7.1. INTRODUCTION

The use of “natural” or alternative medicines has increased markedly over the last few years. More and more older adults (i.e., baby boomers) are using complementary and alternative medicine dietary supplements and herbal remedies without advice from a physician on the assumption that these substances will have a beneficial effect (Cohen, Ek, and Pan 2002). However, this might not be a safe or advisable practice. For example, at least one recent survey revealed a significant problem with herb-chemotherapeutic drug interactions in cancer patients and, notably, at least half of the herbal remedies taken by these patients lacked research data documenting their potential interactions (Engdal, Klepp, and Nilsen 2009). Regrettably, a great deal of the information regarding the effectiveness and safety of these remedies has been garnered from anecdotal or historical accounts, and much of the information offered is generally misleading and might even be detrimental (Ernst and Schmidt 2002).

Ginger (Zingiber officinale Roscoe, Zingiberaceae) is one of the most commonly consumed dietary condiments in the world (Surh et al. 1999). The oleoresin (i.e., oily resin) from the rhizomes (i.e., roots) of ginger contains many bioactive components, such as [6]-gingerol (1-[4′-hydroxy-3′- methoxyphenyl]-5-hydroxy-3-decanone; Figure 7.1), which is the primary pungent ingredient that is believed to exert a variety of remarkable pharmacological and physiological activities. Although ginger is generally considered to be safe (Kaul and Joshi 2001), the lack of a complete understanding of its mechanisms of action suggests caution in its therapeutic use (Wilkinson 2000a). Previous reviews (Barrett, Kiefer, and Rabago 1999; Ness, Sherman, and Pan 1999; Talalay and Talalay 2001) have emphasized the importance of careful scientific research in establishing the safety and efficacy of potential therapeutic plant remedies and in defining the risks and benefits of herbal medicine. Ginger has been used for thousands of years for the treatment of numerous ailments, such as colds, nausea, arthritis, migraines, and hypertension. The medicinal, chemical, and pharmacological properties of ginger have been extensively reviewed (Surh, Lee, and Lee 1998; Ernst and Pittler 2000; Afzal et al. 2001; Bode and Dong 2004; Boone and Shields 2005; Borrelli et al. 2005; Chrubasik and Pittler 2005; Chrubasik, Pittler, and Roufogalis 2005; Grzanna, Lindmark, and Frondoza 2005; Thompson and Potter 2006; Eliopoulos 2007; Shukla and Singh 2007; White 2007; Ali et al. 2008; Nicoll and Henein 2009). Over the last few years, interest in ginger or its various components as valid preventive or therapeutic agents has increased markedly, and scientific studies focusing on verification of ginger’s pharmacological and physiological actions have likewise increased (Ali et al. 2008). The primary purpose of this chapter is to comprehensively examine the available scientific evidence regarding ginger’s proven effectiveness in preventing or treating a variety of pathologic conditions.

FIGURE 7.1

Structure of [6]-gingerol, believed to be the most abundant bioactive component of ginger root.

7.2. HISTORY AND ORIGIN OF GINGER

Ginger is a member of a plant family that includes cardamom and turmeric. Its spicy aroma is mainly due to presence of ketones, especially the gingerols, which appear to be the primary component of ginger studied in much of the health-related scientific research. The rhizome, which is the horizontal stem from which the roots grow, is the main portion of ginger that is consumed. Ginger’s current name comes from the Middle English gingivere, but this spice dates back over 3000 years to the Sanskrit word srngaveram, meaning “horn root,” based on its appearance. In Greek, it was called ziggiberis, and in Latin, zinziberi. Interestingly, ginger does not grow in the wild and its actual origins are uncertain.

Indians and Chinese are believed to have produced ginger as a tonic root for over 5000 years to treat many ailments, and this plant is now cultivated throughout the humid tropics, with India being the largest producer. Ginger was used as a flavoring agent long before history was formally recorded. It was an exceedingly important article of trade and was exported from India to the Roman Empire over 2000 years ago, where it was especially valued for its medicinal properties. Ginger continued to be a highly sought after commodity in Europe even after the fall of the Roman Empire, with Arab merchants controlling the trade in ginger and other spices for centuries. In the thirteenth and fourteenth centuries, the value of a pound of ginger was equivalent to the cost of a sheep. By medieval times, it was being imported in preserved form to be used in sweets. Queen Elizabeth I of England is credited with the invention of the gingerbread man, which became a popular Christmas treat.

