**2.4 Anticancer activities of ginger combinations**

Shogaol and gingerol compounds and their derivatives isolated from ginger have shown activity against different types of cancers; breast cancer, lung cancer, cervical cancer, prostate cancer, liver cancer, blood cancer, and colorectal cancer [29]. Combinations of pure ginger phytochemicals, 6-gingerol (6G), 8-gingerol (8G), 10-gingerol (10G), and 6-shogoal (6S) have shown strong synergistic antiproliferative activities against prostate cancer cell lines with CI50 values ranging between 0.03 and 0.88 [15]. The highest synergistic activities were observed in 6G + 8G, 8G + 10G, 10G + 6G, and 6S + 10G combinations with CI50 values below 0.4 when tested against human prostate cancer cell lines [15]. In another follow-up study, a combination of 6-gingerol, a pure compound isolated from a Chinese *Tongling* White Ginger, with standard drugs depicted synergistic anticancer activities when tested against human cervical adenocarcinoma cells [30]. The combination of 6-gingerol with 5-FU (inhibition of S-phase of cell cycle and PI3K signaling pathway inhibitor) and Ptx (inhibition of G2/M-phase of cell cycle and mTOR inhibitor) at different concentrations showed synergism after 48 h treatment on Hela cells. A combination of 6-gingerol (45 μM) with Ptx (0.36 μM) inhibited 83.2% growth of the treated cells and a combination of 6-gingerol (45 μM) with 5-FU (22.5 μM) inhibited 52% growth of the cells. All nine combinations of 6-gingerol with Ptx portrayed strong synergism with CI values of less than 0.4 [30]. This study displays the synergistic interactions of ginger phytochemicals when used in combination with each other. This shows the value of using whole extracts in traditional medicine and therefore the popularity of herbal medication unlike the use of synthetic drugs that are based on one active ingredient.

Synergism has been observed when crude water ginger extract was combined with Gelam honey and tested against colorectal cancer cell line HT29 [31]. The 3-(4,5-dimethylthiazol-2-ly)-2,5-diphenyltetrazolium bromide (MTT) assay of these combinations depicted synergism with CI50 values of less than 1 [32]. When tested singly against human colorectal adenocarcinoma cell line HT29, ginger extracts showed anticancer activity with an IC50 value of 5.2 mg/mL and Gelam honey showed an IC50 value of 80 mg/mL while a combination of an IC50 value of 0.3 mg/mL was observed [32]. These results indicate the activity of ginger is more effective when used in combination than when used alone against colorectal cancer [31, 32]. In a similar study, a combination of ginger extracts with Gelam honey showed synergistic activities (CI <1) with higher apoptotic activities when each is combined with 5-FU and tested against HCT 116 colon cancer cell lines [9].

Combinations of ginger extracts, especially combination of ginger phytochemicals, have possible use in treatment of cancer and reduction of emergence of anticancer drug resistance. With the increased emergence of anticancer drug resistance and the side effects of anticancer drugs, the use of safe and effective anticancer ginger combinations that do not have side effects is indispensable.

#### **2.5 Antidiabetic activities of ginger combinations**

Extracts of ginger, green tea (*Camellia sinensis* L.), and cinnamon (*Cinnamomum verum* J.Presl) were tested separately and then combined against diabetes and postprandial glucose patterns. The three herbs, ginger, green tea, and cinnamon, exerted a glycemic index (GI) of 72, 79, and 63, respectively, when tested singly using healthy human volunteers of both genders. Synergism was depicted when all extracts were combined with a GI of 60 [33]. Therefore, the highest effect of lowering postprandial glucose in humans was portrayed when the herbs were used in combination showing the potential use of ginger, green tea, and cinnamon combinations in controlling blood sugar level.

In another study by Ali et al. [34], aqueous ginger extracts showed anti-hyperglycemia and anti-inflammatory activities when tested alone against type 2 diabetes in rats, *in vivo* [35]. When the same aqueous extracts were combined with probiotics of eight good bacteria, they portrayed synergism. The combination showed substantial improvement in oral glucose tolerance test, serum insulin, C-peptide, and lipid abnormalities than when the species extracts were used alone [35].

Extracts of three commonly used culinary natural spices, ginger, garlic (*Allium sativum* L.), and cayenne pepper (*C. fructensces*) have shown prophylactic and therapeutic activities against cardiovascular diseases, atherosclerosis, and antidiabetic diseases [26, 36]. Synergism was observed when the three spices were tested in combination (1:1:1:1) against hypercholesterolemic activity.

The various phytochemicals in extracts of the spices acting in a beneficial manner explain the observed anti-hypercholesterolemic activity that was higher in combination through synergism than when the three spices were tested singly [26]. The use of ginger combinations in blood sugar regulation in traditional medicine is, therefore, preferred to the synthetic antidiabetic drugs, which rely on one single active ingredient. These studies depict a possible use of ginger combinations in blood sugar balance.

