PMID: 

J Cell Physiol. 2018 12 ;233(12):9538-9547. Epub 2018 Jun 26. PMID: 29943808

Abstract Title: 

Zerumbone inhibits epithelial-mesenchymal transition and cancer stem cells properties by inhibiting theβ-catenin pathway through miR-200c.

Abstract: 

Colorectal cancer (CRC) is one of the most lethal and rampant human malignancies in the world. Zerumbone, a sesquiterpene isolated from subtropical ginger, has been found to exhibit an antitumor effect in various cancer types. However, the effect of Zerumbone on the biological properties of CRC, including epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) has not been fully elucidated. Here, we investigated the inhibitory action of Zerumbone on the EMT process, CSC markers, and theβ-catenin signaling pathway in the presence or absence of miR-200c. The effect of Zerumbone on HCT-116 and SW-48 cells viability was examined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. The effects of Zerumbone on EMT-related genes, CSCs markers, cell migration, invasion, sphere-forming, and β-catenin signaling pathway were explored. To evaluate the role of miR-200c in anticancer effects by Zerumbone, miR-200c was downregulated by LNA-anti-miR-200c. Zerumbone significantly inhibited cell viability, migration, invasion, and sphere-forming potential in HCT-116 andSW-48 cell lines. Zerumbone significantly suppressed the EMT and CSC properties as well as downregulated the β-catenin. Silencing of miR200c reduced the inhibitory effects of Zerumbone on EMT and CSCs in CRC cells. These data indicated that Zerumbone may be a promising candidate for reducing the risk of CRC progression by suppressing the β-catenin pathway via miR-200c.

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PMID: 

Chin J Physiol. 2018 Jun ;61(3):171-180. PMID: 29962177

Abstract Title: 

Zerumbone from Zingiber zerumbet Ameliorates Lipopolysaccharide-Induced ICAM-1 and Cytokines Expression via p38 MAPK/JNK-IκB/NF-κB Pathway in Mouse Model of Acute Lung Injury.

Abstract: 

Acute lung injury (ALI) is a clinical syndrome with high morbidity and mortality rates mainly caused by Gram-negative bacteria. Nevertheless, an effective treatment strategy for ALI is yet to be developed. Zerumbone, a sesquiterpene isolated from Zingiber zerumbet Smith, possesses several advantageous bioeffects such as antioxidation, anti-inflammation, and antiulcer. Pretreatment of zerumbone inhibited lipopolysaccharide (LPS)-induced arterial blood gas exchange, neutrophils infiltration, and increased pulmonary vascular permeability. LPS-induced expression of intercellular adhesion molecule-1 (ICAM-1) was inhibited by zerumbone at a lower concentration than that of vascular cell adhesion molecule-1 (VCAM-1). In addition, proinflammatory cytokines, such as interleukin (IL)-1β and macrophage inflammatory protein (MIP)-2 were suppressed by zerumbone. The phosphorylation of nuclear factor (NF)-κB, a proinflammatory transcription factor, and degradation of inhibitor of κB (IκB), an inhibitor of NF-κB, were also reduced by zerumbone. Furthermore, we found the inhibitory concentration of zerumbone on phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) was lower than that of extracellular signal-regulated kinase (ERK). In conclusion, zerumbone could be a potential protective agent for ALI, possibly via expression of ICAM-1, IL-1β, and MIP-2. The protective mechanism of zerumbone was by reversing the activation of p38 MAPK/JNK-IκB/NF-κB pathway.

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PMID: 

Oncol Lett. 2018 Oct ;16(4):4379-4383. Epub 2018 Jul 20. PMID: 30197671

Abstract Title: 

Effects of zerumbone on proliferation and apoptosis of esophageal cancer cells and on P53 and Bcl-2 expression levels.