7.3. USAGE, PREPARATION, AND PROCESSING

Ginger is used in numerous forms, including fresh, dried, pickled, preserved, crystallized, candied, and powdered or ground. The flavor is somewhat peppery and slightly sweet, with a strong and spicy aroma. The concentration of essential oils increases as ginger ages and, therefore, the intended use of the rhizome determines the time when it is harvested. If extracting the oil is the main purpose, then ginger can be harvested at 9 months or longer. Ginger is commonly pickled in sweet vinegar, which turns it a pink color; this form is popular with sushi. Ginger harvested at 8-9 months has a tough skin that must be removed before eating, and the root is more pungent and is used dried or pulverized into ground ginger. This is the form most commonly found in our spice racks and used in cookies, cakes, and curry mixes. Candied or crystallized ginger is cooked in sugar syrup and coated with granulated sugar. Ginger harvested at 5 months is not yet mature and has a very thin skin, and the rhizomes are tender with a mild flavor and are best used in fresh or preserved forms.

7.4. BIOACTIVE COMPONENTS OF GINGER

At least 115 constituents in fresh and dried ginger varieties have been identified by a variety of analytical processes. Gingerols are the major constituents of fresh ginger and are found slightly reduced in dry ginger, whereas the concentrations of shogaols, which are the major gingerol dehydration products, are more abundant (Jolad et al. 2005) in dry ginger than in fresh ginger. At least 31 gingerol-related compounds have been identified from the methanolic crude extracts of fresh ginger rhizome (Jiang, Solyom et al. 2005). Ginger has been fractionated into at least 14 bioactive compounds, including [4]-gingerol, [6]-gingerol, [8]-gingerol, [10]-gingerol, [6]-paradol, [14]-shogaol, [6]-shogaol, 1-dehydro-[10]-gingerdione, [10]-gingerdione, hexahydrocurcumin, tetrahydrocurcumin, gingerenone A, 1,7-bis-(4′ hydroxyl-3′ methoxyphenyl)-5-methoxyhepthan-3-one, and methoxy-[10]-gingerol (Koh et al. 2009). The proportion of each individual component in a sample of ginger depends on country of origin, commercial processor, and whether the ginger is fresh, dried, or processed (Schwertner, Rios, and Pascoe 2006). Of the bioactive pungent components of Jamaican ginger, including [6]-, [8]-, and [10]-gingerols and [6]-shogaol, [6]-gingerol appears to be the most abundant pungent bioactive compound in most of the oleoresin samples studied (Bailey-Shaw et al. 2008). Although phylogenetic analysis has showed that all ginger samples from widely different geographical origins are genetically indistinguishable, metabolic profiling showed some quantitative differences in the contents of [6]-, [8]-, and [10]-gingerols (Jiang et al. 2006). An examination of the concentrations of [6]-, [8]-, and [10]-gingerols and [6]-shogaol in 10 different ginger-root dietary supplements purchased randomly from a variety of pharmacies and health food stores yielded some disconcerting results (Schwertner, Rios, and Pascoe 2006). Perhaps not surprisingly, the content of these active components was found to vary extensively from none or very minute amounts to several milligrams per gram. In addition, the suggested serving size ranged from about 250 mg to 4.8 g/day (Schwertner, Rios, and Pascoe 2006). The basis for the wide range of dosing is not clear. These studies suggest that ginger contains a variety of bioactive compounds and standardization of contents is critically lacking.

7.5. METABOLISM OF GINGER

Although ginger is one of the most widely consumed spices in the world, not a great deal is known regarding its metabolism or metabolites. Evaluating the bioactivity of ginger is necessary for completely understanding its mechanism of action and potential therapeutic effects. Although many food-derived supplements are consumed today with little knowledge of their activity or safety, more attention is beginning to be given to addressing these issues. The most well-studied bioactive component of ginger is probably [6]-gingerol (Surh et al. 1999). The careful isolation of several metabolites of [6]-gingerol following its oral administration (50 mg/kg) to rats was reported (Nakazawa and Ohsawa 2002). A primary metabolite, (S)-[6]-gingerol-4′-0-β-glucuronide, was detected in the bile and several minor metabolites were found in β-glucuronidase-treated urine, suggesting that [6]-gingerol undergoes conjugation and oxidation of its phenolic side chain (Nakazawa and Ohsawa 2002). Gingerol is rapidly cleared from rat plasma following intravenous administration (3 mg/kg; Ding et al. 1991), and it was reported to be metabolized enzymatically in a stereospecific reduction to gingerdiol (Surh and Lee 1994).