#### **2.6 Antidepressant activities of ginger combinations**

Depression is mainly caused by an imbalance of neurotransmitters; serotonin, norepinephrine, and dopamine. Antidepressants are used to maintain a balance

*Pharmacological Properties of Ginger Combinations DOI: http://dx.doi.org/10.5772/intechopen.107214*

of neurotransmitters, especially serotonin. Honokiol and magnolol (HMM) from magnolia bark (*Magnoliae officinalis* Rehd. Et Wils), and ginger essential oils (GEO) and polysaccharides (PGR) from both plant species were combined and tested for antidepressant activities in mice by measuring serotonin and noradrenaline levels in the hippocampus, prefrontal cortex, and striatum [37]. Most combinations of the compounds from the two plant species showed synergism. The most effective antidepressant synergistic effects were observed when 39 mg/kg of OGR were combined with 15 mg/kg of HMM after two weeks of antidepressant treatment. This resulted in a significant increase in serotonin and noradrenaline in the prefrontal cortex [37]. These results are in agreement with similar synergistic antidepressant effects of OGR in combination with HMM as reported by Qiang et al. [38].

Anxiety and depression are increased by mercury II chloride (HgCl2) in mice [39]. In a study by Benkermiche et al. [40], ginger extracts combined with black cumin (*Nigella sativa* L.) oil showed prophylaxis synergistic effects on anxiety and depression behavior in Wistar rats that had been exposed to HgCl2 [34]. This could be attributed to the pure compounds like 6-gingerol, isolated from ginger, which has shown neuroprotective effects in rodents [41], and the antidepressant activities of thymoquinone, the active ingredient in *N. sativa* which act synergistically when combined [14]. With increased reports of anxiety, depression, and even suicide, these studies are crucial as they are suggestive of possible use of ginger combinations both as a prophylaxis and therapeutic against depression.

#### **2.7 Pharmacological activities of ginger combinations for herbal tea formulations**

In production of herbal teas, various parts of medicinal plants are used; roots, stems, leaves, barks, flowers, and seeds. Most of these herbal teas are usually used in combination, packed in bags, and sold for use in different countries [42]. The herbal tea formulations are preferred because use of medicinal plants in combination leads to presence of various bioactive phytochemicals in one package, which has shown to reverse and prevent various metabolic diseases [40]. Studies of tea and herbal infusion combinations have shown increased pharmacological activities against various diseases [38]. Apart from the medicinal benefits, the use of these herbal tea formulations is promoted because consumers believe that they are natural and safe without any side effects [43]. In addition, herbal formulations, especially with ginger, provide tea with the desired taste and aroma [4].

In a study by Yusuf et al. [44], herbal tea formulations of powdered dried leaves of mango tree (*Mangifera indica* L.), leaves of drumstick tree (*Moringa oleifera* Lam.), and ginger powder have shown to have potential nutritional and health benefits in prevention of various metabolic diseases. Presence of bioactive phytochemical compounds such as tannins, flavonoids, terpenoids, and cardiac glycosides in these formulations indicate that such a composite blend is a reservoir of various antioxidants acting together in a beneficial way through synergism when used in combination thereby promoting health due to the therapeutic and healing properties of the phytochemicals contained in these plants [45]. In addition to the medicinal properties of ginger when used as a herbal tea formulation in combination with leaves of mango and drumstick tree, the combination provides herbal teas with the desired and appealing sensory attributes such as color, aroma, flavor, texture, taste, mouth feel, and overall acceptability [40]. This makes the medicinal use of ginger herbal tea formulations when combined with other natural spices preferable than standard approved drugs.

Ginger is used in coffee (*Coffea arabica* L.) herbal tea drinks. When used as an oxidant, ginger offers protection to the human body from various diseases that are attributed to reactions of radicals [7]. In this protection, ginger acts as a radical-scavenger, by inhibiting peroxidation and other free radical-mediated processes [13, 43]. When used alone, water extracts of ginger and coffee showed antiradical activities with EC50 values of 3.82 mg/mL and 1.78 mg/mL. Chlorogenic acid a pure compound isolated from ginger showed antiradical activity with an EC50 value of 36.76 μg/mL and caffeic acid isolated from coffee showed antiradical activity with an EC50 value of 22.37 μg/mL [13]. When coffee and ginger were combined, synergism was observed by the antiradical scavengers from extracts of the two plant species. This explains the medicinal benefits of the use of ginger when used in combination with herbal tea formulations for prevention of diseases.

