6-Shogaol: From Biological Activities to Micellar Delivery Enhancement

6-shogaol is a promising anti-cancer and anti-inflammatory agent. However, the treatment effectiveness of 6-shogaol is limited by poor water solubility, poor oral absorption and rapid metabolism. The potentiality of 6-shogaol is supported by several lines of evidence as an agent for the prevention and treatment of a variety of cancers including gastrointestinal, melanoma, breast, lung, head and neck.

6-Shogaol Inhibits Breast Cancer Cells and Stem Cell-Like Spheroids

Ginger (Zingiber officinale) is a well known herb consumed as a spice and food as well as widely used as herbal medicine for various ailments. A number of biologically active ingredients including gingerols and its various derivatives have been identified and synthesized from ginger in recent years. One important class of derivatives are shogaols that are primarily the dehydrated products of gingerols and are found exclusively in dried ginger. Among the shogaols, 6-shogaol has achieved a great deal of attention due to its potent anticancer activity against various cancer cells. It has been shown to induce mitotic arrest and reduce viability of gastric cancer cells. Aberrant mitosis followed by apoptosis has also been found to be induced by 6-shogaol in HCT-116 colon cancer cells. In human hepatoma p53 mutant Mahlavu subline, it induces apoptosis via oxidative stress pathway in a caspase dependent mechanism. It has also been shown to induce autophagy in HNSCLC A-549 cells via inhibition of the AKT/mTOR pathway. In another study, 6-shogaol has been reported to exhibit anti-invasive effects in breast cancer cells by reducing MMP-9 expression through NF-κB activation. Recently, PPAR-γ dependent apoptosis in MCF-7 and HT-29 cells by 6-shogaol has also been reported. Additionally, recent studies have implicated microtubule as a possible target of it as it interacts with the sulphydryl groups of cysteines in tubulin through its side chain containing the α, β unsaturated carbonyl moiety. All these studies place 6-shogaol as a promising agent to be studied further in view of its future therapeutic potential in cancer therapy.[1]

Several in vitro studies have shown that cancer stem cells are resistant to conventional chemotherapeutic drugs. Interestingly, a number of dietary compounds like curcumin, piperine, sulforaphane have recently been identified to target CSCs. However, various factors such as toxicity, weak dose response etc. largely limit their application. Since 6-shogaol has been reported as a potent anticancer agent against various cancer cells, we have investigated its inhibitory effect on breast cancer cells and cancer stem cell-like spheroids. Here we demonstrate that 6-shogaol shows anti-proliferative activity against breast cancer cells and spheroids and suppresses the size and colony forming ability of spheroids by altering the Notch signaling pathway. Investigation of the death mechanism shows that autophagy is a predominant mode of cell death caused by it in breast cancer cells. An earlier pharmacokinetic study of 6-shogaol and three gingerols on healthy humans reported that after p.o. (orally administered) dosing, all these compounds were absorbed. These compounds were later found to be metabolized as glucuronide and sulfate conjugates. No serious adverse effects were seen on those persons after ingestion of a single dose of 2 g of standardized ginger extract. A former report also showed that 6-shogaol was not toxic to normal cells like MRC5, NP69, HaCaT and HMEC. Our results on immortalized noncancerous cells thus supported that 6-shogaol did not have potent cytotoxicity to normal cells.

Treatment with 6-shogaol caused cytoplasmic vacuole formation and cleavage of microtubule associated protein Light Chain3 (LC3) in both monolayer and spheroid culture indicating that it induced autophagy. Kinetic analysis of the LC3 expression and a combination treatment with chloroquine revealed that the autophagic flux instigated cell death in it treated breast cancer cells in contrast to the autophagy inhibitor chloroquine. Furthermore, 6-shogaol-induced cell death got suppressed in the presence of chloroquine and a very low level of apoptosis was exhibited even after prolonged treatment of the compound, suggesting that autophagy is the major mode of cell death induced by 6-shogaol in breast cancer cells. It reduced the expression levels of Cleaved Notch1 and its target proteins Hes1 and Cyclin D1 in spheroids, and the reduction was further pronounced in the presence of a γ-secretase inhibitor. Secondary sphere formation in the presence of the inhibitor was also further reduced by 6-shogaol.