A method has been developed for the simultaneous quantification of [6]-, [8]-, and [10]-gingerol and [6]-shogaol in rat plasma in pharmacokinetic studies after oral administration of ginger oleoresin (Wang et al. 2009b). The investigators were able to identify a glucuronide of [6]-gingerol after hydrolysis of β-glucuronidase, and the intestinal glucuronidation was further confirmed by comparing plasma samples of hepatic portal vein and femoral vein (Wang et al. 2009b). This method was also used to obtain pharmacokinetics, tissue distribution, and excretion studies of 6-gingerol after oral or intraperitoneal administration in rats (Wang et al. 2009a). In a study in which a ginger extract (approximately 53% [6]-gingerol) was administered to rats by oral ingestion, [6]-gingerol was absorbed rapidly into the plasma, with a maximal concentration (4.23 μg/mL) being reached after 10 minutes (Jiang, Wang, and Mi 2008). The [6]-gingerol was distributed to various tissues and the most concentration was found in the gastrointestinal tract. Peak concentrations of [6]-gingerol were reached in most tissues at about 30 minutes, and the concentration in tissues was higher than that in plasma (Jiang, Wang, and Mi 2008).

At least one clinical trial focused on the pharmacokinetics of [6]-, [8]-, and [10]-gingerols and [6]-shogaol along with their respective conjugate metabolites (Zick et al. 2008). In this case, human volunteers were given ginger at doses ranging from 100 mg to 2 g and blood samples were taken at 15 minutes to 72 hours after a single oral dose. Results indicated that the free forms of [6]-, [8]-, and [10]-gingerols or [6]-shogaol were not detectable, whereas the respective glucuronide of each compound was detected, suggesting that these ginger components are readily absorbed after oral consumption and can be detected as glucuronide conjugates (Zick et al. 2008). Although progress in determining the active components and metabolites of ginger and understanding their pharmacokinetics has been made, more work is clearly needed.

7.6. HEALTH EFFECTS: THE SCIENTIFIC EVIDENCE

Because ginger and its metabolites appear to accumulate in the gastrointestinal tract, the consistent observations of ginger exerting many of its effects in this area are not surprising. Ginger has been purported to exert a variety of powerful therapeutic and preventive effects and has been used for thousands of years for the treatment of hundreds of ailments from colds to cancer. Like many medicinal herbs, much of the information has been handed down by word of mouth with little controlled scientific evidence to support the numerous claims. However, in the last few years, more organized scientific investigations have focused on the mechanisms and targets of ginger and its various components. In Sections 7.6.1 through 7.6.5, the evidence for the effectiveness of ginger as an antioxidant, anti-inflammatory agent, antinausea compound, and anticancer agent as well as the protective effect of ginger against other disease conditions are reviewed (Figure 7.2).

FIGURE 7.2

The variety of protective effects wielded by ginger.

7.6.4. Anticarcinogenic Activities of Ginger

A great deal of interest by numerous research groups, including our own, is now being focused on the cancer-preventive and potential cancer therapeutic applications of ginger and its various components. Several aspects of the chemopreventive effects of numerous phytochemical dietary and medicinal substances, including ginger, have been reviewed previously (Surh, Lee, and Lee 1998; Surh 1999, 2002; Bode and Dong 2004; Shukla and Singh 2007; Aggarwal et al. 2008). Studies focused on the anticancer activities of various forms of ginger from a crude or partially purified extract to gingerols, especially [6]-gingerol; shogaols, especially [6]-shogaol; and zerumbone, a sesquiterpene compound derived from ginger and a number of minor components and metabolites. The effectiveness of ginger in preventing or suppressing cancer growth has been examined in a variety of cancer types, including lymphoma, hepatoma, colorectal cancer, breast cancer, skin cancer, liver cancer, and bladder cancer. The mechanisms proposed to explain the anticancer activities of ginger and its components include antioxidant activity and the ability to induce apoptosis, decrease proliferation, cause cell-cycle arrest, and suppress activator protein 1 (AP-1) and NF-κB/COX-2 signaling pathways (Figure 7.3).

FIGURE 7.3

The anticancer activities exerted by ginger.