When the plant extracts are digested, which imitates the drinking of herbal teas, the synergism increased *in vitro*. The combination of the pure compounds, chlorogenic acid from ginger and caffeic acid from coffee, showed antagonism for antiradical activity [13]. Phenolic compounds in ginger and coffee that are used in herbal teas act as an anti-inflammation through inhibition of pro-oxidative enzymes such as lipoxygenase (LOX) mediated arachidonic acid metabolism [20]. Water extracts of ginger and coffee showed LOX-inhibition activities with EC50 values of 3.83 mg/mL and 4.85 mg/mL, respectively. The combination of these extracts showed synergism as the Lox-inhibition activities of the pure compounds increased when digested *in vitro* [20]. Pure compounds, chlorogenic acid from ginger and caffeic acid from coffee, had a LOX-inhibition activity with EC50 values of 41.05 μg/mL and 22.86 μg/mL, respectively. When these compounds were combined, they showed stronger synergism [13]. Therefore, the ability of ginger to scavenge free radicals and inhibit lipoxygenase (LOX) is increased when ginger is used in combination with coffee. Since tea is the second most popular drink, second to water [12], the use of ginger in tea is, therefore, highly recommended as it makes the drink medicinal while improving the taste and aroma of tea.

#### **2.8 Other pharmacological activities of ginger combinations**

Synergism was shown when ginger was combined with nifedipine (a drug used to treat high blood pressure) in hypersensitive and normal patients. A combination of 1 g of ginger and 10 mg of nifedipine showed that a percentage inhibition of platelet induced by collagen, adenosine diphosphate (ADP), and epinephrine was 64.2%, 63.8%, 61.1%, respectively [44]. Ginger potentiated the antiplatelet aggression activity of nifedipine. The inhibition of platelet aggression suggests the use of ginger and nifedipine combination against cardiovascular and cerebrovascular complications [44].

Cisplatin is an anticancer drug in which reactive oxygen molecules (ROM) are involved in nephrotoxicity. Combinations of ginger ethanol extract (250 mg/kg of body weight) with vitamin E (α-tocopherol) (250 mg/kg) showed synergism against cisplatin-induced renal failure in mice [46]. In this combination, the activities of renal antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) were increased while the level of malondialdehyde (MDA) was reduced [46]. The activity of the combination against cisplatin-induced acute renal failure is by increasing the antioxidant body's defense system. Therefore, the ginger-cisplatin combination aids the body's natural defense mechanism against renal failure. This study showed a potential use of ginger in combination with vitamin E against cisplatin-induced renal failure.

#### *Pharmacological Properties of Ginger Combinations DOI: http://dx.doi.org/10.5772/intechopen.107214*

A specific ginger and glucosamine combination (Zinaxin Glucosamine; 170 mg EV.EXT 35 mixture and 500 mg glucosamine, as glucosamine sulfate, per capsule) showed potential use for mucosa protection by increased synthesis of mucosa prostaglandins (E1, E2, F2α, and 6-keto PGF1α) in knee and hip of osteoarthritis patients [47]. The gastrointestinal pain and dyspepsia were greatly reduced when compared with diclofenac. The study showed that this combination is as effective as diclofenac but has a better potential use as it concurrently provides gastro-protection, pain relief, and efficacy in osteoarthritis patients [47]. These extra health benefits in the use of natural remedies in phytomedicine make herbal medication popular, unlike pharmaceutical drugs that have adverse side effects. These results are in agreement with another recent study by Rondanelli et al. [48] on the use of ginger to relieve pain in osteoarthritis patients [49].

A study by Mustafa et al. [50] has shown that a combination of ginger powder and zinc supplements has potential pharmacological use in human health. This combination showed activity against oxidative damage, inflammation, and autophagy induced by fructose in rats with metabolic syndrome (MS). The combination also showed potential use in controlling glucose and lipid metabolism and the zinc homeostasis in rats with MS. The ginger powder and zinc supplement combination was shown to downregulate the expression of NF-κB, SREBP-1c, and mTORC1c genes and upregulate the expression of Nrf-2 and PPAR-α in the liver of rats with MS [51].

In another study, nanoparticles NPS-PEG-FA loaded with the active ginger phytochemical 6-shogaol, demonstrated activity by alleviating colitis symptoms and increased colitis wound healing using mice model [30]. These results are suggestive of the therapeutic use of this approach in treatment of inflammatory bowels. In a similar study, semisolid poly (vinyl alcohol) hydrogels of ginger essential oil (GEO) encapsulation with chitosan nanoparticles (CNPs) displayed activity in wound healing. Increasing the amount of GEO in the hydrogels leads to a decrease in percentage encapsulation efficiency and increased percentage loading capacity [52, 53].

These studies on combination of ginger with standard approved drugs and nanoparticles reveal potential use of the medicinal plant species combinations in prevention and treatment of diseases. The use of these natural herbs combinations is also likely to reduce the emergence of resistance to these diseases.
