rest . Dias et al . ( 2006 ) did not find any chemopreventive ef - fect of ginger"
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    ABSTRACT: Ginger rhizome (Zingiber officinale Roscoe) is widely cultivated as a spice for its aromatic and pungent components. The essential oil and oleoresins from ginger are valuable products responsible for the characteristic flavor and pungency. Both are used in several food products such as soft beverages and also in many types of pharmaceutical formulations. More than 100 compounds have been reported from ginger, some of which are isolated and characterized, others are tentatively identified by GC-MS and / or LC-MS. [6]-Gingerol, the major gingerol in ginger rhizomes, has been found to possess many interesting pharmacological and physiological activities, such as anti-inflammatory, analgesic, and cardiotonic effects. Ginger is considered as "generally recognized as safe" (GRAS) by Food and Drug Administration (FDA), USA. Due to all these properties, ginger has gained considerable attention in developed countries in recent years, especially for its use in the treatment of inflammatory conditions. The present review is a persuasive presentation of the current information on processing, chemistry, biological activities, and medicinal uses of ginger. Further studies are required for the validation of the beneficial uses. Formulation for novel products and new usages may emerge in the years to come, based on the revealed results of various studies.
    Critical reviews in food science and nutrition 08/2012; 52(8):651-88. DOI:10.1080/10408398.2010.505689 · 5.55 Impact Factor
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    • "In addition, anticancer and chemopreventive activities of 6-gingerol have been reported. 6- gingerol exerted inhibitory effects on cell viability and DNA synthesis, also induced apoptosis in pro-myelocytic leukemia HL-60 cells [14] and has affects of chemoprevention to gastric-intestinal cancers [15]. "
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    ABSTRACT: To investigate the possible antitumor activity of ginger extract against hepatic carcinogenesis initiated by diethylnitrosoamines (DEN) and promoted by carbon tetrachloride (CCl(4) ). A total of 60 male Wistar albino rats were divided into four groups with 15 animals in each group. Rats in group 1 (control group) received a single intraperitoneal (i.p.) injection of normal saline. Animals in group 2 were given ginger (50 mg/kg/day) in drinking water for 8 weeks. Rats in group 3 (DEN group) were injected with a single dose of DEN (200 mg/kg, i.p.), 2 weeks later received a single dose of CCl(4) (2 mL/kg i.g) by gavage as 1:1 dilution in corn oil. Animals in group 4 (DEN-ginger group) received the same carcinogenesis induction protocol as in group 3 plus ginger (50 mg/kg/day) in drinking water for 2 weeks before induction of hepatocarcinogenesis and continued throughout the experimental period. DEN-initiated and CCl(4) -promoted hepatocarcinogenesis in male Wistar rats was manifested biochemically by elevation of serum hepatic tumor markers tested; α-fetoprotein and carcinoembryonic antigen. In addition, hepatocarcinogenesis was further confirmed by a significant increase in hepatic tissue growth factors; vascular endothelial growth factor, basic fibroblast growth factor, and hydroxyproline content. A marked decrease in endostatin and metallothonein were also observed. Long-term ginger extract administration 2 weeks before induction of hepatocarcinogenesis and throughout the experimental period prevented the decrease of the hepatic content of metallothionein and endostatin and the increase in the growth factors induced by the carcinogen. Moreover, ginger extract normalize serum hepatic tumor markers. Histopathological examination of liver tissue also correlated with the biochemical observations. These findings suggest a protective effect of ginger extract against premalignant stages of liver cancer in the DEN-initiated and CCl(4) -promoted hepatocarcinogenesis model in rats.
    BioFactors 11/2010; 36(6):483-90. DOI:10.1002/biof.122 · 3.00 Impact Factor
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    • "In our study, we have shown that ginger at increasing concentration was not only able to inhibit DNA synthesis but also induced apoptosis especially at higher concentration and the percentage of cells that underwent apoptosis, increased dose dependently for both cells. Our observation of apoptosis in mutant p53-expressing HT 29 is similar to the study by Park et al. (2006) who found that [6]-gingerol induced apoptotic death in pancreatic cells. The percentage of late apoptotic cells was low compared to early apoptotic cells as detected by annexin V staining, suggesting that apoptosis occurred rather slow in colon cancer cells after treatment (Huang and Pardee, 1999). "
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    ABSTRACT: Although many studies have shown the antitumor properties of ginger extract (Zingiber officinale), little is known regarding the mechanism of its effects. This study was conducted to determine the mechanism of antitumor effects of ginger extract by evaluating apoptosis rate and cell cycle progression status in colon cancer cell lines HCT 116 and p53 defective HT 29. HCT 116 and HT 29 cells were cultured in the presence of ginger extract at various concentrations for 24 h. The percentage of cell viability was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-di phenyl tetrazolium bromide (MTT) assay. Our results showed that ginger extract inhibited proliferation of HCT 116 and HT 29 cells with an IC 50 of 496 ± 34.2 µg/ml and 455 ± 18.6 µg/ml, respectively. We also found that ginger extract at increasing concentrations induced apoptosis dose dependently in both colon cancer cells. Apoptosis rates were 11.15, 35.05 and 57.49% for HCT 116 and 4.39, 19.81 and 28.09% for HT 29 at 200, 500 and 800 µg/ml of ginger extract, respectively. Ginger extract arrested HCT 116 and HT 29 cells at G 0 /G 1 and G 2 /M phases with corresponding decreased in S-phase. This study suggests that ginger extract may exert its antitumor effects on colon cancer cells by suppressing its growth, arresting the G 0 /G 1 -phase, reducing DNA synthesis and inducing apoptosis. Key words: Zingiber officinale, HCT 116, HT 29, G 0 /G 1 phase, S phase, apoptosis.
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