The anticancer activities of [6]-gingerol and zerumbone have been associated with their antioxidant activities. Several ginger components were reported to have effective anticancer promoter activity based on their ability to inhibit TPA-induced Epstein-Barr virus early antigen (EBV-EA) in Raji cells (Vimala, Norhanom, and Yadav 1999; Kapadia et al. 2002). [6]-gingerol was reported to suppress the reactive oxygen species-potentiated invasive capacity of ascites hepatoma AH109A cells by reducing peroxide levels (Yagihashi, Miura, and Yagasaki 2008). In normal RL34 rat liver epithelial cells, zerumbone was found to induce glutathione S-transferase and the nuclear localization of the transcription factor Nrf2, which binds to the antioxidant response element (ARE) of phase II enzyme genes (Nakamura et al. 2004). Zerumbone potentiated the expression of several Nrf2/ARE-dependent phase II enzyme genes, including Y-glutamyl-cysteine synthetase, glutathione peroxidase, and hemeoxygenase-1 (Nakamura et al. 2004). Others have reported that zerumbone decreases TPA-induced hydrogen peroxide formation and edema corresponding to enhanced levels of various antioxidant enzymes (Murakami et al. 2004). These types of changes have been linked with lower 7,12-dimethylbenz[a]anthracene (DMBA)-initiated/TPA-promoted tumor incidence, number of tumors per mouse, and tumor volume (Murakami et al. 2004).

Zerumbone has also been reported to downregulate CXC chemokine receptor 4 (CXCR4), which is highly expressed in various tumors, including breast, ovary, prostate, gastrointestinal, head and neck, bladder, brain, and melanoma tumors (Sung et al. 2008). Because the CXCR4 mediates homing of tumor cells to specific organs that express its ligand, CXCL12, zerumbone was suggested as a potential suppressor of cancer metastasis and was effective in suppressing CXCR4 in a variety of cancers, including those of the pancreas, lung, kidney, and skin (Sung et al. 2008). Furthermore, zerumbone effectively attenuated osteoclast formation induced by human breast tumor cells and by multiple myeloma and decreased osteolysis dose-dependently in MDA-MB-231 breast cancer tumor-bearing athymic nude mice, suggesting that it might be effective in preventing cancer-associated bone loss or osteoporosis (Sung et al. 2009). [6]-gingerol has also been reported to suppress adhesion, invasion, motility, matrix metalloproteinase (MMP)-2, and MMP-9 messenger ribonu-cleic acid (mRNA) expression and protein activities in MDA-MB-231 human breast cancer cell lines (Lee, Seo, Kang, and Kim 2008).

Ginger and its constituents have been reported to inhibit tumor promotion in mouse skin (Katiyar, Agarwal, and Mukhtar 1996). In particular, [6]-gingerol has been reported to be highly effective as an anticancer agent in skin in vivo in the two-stage initiation-promotion mouse skin model. In this model, tumors are initiated by a one time application of DMBA followed by repeated topical applications of TPA beginning a few days later. Topical application of [6]-gingerol on the shaved backs of female ICR mice decreased the incidence of DMBA-initiated/TPA-promoted skin papilloma formation and also suppressed TPA-induced epidermal ornithine decarboxylase activity and inflammation (Park et al. 1998). Results of a similar study indicated that in the DMBA/TPA skin tumor model, topical application of [6]-paradol or [6]-dehydroparadol prior to the application of TPA significantly decreased both the number of tumors per mouse and the number of mice exhibiting tumors (Chung et al. 2001).

Earlier studies suggest that gingerol is an effective inhibitor of azoxymethane-induced intestinal carcinogenesis in rats (Yoshimi et al. 1992). Ginger supplementation (50 mg/kg BW) was reported to suppress the number of tumors as well as the incidence of 1, 2-dimethylhydrazine (DMH)-induced colon cancer (Manju and Nalini 2005). The effect was attributed to decreased oxidative damage associated with enhanced catalase, superoxide dismutase, glutathione peroxidase, and glutathione transferase activities as well as increased GSH (Manju and Nalini 2005). This group later reported that administration of ginger to DMH-treated rats significantly decreased the incidence and number of tumors as well as the activity of microbial enzymes, β-glucuronidase, and mucinase (Manju and Nalini 2006). Finally, Wistar rats that were fed a ginger extract (1% mixed in diet) exhibited significantly lower multiplicity of urothelial lesions (hyperplasia and neoplasia) than untreated groups (Ihlaseh et al. 2006).

