shogaol and Colonic-Neoplasms

Cancer is ranked as the first or second cause of death in 112 countries across the world with an estimated 19.3 million new cases of cancer along with 10 million deaths occurring in 2020. Colon cancer is the second most common cancer in women and the fourth most common cancer worldwide. Investigating methods to reduce or prevent cancer through natural and holistic processes are becoming more of a common research topic around the world. Influenced through traditional Chinese medical practices and Ayurvedic medicine, scientists are now exploring anticancerous compounds present in plants and foods used in these cultures. For instance, ginger (Zingiber officinale) has been used for centuries all over Asia for medicinal purposes and contains anticancer compounds. Our review focuses on one of ginger's constituents, 6-shogaol, and its role in colon cancer. We found that 6-shogaol has a significant effect on apoptosis by influencing caspase pathways and cell cycle arrest.

Topics: Apoptosis; Catechols; Colonic Neoplasms; Female; Humans; Zingiber officinale

Topics: Adenoma; Animals; Anti-Inflammatory Agents; Antioxidants; Azoxymethane; Colonic Neoplasms; Colorectal Neoplasms; Disease Models, Animal; Inflammation; Male; Mice

The development and growth of colorectal cancer based on constitutive activation of numerous signaling pathways that stimulate proliferation and metastasis. Plant-derived agents excel by targeting multiple aspects of tumor progression. Previous investigations have shown that ginger derivatives- shogaols possess anti-cancer and anti-inflammatory effects. In the present study, we have examined the anti-cancer effects of 6-shogaol alongside with the most widely used chemotherapeutic agents/regimens in the tumor-like microenvironment conditions.. Cytotoxicity on two colon cancer cell lines (SW480 and SW620) was measured by MTT test. Apoptosisassay, immunocytochemical and Western blotting analysis for autophagy and apoptosis detection were performed.. Here, we report that 6-shogaol by itself or in combination with chemotherapeutic agents/regimens exerted a cytotoxic effect on CRC cells. Cell death might be linked with the activation of autophagy and apoptosis-related pathways. In the tumor-like microenvironment, which is characterized by hypoxia and glucose starvation, 6-shogaol with chemotherapeutics is significantly more potent than conventional chemotherapy alone.. Collectively, our data suggest that the addition of 6-shogaol to established chemotherapeutic regimens could potentially be a remarkable therapeutic strategy for colorectal cancer.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Catechols; Cell Hypoxia; Cell Line, Tumor; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Humans; Immunosuppressive Agents; Irinotecan; Oxaliplatin; Topoisomerase I Inhibitors

There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. In this study, we characterized a specific population of nanoparticles derived from edible ginger (GDNPs 2) and demonstrated their efficient colon targeting following oral administration. GDNPs 2 had an average size of ∼230 nm and exhibited a negative zeta potential. These nanoparticles contained high levels of lipids, a few proteins, ∼125 microRNAs (miRNAs), and large amounts of ginger bioactive constituents (6-gingerol and 6-shogaol). We also demonstrated that GDNPs 2 were mainly taken up by intestinal epithelial cells (IECs) and macrophages, and were nontoxic. Using different mouse colitis models, we showed that GDNPs 2 reduced acute colitis, enhanced intestinal repair, and prevented chronic colitis and colitis-associated cancer (CAC). 2D-DIGE/MS analyses further identified molecular target candidates of GDNPs 2 involved in these mouse models. Oral administration of GDNPs 2 increased the survival and proliferation of IECs and reduced the pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), and increased the anti-inflammatory cytokines (IL-10 and IL-22) in colitis models, suggesting that GDNPs 2 has the potential to attenuate damaging factors while promoting the healing effect. In conclusion, GDNPs 2, nanoparticles derived from edible ginger, represent a novel, natural delivery mechanism for improving IBD prevention and treatment with an added benefit of overcoming limitations such as potential toxicity and limited production scale that are common with synthetic nanoparticles.

Topics: Animals; Antineoplastic Agents, Phytogenic; Catechols; Cell Line; Cell Line, Tumor; Colitis, Ulcerative; Colonic Neoplasms; Fatty Alcohols; Female; Humans; Inflammatory Bowel Diseases; Mice; Mice, Inbred C57BL; Nanoparticles; Phytotherapy; Zingiber officinale

In this study, we showed the ability of representative shogaol, which as a major component of ginger, to overcome TRAIL resistance by increasing apoptosis in colon cancer cells. Shogaol increased death receptor 5 (DR5) levels. Furthermore, shogaol decreased the expression level of antiapoptotic proteins (survivin and Bcl-2) and increased pro-apoptotic protein, Bax. Shogaol treatment induced apoptosis and a robust reduction in the levels of the antiapoptotic protein survivin but did not affect the levels of many other apoptosis regulators. Moreover, knockdown of survivin sensitized colon cancer cells to resistant of TRAIL-induced apoptosis. Therefore, we showed the functions of shogaol as a sensitizing agent to induce cell death of TRAIL-resistant colon cancer cells. This study gives rise to the possibility of applying shogaol as an antitumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant colon tumor therapy.

