gingerol and Colorectal-Neoplasms

Colorectal cancer (CRC) has been linked to dietary consumption of benzo[a]pyrene (B[a]P). 6-Gingerol (6-G), a component of ginger has been reported to possess anti-inflammatory and antioxidant activities, but little is known regarding the mechanism of 6-G in CRC chemoprevention. We therefore investigated the effect of 6-G on B[a]P. and dextran sulphate sodium (DSS) induced CRC in mice. Mice in Group I and Group II received corn oil and 6-G orally at 2 ml/kg and 100 mg/kg, respectively for 126 days. Group III were administered 125 mg/kg of B[a]P for 5 days followed by 3 cycles of 4% dextran sulphate sodium (DSS). Group IV received 6-G for 7 days followed by co-administration with 125 mg/kg of B[a]P. for 5 days and 3 cycles of 4% DSS. Tumor formation was reduced and expression of Ki-67, WNT3a, DVL-2 and β-catenin following 6-G exposure. Also, 6-G increases expression of APC, P53, TUNEL positive nuclei and subsequently decreased the expression of TNF-α, IL-1β, INOS, COX-2 and cyclin D1. 6-G inhibited angiogenesis by decreasing the concentration of VEGF, Angiopoietin-1, FGF and GDF-15 in the colon of B[a]P. and DSS exposed mice. Overall, 6-G attenuated B[a]P and DSS-induced CRC in mice via anti-inflammatory, anti-proliferative and apoptotic mechanisms.

Topics: Animals; Benzo(a)pyrene; beta Catenin; Catechols; Colorectal Neoplasms; Dextran Sulfate; Disease Progression; Fatty Alcohols; Genes, APC; Male; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A

Our previous study reported that combined treatment of γ-tocotrienol with 6-gingerol showed promising anticancer effects by synergistically inhibiting proliferation of human colorectal cancer cell lines. This study aimed to identify and elucidate molecular mechanisms involved in the suppression of SW837 colorectal cancer cells modulated by combined treatment of γ-tocotrienol and 6-gingerol. Total RNA from both untreated and treated cells was prepared for transcriptome analysis using RNA sequencing techniques. We performed high-throughput sequencing at approximately 30-60 million coverage on both untreated and 6G + γT3-treated cells. The results showed that cancer-specific differential gene expression occurred and functional enrichment pathway analysis suggested that more than one pathway was modulated in 6G + γT3-treated cells. Combined treatment with 6G + γT3 augmented its chemotherapeutic effect by interfering with the cell cycle process, downregulating the Wnt signalling pathway and inducing apoptosis mainly through caspase-independent programmed cell death through mitochondrial dysfunction, activation of ER-UPR, disruption of DNA repair mechanisms and inactivation of the cell cycle process through the downregulation of main genes in proliferation such as FOXM1 and its downstream genes. The combined treatment exerted its cytotoxic effect through upregulation of genes in stress response activation and cytostatic effects demonstrated by downregulation of main regulator genes in the cell cycle. Selected genes involved in particular pathways including ATF6, DDIT3, GADD34, FOXM1, CDK1 and p21 displayed concordant patterns of gene expression between RNA sequencing and RT-qPCR. This study provides new insights into combined treatment with bioactive compounds not only in terms of its pleiotropic effects that enhance multiple pathways but also specific target genes that could be exploited for therapeutic purposes, especially in suppressing cancer cell growth.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Catechols; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Chromans; Colorectal Neoplasms; DNA Repair; Fatty Alcohols; Forkhead Box Protein M1; Gene Expression Profiling; Humans; Signal Transduction; Tocotrienols; Vitamin E; Wnt Signaling Pathway

Leukotriene A4 hydrolase (LTA

Topics: Aminopeptidases; Antineoplastic Agents; Catechols; Cell Proliferation; Colorectal Neoplasms; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epoxide Hydrolases; Fatty Alcohols; Humans; Molecular Docking Simulation; Molecular Structure; Recombinant Proteins; Structure-Activity Relationship; Tumor Cells, Cultured

The effect of [10]-gingerol on cytosol free Ca(2+) concentration ([Ca(2+)](i)) and viability is large unknown. This study examines the early signaling effects of [10]-gingerol on human colorectal cancer cells. It was found that this compound caused a slow and sustained rise of [Ca(2+)](i) in a concentration-dependent manner. [10]-Gingerol also induced a [Ca(2+)](i) rise when extracellular Ca(2+) was removed, but the magnitude was reduced by 38%. In a Ca(2+)-free medium, the [10]-gingerol-induced [Ca(2+)](i) rise was partially abolished by depleting stored Ca(2+) with thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor). The elevation of [10]-gingerol-caused [Ca(2+)](i) in a Ca(2+)-containing medium was not affected by modulation of protein kinase C activity. The [10]-gingerol-induced Ca(2+) influx was insensitive to L-type Ca(2+) channel blockers. At concentrations of 10-100 mM, [10]-gingerol killed cells in a concentration-dependent manner. These findings suggest that [10]-gingerol induces [Ca(2+)](i) rise by causing Ca(2+) release from the endoplasmic reticulum and Ca(2+) influx from non-L-type Ca(2+) channels in SW480 cancer cells.