Studies suggest that ginger compounds suppress proliferation of human cancer cells through the induction of apoptosis (Lee et al. 1998; Lee and Surh 1998; Thatte, Bagadey, and Dahanukar 2000). A saline extract prepared from ginger extract suppressed the proliferation of HEp-2 cells by inducing cytotoxic effects and DNA fragmentation (Vijaya Padma, Arul Diana Christie, and Ramkuma 2007). Ginger extract and especially [6]-gingerol were reported to effectively decrease proliferation of YYT colon cancer cells and the angiogenic potential of endothelial cell tubule formation in immortalized MS1 endothelial cells (Brown et al. 2009). [10]-gingerol was reported to cause a significant and prolonged increase in intracellular calcium and cytotoxicity in human colorectal cancer SW480 cells (Chen, Li, and Kuo 2009). [6]-gingerol was reported to inhibit both proliferation and invasion of ascites hepatoma AH109A cells and appeared to act by causing an S-phase arrest, elongated doubling time of hepatoma cells, and an increased rate of apoptosis (Yagihashi, Miura, and Yagasaki 2008). This compound also induced cell-cycle arrest and suppressed the growth of human pancreatic cancer cell lines, human pancreatic adenocarcinoma (HPAC) cells, which express wild-type p53 and BxPC-3 cells that express a mutant p53 protein (Park et al. 2006). Interestingly, [6]-gingerol appeared to be most effective in inducing apoptosis in p53-mutant cells and induced arrest, but not apoptosis, in p53-expressing cells (Park et al. 2006). [6]-gingerol was further reported to suppress proliferation and induce apoptosis or G1 cell-cycle arrest in several colorectal cell lines, including HCT116, SW480, HT29, LoVo, and Caco2 cells (Lee, Cekanova, and Baek 2008). These effects were associated with a decreased abundance of cyclin D1 (a proto-oncoprotein that is overexpressed in cancer) and increased expression of a nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1), a proapoptotic and antitumorigenic protein (Lee, Cekanova, and Baek 2008).

Through the comparison of promotion-sensitive (P⁺) and promotion-resistant (P^-) derivatives of the mouse epidermal JB6 cell lines, AP-1 was reported to have a critical role in tumor promotion (Huang, Ma, Bowden, and Dong 1996; Huang, Ma, and Dong 1996). In addition, blocking the tumor promoter–induced activation of AP-1 inhibited neoplastic transformation (Dong et al. 1994). Epidermal growth factor (EGF) is known to induce a relatively high level of AP-1 activity and cell transformation (Huang, Ma, and Dong 1996). We previously investigated the effect of two structurally related compounds of the ginger family, [6]-gingerol and [6]-paradol, on EGF-induced cell transformation and AP-1 activation (Bode et al. 2001). Our results provided the first evidence that both compounds block EGF-induced cell transformation, but by different mechanisms. [6]-gingerol appeared to act by directly inhibiting AP-1 DNA binding activity and transactivation, whereas [6]-paradol appeared to act by inducing apoptosis (Bode et al. 2001). Others report that [6]-gingerol causes DNA fragmentation and suppresses Bcl-2 expression in promyelocytic leukemia HL-60 cells (Wang et al. 2003), and also induces growth inhibition and caspase-mediated apoptosis in human epidermoid carcinoma A431 cells (Nigam et al. 2009). [6]-paradol and other structurally related derivatives, such as [10]-paradol, [3]-dehydroparadol, [6]-dehydroparadol, and [10]-dehydroparadol, inhibited proliferation of KB oral squamous carcinoma cells in a time-and dose-dependent manner (Keum et al. 2002). [6]-dehydroparadol (75 μM) was more potent than the other compounds tested, and it induced apoptosis through a caspase-3-dependent mechanism (Keum et al. 2002).