Abstract: 

The effects of zerumbone on the proliferation and apoptosis of esophagus cancer cells and on the P53 and Bcl-2 expression levels were studied. The esophagus cancer EC-109 cells were cultured and inoculated. The effect of zerumbone on proliferation of EC-109 cells was detected via the Cell Counting Kit-8 (CCK-8) method. Cell apoptosis was detected via TdT-mediated dUTP nick end-labeling (TUNEL) staining. Moreover, the mRNA expression levels of P53 and Bcl-2 were detected via reverse transcription-polymerase chain reaction (RT-PCR), and the protein expression levels of P53 and Bcl-2 were evaluated via western blotting. CCK-8 detection results showed that compared with control group, zerumbone in different concentrations could inhibit the activity of EC-109, and the proliferation inhibition rate was significantly increased in a concentration-dependent manner with the increase of concentration. TUNEL staining showed that cell apoptosis gradually occurred in administration group, and the number of apoptotic cells was increased in a concentration-dependent manner with the increase of concentration. RT-PCR detection results showed that the mRNA expression level of P53 in administration group was significantly increased compared with that in control group, but that of Bcl-2 was significantly decreased. Western blotting showed that the protein expression level of Bcl-2 in administration group in different concentrations was significantly increased with the increase of zerumbone concentration, but that of Bcl-2 was significantly decreased in a concentration-dependent manner. Zerumbone can inhibit the proliferation and induce apoptosis of esophageal cancer EC-109 cells, and its induction of apoptosis may be realized through upregulating the mRNA expression of P53 and downregulating the mRNA expression of Bcl-2, and upregulating the protein expression of P53 and downregulating the protein expression of Bcl-2.

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PMID: 

Biomed Res Int. 2018 ;2018:8691569. Epub 2018 Oct 15. PMID: 30410940

Abstract Title: 

Zerumbone-Loaded Nanostructured Lipid Carrier Induces Apoptosis of Canine Mammary Adenocarcinoma Cells.

Abstract: 

Canine mammary gland tumor (CMT) is the most common tumor in intact female dog. Zerumbone (ZER) has promising anticancer properties, but plagued with poor water solubility, poor absorption, bioavailability, and delivery to target tissues. To solubilize, ZER was loaded into nanostructured lipid carrier (NLC) to produce ZER-loaded NLC (ZER-NLC). The objectives of this study were to determine the antiproliferative effect and the mode of cell death induced by ZER-NLC and ZER on a canine mammary gland tumor (CMT) adenocarcinoma primary cell line. There was no significant difference (>0.05) between ZER-NLC and ZER treatments in the inhibition of CMT cell proliferation; thus, the loading of ZER into NLC did not compromise the cytotoxic effect of ZER. Microscopically, ZER-NLC- and ZER-treated CMT cells showed apoptotic cell morphology. ZER-NLC and ZER treatments significantly downregulated the antiapoptotic Bcl-2 and upregulated the proapoptotic Bax gene expressions in CMT cells. Both ZER-NLC and ZER-treated CMT cells showed significant (

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PMID: 

Biomed Pharmacother. 2019 Jan ;109:2447-2455. Epub 2018 Dec 1. PMID: 30551505

Abstract Title: 

Zerumbone inhibits migration in ESCC via promoting Rac1 ubiquitination.

Abstract: 

Zerumbone has been reported to maintain the anti-cancer effects in many malignant cells. However, the effect and mechanism of Zerumbone on esophageal squamous cell carcinomas (ESCC) is rarely investigated. Here we report the inhibitory effect of Zerumbone (hereinafter referred to as ZER) on ESCC migration and the underlying molecular mechanism. ZER could inhibit the migration of human esophageal squamous cancer KYSE-30 cells and KYSE-150 cells. ZER induced Rac1 protein down-regulation in a dose- and time-dependent manner. The reduction of Rac1 protein was crucial for ZER-induced inhibition of cell migration, as Rac1 knockdown could enhance ZER-induced inhibition of cell migration. We further demonstrated that the decrease of Rac1 after ZER treatment is via proteasome-dependent degradation pathway, and ZER treatment drastically enhanced ubiquitination of Rac1, which finally caused Rac1 degradation. Collectively, our results indicated that ZER inhibits cell migration by suppressing Rac1 expression. This suppresion is achieved through promoting Rac1 ubiquitination and degradation. Thus, the study raises the possibility of ZER as a potential drug for ESCC due to its ability to inhibit cell migration.

