6-Shogaol

The rhizome of Zingiber officinale Roscoe.

6-shogaol, an active compound isolated from Ginger (Zingiber officinale Rosc), exhibits a variety of biological activities including anticancer, anti-inflammation, and anti-oxidation.

In Vitro:6-shogaol has anticancer activity against several cell lines[1]. 6-shogaol is identified to be cytotoxic in various cell lines, with KB (IC50=7.4±2.2 μM) and HL60 (IC50=7.9±2.0 μM) cells most susceptible to 6-shogaol[2]. 6-shogaol (IC50=8 μM) has much stronger growth inhibitory effects than 6-gingerol (IC50=150 μM) on HCT-116 human colon cancer cells[3]. 6-shogaol stimulates phosphorylations of mitogen-activated protein kinases (MAPKs) such as ERK, JNK, and p38. Moreover, the 6-shogaol-induced expressions of Nrf2 and HO-1 are attenuated by treatments of SB202190 (a p38 specific inhibitor) and LY294002 (an Akt specific inhibitor)[4].

In Vivo:The 6-shogaol decreases the diethylnitrosamine (DEN)-mediated elevations of serum aspartate transaminase and alanine transaminase as well as the DEN-induced hepatic lipid peroxidation. Inductions of Nrf2 and HO-1 by 6-shogaol are also confirmed in the mice. The administration of 6-shogaol to the mice also restores the DEN-reduced activity and protein expression of hepatic antioxidant enzymes such as superoxide dismutase, glutathione peroxidase and catalase[4].

References:
[1]. Semwal RB, et al. Gingerols and shogaols: Important nutraceutical principles from ginger. Phytochemistry. 2015 Sep;117:554-68. [2]. Peng F, et al. Cytotoxic, cytoprotective and antioxidant effects of isolated phenolic compounds from fresh ginger. Fitoterapia. 2012 Apr;83(3):568-85. [3]. Sang S, et al. Increased growth inhibitory effects on human cancer cells and anti-inflammatory potency of shogaols from Zingiber officinale relative to gingerols. J Agric Food Chem. 2009 Nov 25;57(22):10645-50. [4]. Bak MJ, et al. 6-shogaol-rich extract from ginger up-regulated the antioxidant defense systems in cells and mice. Molecules. 2012 Jul 4;17(7):8037-55.

6-Shogaol induces apoptosis in human hepatocellular carcinoma cells and exhibits anti-tumor activity in vivo through endoplasmic reticulum stress.[Pubmed:22768104]

PLoS One. 2012;7(6):e39664.

6-Shogaol is an active compound isolated from Ginger (Zingiber officinale Rosc). In this work, we demonstrated that 6-Shogaol induces apoptosis in human hepatocellular carcinoma cells in relation to caspase activation and endoplasmic reticulum (ER) stress signaling. Proteomic analysis revealed that ER stress was accompanied by 6-Shogaol-induced apoptosis in hepatocellular carcinoma cells. 6-Shogaol affected the ER stress signaling by regulating unfolded protein response (UPR) sensor PERK and its downstream target eIF2alpha. However, the effect on the other two UPR sensors IRE1 and ATF6 was not obvious. In prolonged ER stress, 6-Shogaol inhibited the phosphorylation of eIF2alpha and triggered apoptosis in SMMC-7721 cells. Salubrinal, an activator of the PERK/eIF2alpha pathway, strikingly enhanced the phosphorylation of eIF2alpha in SMMC-7721 cells with no toxicity. However, combined treatment with 6-Shogaol and salubrinal resulted in significantly increase of apoptosis and dephosphorylation of eIF2alpha. Overexpression of eIF2alpha prevented 6-Shogaol-mediated apoptosis in SMMC-7721 cells, whereas inhibition of eIF2alpha by small interfering RNA markedly enhanced 6-Shogaol-mediated cell death. Furthermore, 6-Shogaol-mediated inhibition of tumor growth of mouse SMMC-7721 xenograft was associated with induction of apoptosis, activation of caspase-3, and inactivation of eIF2alpha. Altogether our results indicate that the PERK/eIF2alpha pathway plays an important role in 6-Shogaol-mediated ER stress and apoptosis in SMMC-7721 cells in vitro and in vivo.

6-shogaol, an active constituent of dietary ginger, impairs cancer development and lung metastasis by inhibiting the secretion of CC-chemokine ligand 2 (CCL2) in tumor-associated dendritic cells.[Pubmed:25621970]

J Agric Food Chem. 2015 Feb 18;63(6):1730-8.