[6]-shogaol [1-(4-hydroxy-3-methoxyphenyl)-4-decen-3-one], an alkanone from ginger, exhibited the most potent cytotoxicity against human A549, SK-OV-3, SK-MEL-2, and HCT15 tumor cells, compared to [4]-, [6]-, [8]-, and [10]-gingerols (Kim et al. 2008). This compound also inhibited proliferation of several transgenic mouse ovarian cancer cell lines, including C1 and C2 (Kim et al. 2008). Further, [6]-shogaol was reported to inhibit the growth of and induce apoptosis in COLO 205 cells (Pan et al. 2008). Treatment with [6]-shogaol, but not [6]-gingerol, induced DNA fragmentation in COLO 205 colon cancer cells. Apoptosis was mediated by activation of caspase-9, -3, and -8, resulting in the release of mitochondrial cytochrome c, upregulation of proapoptotic Bax, and downregulation of antiapoptotic Bcl2, and the induction of growth arrest and DNA damage (GADD)-inducible transcription factor 153 (GADD153) mRNA and protein (Pan et al. 2008). [6]-shogaol induced apoptosis of hepatoma cells mediated by activation of caspase-3 and -7 (Chen et al. 2007). The compound was also reported to reduce the viability of gastric cancer cells by directly damaging microtubules and inducing mitotic arrest (Ishiguro et al. 2007).

NF-κB is a rapidly induced stress-responsive transcription factor that functions to intensify the transcription of a variety of genes, including cytokines, growth factors, and acute response proteins (Baldwin 1996). Its activation is also linked to mitogen-activated protein (MAP) kinase signaling pathways (Schulze-Osthoff et al. 1997). The mechanism for NF-κB activation is well known. In its inactive form, NF-κB is found in the cytosol bound to an inhibitory protein called inhibitory kappa B (IκB). When stimulated, IκB is phosphorylated by an IκB kinase, which releases it from NF-κB and is subsequently degraded. Following its separation from IκB, NF-κB is translocated into the nucleus, where it activates gene transcription by binding to its specific DNA sequence found in certain genes. Importantly, NF-κB activation is associated with initiation or acceleration of tumorigenesis (Gilmore 1997), and in JB6 cells, inhibition of NF-κB also blocks tumor promoter-induced cell transformation (Li et al. 1997). [6]-gingerol might exert its effects by suppressing the NF-κB/COX-2 pathway. This idea is supported by data indicating that the reduction of UVB-induced expression and transactivation of COX-2 by [6]-gingerol was associated with the suppression of IκBα phosphorylation (Ser32) resulting in a decreased translocation of NF-κB from cytosol to nucleus in HaCaT cells (Kim et al. 2007). A ginger extract fed to rats with experimentally induced liver cancer resulted in decreased NF-κB and TNF-α expression (Habib et al. 2008). [6]-gingerol was reported to suppress TNF related apoptosis induced ligand (TRAIL)-induced NF-κB activation, resulting in apoptosis mediated by caspase-3 or -7 activation, which was associated with the down-regulation of clAP1, a negative regulator of these caspases (Ishiguro et al. 2007).

Zerumbone has been reported to suppress NF-κB activation induced by a variety of stimuli, including tumor necrosis factor (TNF), cigarette smoke condensate, and hydrogen peroxide (Takada, Murakami, and Aggarwal 2005). It also suppressed IκBα kinase phosphorylation and degradation, resulting in a downregulation of constitutively active NF-κB and many of its regulated gene targets, such as COX-2, cyclin D1, Bcl2, and other antiapoptotic genes, thereby enhancing apoptosis induced by chemotherapeutic agents (Takada, Murakami, and Aggarwal 2005). Zerumbone was also reported to suppress receptor activator of NF-κB ligand (RANKL) activity in mouse monocytes (osteoclast precursor cells) by inhibiting IκBα kinase activity, phosphorylation, and degradation (Sung et al. 2009). Oral administration of zerumbone (100, 250, or 500 ppm) to ICR mice decreased inflammation and the multiplicity of colon adenocarcinomas induced by intraperitoneal injection of azoxymethane (AOM, 10 mg/kg BW; Kim et al. 2009). Additionally, zerumbone (250 or 500 ppm) effectively suppressed 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung adenoma formation in female A/J mice (Kim et al. 2009). This ginger derivative appeared to exert its effects by inhibition of proliferation, induction of apoptosis, and suppression of NF-κB and heme oxygenase expression in both colon and lung cancer tissues (Kim et al. 2009). In an earlier study, [6]-gingerol was reported to inhibit both the vascular endothelial growth factor (VEGF)-and basic fibroblast growth factor (bFGF)-induced proliferation of human endothelial cells and cause cell-cycle arrest in the G1 phase (Kim, Min et al. 2005). [6]-gingerol also blocked capillary-like tube formation by endothelial cells in response to vascular endothelial growth factor (VEGF), and strongly inhibited sprouting of endothelial cells in the rat aorta and formation of new blood vessels in the mouse cornea in response to VEGF (Kim, Min et al. 2005).

