[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: 1.29). 11/2006; 47(5):688-97. DOI: 10.3349/ymj.2006.47.5.688
Source: PubMed


[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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    • "According to the Chinese Pharmacopoeia, the medicinal uses and indications of ginger include epigastric pain, vomiting, diarrhea, weak pulse, dyspnea, cough, and sputum production [5]. Also, ginger has well recognized antibacterial [6] [7] [8] [9], antifungal/antimycotic [10] [11], and anticancer [12] properties. "
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    ABSTRACT: Background and Objectives. Tooth decay is an infectious disease of microbial origin. Considering the increasing prevalence of antibiotic resistance due to their overuse and also their side effects, medicinal plants are now considered for use against bacterial infections. This study aimed to assess the effects of different concentrations of Zingiber officinale extract on proliferation of Streptococcus mutans and Streptococcus sanguinis in vitro. Materials and Methods. In this experimental study, serial dilutions of the extract were prepared in two sets of 10 test tubes for each bacterium (total of 20). Standard amounts of bacterial suspension were added; 100ƛ of each tube was cultured on prepared solid agar plates and incubated at 37°C for 24 hours. Serial dilutions of the extract were prepared in another 20 tubes and 100ƛ of each tube was added to blood agar culture medium while being prepared. The mixture was transferred to the plates. The bacteria were inoculated on plates and incubated as described. Results. The minimum inhibitory concentration (MIC) was 0.02 mg/mL for S. mutans and 0.3 mg/mL for S. sanguinis. The minimum bactericidal concentration (MBC) was 0.04 mg for S. mutans and 0.6 mg for S. sanguinis. Conclusion. Zingiber officinale extract has significant antibacterial activity against S. mutans and S. sanguinis cariogenic microorganisms.
    International Journal of Dentistry 09/2015; 2015(1):489842. DOI:10.1155/2015/489842
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    • "Joo and Lim (2011) HuH-7 (human hepatocellular carcinoma cells) 6-GN Induction of a transient rise in [Ca 2+ ]i and rapid NFB activation through TRPV1 in cancer cells. Increased the mRNA levels of NFB target genes Li et al. (2013b) Pancreatic cancer BxPC-3 and HPAC (human pancreatic cancer cells) 6-GN Inhibition of growth of HPAC-expressing wild-type p53 and BxPC- 3-expressing mutated p53 cell lines (at 400 lM) apoptotic cell death of the highly resistant mutant p53 cells and cytostatic effect on wild-type p53-expressing cells through temporal growth arrest Park et al. (2006) Prostate cancer LNCaP (human prostate adenocarcinoma cells) 6-GN Modulatory effects on testosterone-induced alterations of apoptosis-related proteins in androgen-sensitive LNCaP cells and in the ventral prostate of Swiss albino mice at 10 mg/kg, b.w. orally for 15 days protective effect against prostate cancer by modulating specific proteins involved in the apoptosis pathway Shukla et al. (2007) Neuroblastoma cancer SH-SY5Y (human neuroblastoma cells) 4-GN and 6-GN Inhibition of cancer cell colony formation under anchorageindependent conditions at 100 lM Gan et al. (2011) motor activity and prolonged hexobarbital-induced sleeping time (Suekawa et al., 1984). "
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    ABSTRACT: Gingerols are the major pungent compounds present in the rhizomes of ginger (Zingiber officinale Roscoe) and are renowned for their contribution to human health and nutrition. Medicinal properties of ginger, including the alleviation of nausea, arthritis and pain, have been associated with the gingerols. Gingerol analogues are thermally labile and easily undergo dehydration reactions to form the corresponding shogaols, which impart the characteristic pungent taste to dried ginger. Both gingerols and shogaols exhibit a host of biological activities, ranging from anticancer, anti-oxidant, antimicrobial, anti-inflammatory and anti-allergic to various central nervous system activities. Shogaols are important biomarkers used for the quality control of many ginger-containing products, due to their diverse biological activities. In this review, a large body of available knowledge on the biosynthesis, chemical synthesis and pharmacological activities, as well as on the structure-activity relationships of various gingerols and shogaols, have been collated, coherently summarised and discussed. The manuscript highlights convincing evidence indicating that these phenolic compounds could serve as important lead molecules for the development of therapeutic agents to treat various life-threatening human diseases, particularly cancer. Inclusion of ginger or ginger extracts in nutraceutical formulations could provide valuable protection against diabetes, cardiac and hepatic disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Phytochemistry 07/2015; 117. DOI:10.1016/j.phytochem.2015.07.012 · 2.55 Impact Factor
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    • "Inhibition of the constituents of MAP kinase pathway has long been recognized as ideal approach to arrest the progression of colon cancer [46].There are reports on other natural compounds like epicatechin gallate, curcumin, silibinin and red ginseng of inducing apoptosis in colon cancer cells via inhibition of MAP kinases [15], [47], [48], [49]. [6]-gingerol was previously shown to inhibit the phosphorylation of ERK1/2, JNK and p38 MAP kinases in mouse skin cancer cell lines, hepatocarcinoma cells and pancreatic cancer cells [28], [34], [36], [50]. But, to the best of our knowledge present study reports for the first time the inhibition of ERK1/2 and JNK MAP kinases as the mechanism of action of [6]-gingerol in reversing the PMA induced proliferation in colon cancer cells. "
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    ABSTRACT: We report mechanism-based evidence for the anticancer and chemopreventive efficacy of [6]-gingerol, the major active principle of the medicinal plant, Ginger (Zingiber officinale), in colon cancer cells. The compound was evaluated in two human colon cancer cell lines for its cytotoxic effect and the most sensitive cell line, SW-480, was selected for the mechanistic evaluation of its anticancer and chemopreventive efficacy. The non-toxic nature of [6]-gingerol was confirmed by viability assays on rapidly dividing normal mouse colon cells. [6]-gingerol inhibited cell proliferation and induced apoptosis as evidenced by externalization of phosphatidyl serine in SW-480, while the normal colon cells were unaffected. Sensitivity to [6]-gingerol in SW-480 cells was associated with activation of caspases 8, 9, 3 &7 and cleavage of PARP, which attests induction of apoptotic cell death. Mechanistically, [6]-gingerol down-regulated Phorbol Myristate Acetate (PMA) induced phosphorylation of ERK1/2 and JNK MAP kinases and activation of AP-1 transcription factor, but had only little effects on phosphorylation of p38 MAP kinase and activation of NF-kappa B. Additionally, it complemented the inhibitors of either ERK1/2 or JNK MAP kinase in bringing down the PMA-induced cell proliferation in SW-480 cells. We report the inhibition of ERK1/2/JNK/AP-1 pathway as a possible mechanism behind the anticancer as well as chemopreventive efficacy of [6]-gingerol against colon cancer.
    PLoS ONE 08/2014; 9(8):e104401. DOI:10.1371/journal.pone.0104401 · 3.23 Impact Factor
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