6-Shogaol, attenuates neuroinflammation and cognitive deficits

Recently, increased attention has been directed towards medicinal extracts as potential new drug candidates for dementia. Ginger has long been used as an important ingredient in cooking and traditional herbal medicine. In particular, ginger has been known to have disease-modifying effects in Alzheimer's disease (AD). However, there is no evidence of which constituents of ginger exhibit therapeutic effects against AD. A growing number of experimental studies suggest that 6-shogaol, a bioactive component of ginger, may play an important role as a memory-enhancing and anti-oxidant agent against neurological diseases. 6-Shogaol has also recently been shown to have anti-neuroinflammatory effects in lipopolysaccharide (LPS)-treated astrocytes and animal models of Parkinson's disease, LPS-induced inflammation and transient global ischemia. However, it is still unknown whether 6-shogaol has anti-inflammatory effects against oligomeric forms of the Aβ (AβO) in animal brains. Furthermore, the effects of 6-shogaol against memory impairment in dementia models are also yet to be investigated. In this study, we found that administration of 6-shogaol significantly reduced microgliosis and astrogliosis in intrahippocampal AβO-injected mice, ameliorated AβO and scopolamine-induced memory impairment, and elevated NGF levels and pre- and post-synaptic marker in the hippocampus. All these results suggest that 6-shogaol may play a role in inhibiting glial cell activation and reducing memory impairment in animal models of dementia.[2]

Hepatoprotective Effect of 6-Shogaol Loaded in a Type of Novel Micelles

6-shogaol is a promising anti-cancer and anti-inflammatory agent. However, the treatment effectiveness of 6-shogaol is limited by poor water solubility, poor oral absorption and rapid metabolism. Herein, it loaded in micelles (SMs) were designed to improve 6-shogaol's solubility and bioavailability. The micelles of a PEG derivative of linoleic acid (mPEG2k-LA) were prepared by the nanoprecipitation method with a particle size of 76.8 nm, and entrapment of 81.6 %. Intriguingly, SMs showed a slower release in phosphate buffer saline (PBS) (pH = 7.4) compared to free 6-shogaol while its oral bioavailability increased by 3.2–fold in vivo. More importantly, the in vitro cytotoxic effect in HepG2 cells of SMs was significantly higher than free 6-shogaol. Furthermore, SMs could significantly improve the tissue distribution of it, especially liver and brain. Finally, SMs showed a better hepatoprotective effect against carbon tetrachloride (CCl4)-induced hepatic injury in vivo than free 6-shogaol. These results suggest that the novel micelles could potentiate the activities of it in cancer treatment and hepatoprotection.[3]

Novel mPEG2k-LA micelles were successfully developed for oral delivery of the hydrophobic compound 6-shogaol. A high drug encapsulation of 80% was achieved under drug loading capacity of 7%, which greatly enhanced the 6-shogaol delivery efficiency versus general oral delivery systems. The developed micelles (SMs) showed a slower release rate than the free 6-shogaol. Moreover, SMs significantly improved the anti-cancer activity of it in vitro. In addition, SMs showed enhanced oral bioavailability and liver distribution compared to free 6-shogaol. The in vivo liver protection study also demonstrated that SMs markedly reduced the activities of serum AST, ALT and liver MDA levels, while remarkably increased the antioxidant activities (GSH-Px, T-SOD). Therefore, the novel micelle is expected to serve as a promising carrier for it to enhance its cancer treatment and hepatoprotection.

References

[1]Ray A, Vasudevan S, Sengupta S. 6-Shogaol Inhibits Breast Cancer Cells and Stem Cell-Like Spheroids by Modulation of Notch Signaling Pathway and Induction of Autophagic Cell Death. PLoS One. 2015 Sep 10;10(9):e0137614.

[2]Moon M, Kim HG, Choi JG, Oh H, Lee PK, Ha SK, Kim SY, Park Y, Huh Y, Oh MS. 6-Shogaol, an active constituent of ginger, attenuates neuroinflammation and cognitive deficits in animal models of dementia. Biochem Biophys Res Commun. 2014 Jun 20;449(1):8-13.

[3]Zhang H, Wang Q, Sun C, Zhu Y, Yang Q, Wei Q, Chen J, Deng W, Adu-Frimpong M, Yu J, Xu X. Enhanced Oral Bioavailability, Anti-Tumor Activity and Hepatoprotective Effect of 6-Shogaol Loaded in a Type of Novel Micelles of Polyethylene Glycol and Linoleic Acid Conjugate. Pharmaceutics. 2019 Mar 6;11(3):107.

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