Investigators suggested that the effectiveness of ginger might be related to its ability to inhibit prostaglandin and leukotriene biosynthesis (Srivastava and Mustafa 1992). Some researchers showed that gingerol actively inhibits arachidonate 5-lipoxygenase, an enzyme of leukotriene biosynthesis (Kiuchi et al. 1992). The leukotriene A4 hydrolase (LTA4H) protein is regarded as a relevant target for cancer therapy, and our in silico prediction using a reverse-docking approach revealed that LTA4H might be a potential target for [6]-gingerol (Jeong et al. 2009). Our prediction was supported by work showing that [6]-gingerol suppresses anchorage-independent cancer cell growth by binding to LTA4H and inhibiting LTA4H activity in HCT116 colorectal cancer cells. We further found that [6]-gingerol effectively suppressed tumor growth in vivo in nude mice, an effect that was mediated by the inhibition of LTA4H activity. Collectively, these findings indicate a crucial role of LTA4H in cancer and also support the anticancer efficacy of [6]-gingerol targeting of LTA4H for the prevention of colorectal cancer (Jeong et al. 2009). Importantly, these are the first results that identify a direct target of [6]-gingerol to explain its anticancer activity.

Cyclooxygenase-2 is an important enzyme in prostaglandin biosynthesis, and is regarded as a promising molecular target for many anti-inflammatory as well as chemopreventive agents. Topical application of [6]-gingerol was reported to suppress TPA-induced COX-2 expression, p38 phosphorylation, and NF-κB DNA binding activity in mouse skin (Kim et al. 2004). These results were further expanded to show that pretreatment of mouse skin with [6]-gingerol resulted in decreased TPA-induced NF-κB DNA binding and transcriptional activity by suppressing both IκBα phosphorylation and degradation and p65 phosphorylation and nuclear translocation (Kim, Kundu et al. 2005). The interaction of phosphorylated p65 (Ser536) with CREB (cAMP response element binding) protein, a transcriptional coactivator of NF-κB, was prevented by [6]-gingerol, and the inhibitory effect of [6]-gingerol on p38 phosphorylation, an upstream mediator of COX-2 activation, was observed (Kim, Kundu et al. 2005).

Treatment of cultured ovarian cancer cells with [6]-shogaol caused a marked growth inhibition that was associated with suppression of NF-κB activation as well as the diminished secretion of angiogenic factors, VEGF and IL-8 (Rhode et al. 2007), suggesting a role for this compound in preventing angiogenesis in cancer. In contrast to most reports, dietary consumption of ginger (0.5% or 1.0%) did not suppress aberrant crypt foci (ACF) formation or reduce the number of crypts per ACF in DMH-treated rats compared to untreated control rats (Dias et al. 2006). Dietary ginger did not significantly change the proliferative or apoptotic indexes of the colonic crypt cells induced by DMH (Dias, 2006). In marked contrast to many studies, ginger extract was not able to inhibit the development of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)/N-methyl-N-nitrosourea (MNU)-induced bladder cancer in male Swiss mice. In fact, in BBN/MNU/2% ginger-treated mice, the incidence of grade 2 transitional cell carcinoma was increased (Dias et al. 2006; Bidinotto et al. 2006).

7.7. SAFETY, EFFICACY, AND CONTRAINDICATIONS

Ginger is recognized by the U.S. Food and Drug Administration (FDA) as a food additive that is “generally recognized as safe.” However, and notably, in 1930, thousands of Americans were poisoned and paralyzed by an illicit extract of Jamaican ginger (jake) that was used to circumvent Prohibition laws. The extract had been adulterated with a neurotoxic organophosphate compound, triorthocresyl phosphate (TOCP; Crandall 1931; Morgan and Penovich 1978). The extract was banned in 1931.

Early studies suggest that ginger extract increased the mutagenesis ability of 2(2-furyl)-3(5-nitro-2-fury)acryl amide (AF2) or N-methyl-N′-nitro-N-nitrosoguanidine (NTG), and [6]-gingerol was determined to be an active mutagen (Nakamura and Yamamoto 1982). A later study suggests that [6]-shogaol is much less mutagenic than [6]-gingerol and that the active part of [6]-gingerol is the aliphatic chain moiety containing a hydroxyl group (Nakamura and Yamamoto 1983). To our knowledge, these studies have not been confirmed nor repeated, and no recent evidence suggests that ginger or its components are mutagenic.