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PMID: 

Nutr Cancer. 2019 ;71(1):159-171. Epub 2019 Jan 16. PMID: 30650987

Abstract Title: 

Zerumbone Suppresses Human Colorectal Cancer Invasion and Metastasis via Modulation of FAk/PI3k/NFκB-uPA Pathway.

Abstract: 

The current study explored the basic molecular mechanisms of zerumbone (ZER), an herbal compound, in inhibiting the migration and invasion of colorectal cancer (CRC) cells in vitro. Two types of CRC cells, namely HCT-116 and SW48, were treated with various concentrations of ZER (8, 16, and 24 µM) for 24, 48, and 72 h, respectively. In vitro assays were performed to determine alterations in proliferation ability, mRNA expression and protein levels, and migration and invasion potential of CRC cells. An SYBR Green-based quantitative polymerase chain reaction (PCR) was utilized to detect the gene expression of focal adhesion kinase (FAK), nuclear factor (NF)-κB, and urokinase-type plasminogen activator (uPA) followed by the evaluation of the level of proteins by western blotting. Migration and invasion potentials of HCT-116 and SW48 cells treated by ZER were examined using migration and invasion assay kits, respectively. We compared the results of all experiments with control groups, including FAK inhibitor, ZER + FAK inhibitor-treated cells, NF-β inhibitor, ZER + NF-β inhibitor, and untreated cells. The data in the present study suggest that ZER may exert its antimetastatic effects through inhibition of FAk/PI3k/NF-κB-uPA signaling pathway, thereby possibly representing a novel class of FAK inhibitors.

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PMID: 

Pak J Biol Sci. 2018 Jan ;21(9):475-479. PMID: 30724050

Abstract Title: 

Immunomodulation of Zerumbone via Decreasing the Production of Reactive Oxygen Species from Immune Cells.

Abstract: 

BACKGROUND AND OBJECTIVE: Zerumbone has been reported to exert anti-inflammatory, anti-ulcer and anti-hyperglycemic effects but the specific mechanism through which zerumbone exerts its anti-inflammatory action through inhibiting reactive oxygen species was not well studied. Hence, this paper studied the zerumbone capacity to inhibit intracellular and extracellular Reactive Oxygen Species (ROS) produced by whole blood cell, polymorphoneutrophil (PMNs) and macrophage cells due to the zymogen and phorbolmyristerate acetate (PMA) oxidant effect.MATERIALS AND METHODS: Zymogen and PMA based chemiluminescence assay were used to determine the immunomodulatory effect of zerumbone at concentrations (100, 10 and 1μg mL-1) toward production of Reactive Oxygen Species (ROS) from whole blood, PMNs and macrophage.RESULTS: Zerumbone significantly inhibited intracellular and extracellular ROS production by the zymosan/PMA-activated phagocyte cells with IC50 values of (16.3±0.1, 23.7±0.1 and 4.97±0.1 μg mL-1) against whole blood, PMNs and macrophage respectively.CONCLUSION: The anti-inflammatory activity of zerumbone was so much significant that even strong oxidant (zymogen and PMA) were not able to produce reactive oxygen species when incubated together in phagocytic cells, thus suppress production of ROS. Therefore, it is highly used in herbal medicine as a potent immunomodulatory therapy in various inflammation associated diseases.

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PMID: 

Molecules. 2019 Feb 18 ;24(4). Epub 2019 Feb 18. PMID: 30781671

Abstract Title: 

Potential of Zerumbone as an Anti-Cancer Agent.