Topics: Antineoplastic Agents; Calcium; Calcium Channels, L-Type; Catechols; Cell Survival; Colorectal Neoplasms; Endoplasmic Reticulum; Fatty Alcohols; Humans; Protein Kinase C; Tumor Cells, Cultured

[6]-Gingerol, a natural component of ginger, exhibits anti-inflammatory and antitumorigenic activities. Despite its potential efficacy in cancer, the mechanism by which [6]-gingerol exerts its chemopreventive effects remains elusive. The leukotriene A(4) hydrolase (LTA(4)H) protein is regarded as a relevant target for cancer therapy. Our in silico prediction using a reverse-docking approach revealed that LTA(4)H might be a potential target of [6]-gingerol. We supported our prediction by showing that [6]-gingerol suppresses anchorage-independent cancer cell growth by inhibiting LTA(4)H activity in HCT116 colorectal cancer cells. We showed that [6]-gingerol effectively suppressed tumor growth in vivo in nude mice, an effect that was mediated by inhibition of LTA(4)H activity. Collectively, these findings indicate a crucial role of LTA(4)H in cancer and also support the anticancer efficacy of [6]-gingerol targeting of LTA(4)H for the prevention of colorectal cancer.

Topics: Animals; Anti-Inflammatory Agents; Catechols; Cell Division; Cell Line, Tumor; Colonic Neoplasms; Colorectal Neoplasms; Epoxide Hydrolases; Fatty Alcohols; Female; HCT116 Cells; Humans; Male; Mice; Mice, Nude; Models, Molecular; Protein Conformation; Zingiber officinale

6-Gingerol, a natural product of ginger, has been known to possess anti-tumorigenic and pro-apoptotic activities. However, the mechanisms by which it prevents cancer are not well understood in human colorectal cancer. Cyclin D1 is a proto-oncogene that is overexpressed in many cancers and plays a role in cell proliferation through activation by beta-catenin signaling. Nonsteroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1) is a cytokine associated with pro-apoptotic and anti-tumorigenic properties. In the present study, we examined whether 6-gingerol influences cyclin D1 and NAG-1 expression and determined the mechanisms by which 6-gingerol affects the growth of human colorectal cancer cells in vitro. 6-Gingerol treatment suppressed cell proliferation and induced apoptosis and G(1) cell cycle arrest. Subsequently, 6-gingerol suppressed cyclin D1 expression and induced NAG-1 expression. Cyclin D1 suppression was related to inhibition of beta-catenin translocation and cyclin D1 proteolysis. Furthermore, experiments using inhibitors and siRNA transfection confirm the involvement of the PKCepsilon and glycogen synthase kinase (GSK)-3beta pathways in 6-gingerol-induced NAG-1 expression. The results suggest that 6-gingerol stimulates apoptosis through upregulation of NAG-1 and G(1) cell cycle arrest through downregulation of cyclin D1. Multiple mechanisms appear to be involved in 6-gingerol action, including protein degradation as well as beta-catenin, PKCepsilon, and GSK-3beta pathways.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; beta Catenin; Caco-2 Cells; Catechols; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Cyclin D1; Dose-Response Relationship, Drug; Fatty Alcohols; G1 Phase; HT29 Cells; Humans; Luciferases; Plasmids; Proto-Oncogene Mas; S Phase; Statistics as Topic; Transfection

Ginger, the rhizome of Zingiber officinale, is a traditional medicine with anti-inflammatory and anticarcinogenic properties. This study examined the growth inhibitory effects of the structurally related compounds 6-gingerol and 6-shogaol on human cancer cells. 6-Shogaol [1-(4-hydroxy-3-methoxyphenyl)-4-decen-3-one] inhibits the growth of human cancer cells and induces apoptosis in COLO 205 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS). ROS generation occurs in the early stages of 6-shogaol-induced apoptosis, preceding cytochrome c release, caspase activation, and DNA fragmentation. Up-regulation of Bax, Fas, and FasL, as well as down-regulation of Bcl-2 and Bcl-X(L )were observed in 6-shogaol-treated COLO 205 cells. N-acetylcysteine (NAC), but not by other antioxidants, suppress 6-shogaol-induced apoptosis. The growth arrest and DNA damage (GADD)-inducible transcription factor 153 (GADD153) mRNA and protein is markedly induced in a time- and concentration-dependent manner in response to 6-shogaol.

Topics: Adenocarcinoma; Apoptosis; Caspases; Catechols; Cell Line, Tumor; Colonic Neoplasms; Colorectal Neoplasms; Fatty Alcohols; Humans; Membrane Potentials; Mitochondrial Membranes; Plant Extracts; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Transcription Factor CHOP; Zingiber officinale