This study has two novel findings: it is not only the first to demonstrate that tumor-associated dendritic cells (TADCs) facilitate lung and breast cancer metastasis in vitro and in vivo by secreting inflammatory mediator CC-chemokine ligand 2 (CCL2), but it is also the first to reveal that 6-Shogaol can decrease cancer development and progression by inhibiting the production of TADC-derived CCL2. Human lung cancer A549 and breast cancer MDA-MB-231 cells increase TADCs to express high levels of CCL2, which increase cancer stem cell features, migration, and invasion, as well as immunosuppressive tumor-associated macrophage infiltration. 6-Shogaol decreases cancer-induced up-regulation of CCL2 in TADCs, preventing the enhancing effects of TADCs on tumorigenesis and metastatic properties in A549 and MDA-MB-231 cells. A549 and MDA-MB-231 cells enhance CCL2 expression by increasing the phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the activation of STAT3 induced by A549 and MDA-MB-231 is completely inhibited by 6-Shogaol. 6-Shogaol also decreases the metastasis of lung and breast cancers in mice. 6-Shogaol exerts significant anticancer effects on lung and breast cells in vitro and in vivo by targeting the CCL2 secreted by TADCs. Thus, 6-Shogaol may have the potential of being an efficacious immunotherapeutic agent for cancers.

6-Shogaol enhances renal carcinoma Caki cells to TRAIL-induced apoptosis through reactive oxygen species-mediated cytochrome c release and down-regulation of c-FLIP(L) expression.[Pubmed:25619640]

Chem Biol Interact. 2015 Feb 25;228:69-78.

6-Shogaol, a potent bioactive compound in ginger (Zingiber officinale Roscoe), has been reported for anti-inflammatory and anti-cancer activity. In this study, we investigated the effect of 6-Shogaol to enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The combined treatment with 6-Shogaol and TRAIL markedly induces apoptosis in various cancer cells (renal carcinoma Caki cells, breast carcinoma MDA-MB-231 cells and glioma U118MG cells), but not in normal mesangial cells and normal mouse kidney cells. 6-Shogaol reduced the mitochondrial membrane potential (MMP) and released cytochrome c from mitochondria to cytosol via Bax activation. Furthermore, we found that 6-Shogaol induced down-regulation of c-FLIP(L) expression at the post-translational levels and the overexpression of c-FLIP(L) markedly inhibited 6-Shogaol plus TRAIL-induced apoptosis. Moreover, 6-Shogaol increased reactive oxygen species (ROS) production in Caki cells. Pretreatment with ROS scavengers attenuated 6-Shogaol plus TRAIL-induced apoptosis through inhibition of MMP reduction and down-regulation of c-FLIP(L) expression. In addition, 6-gingerol, another phenolic alkanone isolated from ginger, did not enhance TRAIL-induced apoptosis and down-regulate c-FLIP(L) expression. Taken together, our results demonstrated that 6-Shogaol enhances TRAIL-mediated apoptosis in renal carcinoma Caki cells via ROS-mediated cytochrome c release and down-regulation of c-FLIP(L) expression.

6-Shogaol reduced chronic inflammatory response in the knees of rats treated with complete Freund's adjuvant.[Pubmed:17010215]

BMC Pharmacol. 2006 Oct 1;6:12.

BACKGROUND: 6-Shogaol is one of the major compounds in the ginger rhizome that may contribute to its anti-inflammatory properties. Confirmation of this contribution was sought in this study in Sprague- Dawley rats (200-250 g) treated with a single injection (0.5 ml of 1 mg/ml) of a commercial preparation of complete Freund's Adjuvant (CFA) to induce monoarthritis in the right knee over a period of 28 days. During this development of arthritis, each rat received a daily oral dose of either peanut oil (0.2 ml-control) or 6-Shogaol (6.2 mg/Kg in 0.2 ml peanut oil). RESULTS: Within 2 days of CFA injection, the control group produced maximum edematous swelling of the knee that was sustained up to the end of the investigation period. But, in the 6-Shogaol treated group, significantly lower magnitudes of unsustained swelling of the knees (from 5.1 +/- 0.2 mm to 1.0 +/- 0.2 mm, p < 0.002, n = 6) were produced during the investigation period. Unsustained swelling of the knees (from 3.2 +/- 0.6 mm to 0.8 +/- 1.1 mm, p < 0.00008, n = 6) was also produced after 3 days of treatment with indomethacin (2 mg/Kg/day) as a standard anti-inflammatory drug, but during the first 2 days of drug treatment swelling of the knees was significantly larger (11.6 +/- 2.0 mm, p < 0.0002, n = 6) than either the controls or the 6-Shogaol treated group of rats. This exaggerated effect in the early stage of indomethacin treatment was inhibited by montelukast, a cysteinyl leukotriene receptor antagonist. Also, 6-Shogaol and indomethacin were most effective in reducing swelling of the knees on day 28 when the controls still had maximum swelling. The effect of 6-Shogaol compared to the controls was associated with significantly lower concentration of soluble vascular cell adhesion molecule-1 (VCAM-1) in the blood and infiltration of leukocytes, including lymphocytes and monocytes/macrophages, into the synovial cavity of the knee. There was also preservation of the morphological integrity of the cartilage lining the femur compared to damage to this tissue in the peanut oil treated control group of rats. CONCLUSION: From these results, it is concluded that 6-Shogaol reduced the inflammatory response and protected the femoral cartilage from damage produced in a CFA monoarthritic model of the knee joint of rats.