Topics: Apoptosis; bcl-2-Associated X Protein; Catechols; Cell Line, Tumor; Colonic Neoplasms; Drug Resistance, Neoplasm; Drug Synergism; Humans; Inhibitor of Apoptosis Proteins; Proto-Oncogene Proteins c-bcl-2; Receptors, TNF-Related Apoptosis-Inducing Ligand; Survivin; TNF-Related Apoptosis-Inducing Ligand; Zingiber officinale

Shogaols, the major constituents of thermally processed ginger, have been proven to be highly effective anticancer agents. Our group has identified cysteine-conjugated shogaols (M2, M2', and M2″) as the major metabolites of [6]-, [8]-, and [10]-shogaol in human and found that M2 is a carrier of its parent molecule [6]-shogaol in cancer cells and in mice, while being less toxic to normal colon fibroblast cells. The objectives of this study are to determine whether M2' and M2″ behave in a similar manner to M2, in both metabolism and efficacy as anticancer agents, and to further explore the biological pro-apoptotic mechanisms of the cysteine-conjugated shogaols against human colon cancer cells HCT-116 and HT-29. Our results show that [8]- and [10]-shogaol have similar metabolic profiles to [6]-shogaol and exhibit similar toxicity toward human colon cancer cells. M2' and M2″ both show low toxicity against normal colon cells but retain potency against colon cancer cells, suggesting that they have similar activity to M2. We further demonstrate that the cysteine-conjugated shogaols can cause cancer cell death through the activation of the mitochondrial apoptotic pathway. Our results show that oxidative stress activates a p53 pathway that ultimately leads to p53 up-regulated modulator of apoptosis (PUMA) induction and down-regulation of B-cell lymphoma 2 (Bcl-2), followed by cytochrome c release, perturbation of inhibitory interactions of X-linked inhibitor of apoptosis protein (XIAP) with caspases, and finally caspase 9 and 3 activation and cleavage. A brief screen of the markers attenuated by the proapoptotic activity of M2 revealed similar results for [8]- and [10]-shogaol and their respective cysteine-conjugated metabolites M2' and M2″. This study highlights the cysteine-conjugated metabolites of shogaols as novel dietary colon cancer preventive agents.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Caspase 9; Catechols; Cell Cycle; Colonic Neoplasms; Cysteine; Cytochromes c; HCT116 Cells; HT29 Cells; Humans; Oxidative Stress; Proto-Oncogene Proteins; Signal Transduction; Tumor Suppressor Protein p53; Zingiber officinale

6-Shogaol has been shown to possess many antitumor properties including inhibition of cancer cell growth, inhibition of cancer metastasis, induction of apoptosis in cancer cells and induction of cancer cell differentiation. Despite its prominent antitumor effects, the direct molecular target of 6-shogaol has remained elusive. To identify the direct targets of 6-shogaol, a comprehensive antitumor profile of 6-shogaol (NSC752389) was tested in the NCI-60 cell line in an in vitro screen. The results show that 6-shogaol is COMPARE negative suggesting that it functions via a mechanism of action distinct from existing classes of therapeutic agents. Further analysis using microarray gene profiling and Connectivity Map analysis showed that MCF-7 cells treated with 6-shogaol display gene expression signatures characteristic of peroxisome proliferator activated receptor γ (PPARγ) agonists, suggesting that 6-shogaol may activate the PPARγ signaling pathway for its antitumor effects. Indeed, treatment of MCF-7 and HT29 cells with 6-shogaol induced PPARγ transcriptional activity, suppressed NFκB activity, and induced apoptosis in breast and colon cancer cells in a PPARγ-dependent manner. Furthermore, 6-shogaol is capable of binding to PPARγ with a binding affinity comparable to 15-delta prostaglandin J2, a natural ligand for PPARγ. Together, our findings suggest that the antitumor effects of 6-shogaol are mediated through activation of PPARγ and imply that activation of PPARγ might be beneficial for breast and colon cancer treatment.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Catechols; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Dose-Response Relationship, Drug; Enzyme Activation; Female; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Ligands; MCF-7 Cells; NF-kappa B; Oligonucleotide Array Sequence Analysis; PPAR gamma; Prostaglandin D2; Signal Transduction; Transcription, Genetic

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