Oral administration of a ginger extract (1000 mg/kg) was reported to be tolerated well by pregnant rats, and it exerted no adverse effects on the mothers or in the development of fetuses (Weidner and Sigwart 2001). This result is somewhat in contrast to an earlier study, in which administration of ginger tea to pregnant rats resulted in twice the loss of embryos but heavier surviving fetuses compared to untreated controls (Wilkinson 2000a). Ginger rhizome extract (0.5-10.0 g/kg) administered intraperitoneally to mice was reported to have no clastogenic effects compared to ginger oil, which produced some chromosomal irregularities (Mukhopadhyay and Mukherjee 2000).

Most recently, male and female rats that were fed ginger powder (500, 1000, or 2000 mg/kg BW) by gavage for 35 days did not exhibit any overall mortalities or abnormalities in behavior, growth, or food and water consumption (Rong et al. 2009). No overt organ abnormalities were observed and hematological and blood biochemical parameters in treated and untreated control animals were similar. The only real difference observed was a slightly decreased absolute and relative weight of the testes only at the highest dose (2000 mg/kg; Rong et al. 2009). Observational studies in humans suggest no evidence of teratogenicity from treatments for early pregnancy nausea that included ginger (Jewell and Young 2003). These results were confirmed in a similar trial showing that administration of ginger beginning at the first trimester of pregnancy did not appear to increase the rates of major malformations above the baseline rate of 1-3% (Portnoi et al. 2003). Overall, these data indicate that ginger consumption appears to be very safe with very limited side effects.

7.8. SUMMARY AND CONCLUSIONS

Ginger is not only an extremely popular dietary condiment used for flavoring food but also an herb that has been used for thousands of years as a medicinal herb to treat a variety of ailments. Chemical and metabolic analyses have revealed that ginger comprises hundreds of compounds and metabolites. The most extensively studied bioactive components include gingerols and shogaols, especially [6]-gingerol and [6]-shogaol, respectively. The content of each component is clearly dependent on the source and preparation of the ginger rhizome. Research interest in determining the role of natural compounds in preventing disease has increased markedly over the last few years. In spite of the abundance of research studies, many of the results are phenomenon based and provide data that are descriptive and observational rather than mechanistic. More studies are needed in animals and humans on the kinetics of ginger and its constituents and on the effects of consumption over a long period of time. Specific molecular targets and mechanisms of action need to be identified. Ginger clearly has a vast number of components and metabolites, many of which have not been studied in detail. The lack of standardization of ginger supplements is disconcerting, and whether consumption of high levels of isolated components (e.g., [6]-gingerol) is advisable is uncertain. [6]-gingerol or other ginger components might require inter-reactivity or dependency on other components in the whole food source to exert their positive effects.

Research data indicate that ginger and its constituents accumulate in the gastrointestinal tract, which supports the many observations of ginger’s effectiveness as an antinausea agent and as a possible colon cancer-preventing compound. Ginger acts as a potent antioxidant in vitro and ex vivo, but the data are not obvious for in vivo application and specific targets and mechanisms are lacking. Ginger appears to exert anti-inflammatory effects by suppressing COX-2 with subsequent inhibition of prostaglandin and leukotriene biosynthesis. On the other hand, the data supporting the effectiveness of ginger in alleviating pain and swelling associated with arthritis are somewhat conflicting. The most common use of ginger is to alleviate the vomiting and nausea associated with pregnancy, chemotherapy, and some types of surgery. The clinical data undoubtedly indicate that ginger is at least as effective, and may be better, than vitamin B6 in treating these symptoms. Again, mechanisms are lacking, but no reports indicate that ginger has any adverse side effects or that it can worsen illness in pregnant women or patients. Interest in ginger as an anticancer agent has markedly increased over the last few years and a direct protein target has been identified in colon cancer. Ginger also appears to reduce cholesterol and improve lipid metabolism, thereby helping to decrease the risk of cardiovascular disease and diabetes.

In summary, ginger has been reported to possess diverse pharmacological properties, although its specific biological targets are largely unknown and remain to be determined. However, in spite of the lack of specific mechanistic information, use of ginger appears to be safe and its effects are mighty and amazing in its many applications.

ACKNOWLEDGMENTS

The writing of this chapter was supported by the Hormel Foundation and Pediatrics Pharmaceuticals (Iselin, New Jersey).

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