Antitumor activity of gemcitabine can be potentiated in pancreatic cancer through modulation of TLR4/NF-kappaB signaling by 6-shogaol.[Pubmed:24424498]

AAPS J. 2014 Mar;16(2):246-57.

Advanced pancreatic cancer still has a poor prognosis, even with the approval of several drugs, such as gemcitabine. Therefore, developing effective and safe antitumor agents is urgently needed. 6-Shogaol, a phenol extracted from ginger, has been linked to suppression of proliferation and survival of cancer with different mechanisms. In the present study, we investigated whether 6-Shogaol could suppress pancreatic cancer progress and potentiate pancreatic cancer to gemcitabine treatment in vitro and in vivo. We found that 6-Shogaol prevented the activation of toll like receptor 4 (TLR4)/NF-kappaB signaling. The modulation of NF-kappaB signaling by 6-Shogaol was ascertained by electrophoretic mobility shift assay and western blot analysis. The suppression of NF-kappaB signaling and key cell survival regulators including COX-2, cyclinD1, survivin, cIAP-1, XIAP, Bcl-2, and MMP-9 brought the anti-proliferation effects in pancreatic cancer cells and sensitized them to gemcitabine treatment. Furthermore, in a pancreatic cancer xenograft model, we found a decreased proliferation index (Ki-67) and increased apoptosis by TUNEL staining in 6-Shogaol treated tumors. It was also shown that 6-Shogaol combined with gemcitabine treatment was more effective than drug alone, consistent with the downregulation of NF-kappaB activity along with its target genes COX-2, cyclinD1, survivin, cIAP-1, and XIAP. Overall, our results suggest that 6-Shogaol can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing of TLR4/NF-kappaB-mediated inflammatory pathways linked to tumorigenesis.

6-Shogaol, a ginger product, modulates neuroinflammation: a new approach to neuroprotection.[Pubmed:22465818]

Neuropharmacology. 2012 Aug;63(2):211-23.

Inflammatory processes in the central nervous system play an important role in a number of neurodegenerative diseases mediated by microglial activation, which results in neuronal cell death. Microglia act in immune surveillance and host defense while resting. When activated, they can be deleterious to neurons, even resulting in neurodegeneration. Therefore, the inhibition of microglial activation is considered a useful strategy in searching for neuroprotective agents. In this study, we investigated the effects of 6-Shogaol, a pungent agent from Zingiber officinale Roscoe, on microglia activation in BV-2 and primary microglial cell cultures. 6-Shogaol significantly inhibited the release of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS) induced by lipopolysaccharide (LPS). The effect was better than that of 6-gingerol, wogonin, or N-monomethyl-l-arginine, agents previously reported to inhibit nitric oxide. 6-Shogaol exerted its anti-inflammatory effects by inhibiting the production of prostaglandin E(2) (PGE(2)) and proinflammatory cytokines, such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), and by downregulating cyclooxygenase-2 (COX-2), p38 mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF-kappaB) expression. In addition, 6-Shogaol suppressed the microglial activation induced by LPS both in primary cortical neuron-glia culture and in an in vivo neuroinflammatory model. Moreover, 6-Shogaol showed significant neuroprotective effects in vivo in transient global ischemia via the inhibition of microglia. These results suggest that 6-Shogaol is an effective therapeutic agent for treating neurodegenerative diseases.

Shogaol ([6]-Shogaol), an active compound isolated from Ginger (Zingiber officinale Rosc), exhibits a variety of biological activities including anticancer, anti-inflammation, and anti-oxidation.

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