Abstract: 

Cancer is still a major risk factor to public health globally, causing approximately 9.8 million deaths worldwide in 2018. Despite advances in conventional treatment modalities for cancer treatment, there are still few effective therapies available due to the lack of selectivity, adverse side effects, non-specific toxicities, and tumour recurrence. Therefore, there is an immediate need for essential alternative therapeutics, which can prove to be beneficial and safe against cancer. Various phytochemicals from natural sources have been found to exhibit beneficial medicinal properties against various human diseases. Zerumbone is one such compound isolated fromSmith that possesses diverse pharmacological properties including those of antioxidant, antibacterial, antipyretic, anti-inflammatory, immunomodulatory, as well as anti-neoplastic. Zerumbone has shown its anti-cancer effects by causing significant suppression of proliferation, survival, angiogenesis, invasion, and metastasis through the molecular modulation of different pathways such as NF-κB, Akt, and IL-6/JAK2/STAT3 (interleukin-6/janus kinase-2/signal transducer and activator of transcription 3) and their downstream target proteins. The current review briefly summarizes the modes of action and therapeutic potential of zerumbone against various cancers.

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PMID: 

Food Funct. 2019 Mar 20 ;10(3):1629-1642. PMID: 30834410

Abstract Title: 

Dietary zerumbone from shampoo ginger: new insights into its antioxidant and anticancer activity.

Abstract: 

The dietary sesquiterpene dienone zerumbone (ZER) selectively targets cancer cells, inducing mitochondrial dysfunction and apoptosis, and protects non-cancerous cells towards oxidative stress and insult. This study examines the in vitro effects of ZER on lipid peroxidation in biological systems (cholesterol and phospholipid membrane oxidation) and explores its antitumor action in terms of its ability to modulate cancer cell lipid profile. Evaluation of the antioxidant activity of ZER showed that this compound is unable to trap lipoperoxyl radicals per se. ZER significantly modulated the total lipid and fatty acid profiles in cancer cells, inducing marked changes in the phospholipid/cholesterol ratio, with significant decreases in the levels of oleic and palmitic acids and a marked increase of stearic acid. Cell-based fluorescent measurements of intracellular membranes and lipid droplets using the Nile Red staining technique showed that in cancer cells, ZER induced significant accumulation of cytosolic lipid droplets and altered cell membrane organization/protein dynamics, depolarizing the mitochondrial membranes and inducing apoptosis and alteration of nuclear morphology. The modulatory activity of ZER on the total lipid and fatty acid profiles and lipid droplets may therefore represent another possible mechanism of its anticancer properties.

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PMID: 

Phytother Res. 2019 May ;33(5):1538-1550. Epub 2019 Mar 14. PMID: 30868670

Abstract Title: 

Dietary zerumbone, a sesquiterpene, ameliorates hepatotoxin-mediated acute and chronic liver injury in mice.

Abstract: 

Acute liver injury (ALI) is a life-threatening clinical syndrome. Long-lasting liver injury can lead to chronic hepatic inflammation and fibrogenic responses. Zerumbone (ZER), the main constituent of rhizomes of Zingiber zerumbet Smith, has a variety of functions including anticancer activity. We investigated the role of ZER on the progression of hepatotoxin-induced liver injury. Single or repeated injection of CClwas used to induce acute or chronic liver injury, respectively. Mice were orally administered with ZER (10, 50 mg/kg) during the experimental period. Histopathologic analysis and serum biochemical levels revealed that ZER had hepatoprotective activities against ALI. Similar effects of ZER on injured livers were confirmed by analyses of inflammation and apoptosis-related genes. Western blot analysis showedthat protein levels of apoptotic molecules were decreased, whereas antiapoptotic protein levels were conversely increased in injured livers treated with ZER. Furthermore, chronic liver injury and its associated fibrogenesis in mice were reduced by ZER treatment. These findings from our in vivo experiments further indicate that ZER could alleviate hepatocellular toxicity and inhibit activation of primary hepatic stellate cells. Our results suggest that ZER might have potential as a safe and prophylactic alternative to prevent acute and chronic liver injury.

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