Herbs and Spices in Cancer Prevention and Treatment

Christine M. Kaefer and John A. Milner.

17.1. INTRODUCTION

Historically, spices have shaped many events throughout the world. Many voyagers, including the legendary Christopher Columbus, explored the seas in search of treasured spices. These valued commodities contribute not only flavors but also serve as colorants and preservatives in a wide variety of cultures. Today, spices are increasingly revered not only for their culinary properties but also for their potential health benefits. Although the health attributes associated with spice use may arise from their antioxidant properties, their biological effects may arise from their ability to induce changes in a number of cellular processes, including those involved with drug metabolism, cell division, apoptosis, differentiation, and immunocompetence.

The complexity of understanding the biological response to spices first surfaces in the criteria used to distinguish what constitutes a culinary spice and how they differ from culinary herbs. These terms are often used interchangeably in the scientific and lay literature. The U.S. Food and Drug Administration (FDA) defines a spice as an “aromatic vegetable substance, in the whole, broken, or ground form,” whose significant function in food is “seasoning rather than nutrition” and from which “no portion of any volatile oil or other flavoring principle has been removed” (Food and Drug Administration 2007:205-208). While this is a viable definition, it does not consider the biological consequences of consuming these items and how they differ from herbs. The U.S. National Arboretum offers an alternative definition and describes spices as “flavorings (often of tropical origin) that are dried and culinary herbs that are fresh or dried leaves from plants which can be used for flavoring purposes in food preparation” (United States National Arboretum 2002). We must remember that the quantity of an item consumed does not dictate its importance. Thus, to avoid the health significance in any definition would appear flawed. In this chapter, we use the terms “herbs” and “spices” interchangeably and assume that both have properties that extend beyond simply providing flavor and color.

There is little doubt that nutrition and health are intimately linked (Kennedy 2008). For generations, people have alleged that foods provide greater benefits than simply supplying energy. Beliefs in the medicinal properties of foods have surfaced in many early writings of man. Hippocrates is frequently quoted as having said “Let food be thy medicine and medicine be thy food.” Epidemiological, preclinical, and clinical studies continue to provide fundamental insights into the dynamic relationships between nutrients—defined here as any substance in the diet that brings about a physiological effect—and health. Today, claims about the ability of foods, including spices, to lower disease risk or to enhance the quality of life continue to captivate our lives (Kaefer and Milner 2008; Kochhar 2008; Krishnaswamy 2008; Iyer et al. 2009). Three types of biomarkers— exposure, effect, and susceptibility—are needed to evaluate the effects of spices in cancer prevention and therapy (Figure 17.1). Additional information about the amounts of specific spices required to bring about a response (effect) and the interactions of spices with other constituents of the diet, microbes in the gastrointestinal tract, environmental exposures, and human genetics (susceptibility factors) will be needed to unravel the true benefits of adding spices to the diet.

FIGURE 17.1. (See color insert.

FIGURE 17.1

(See color insert.) Three types of biomarkers (exposure, effect, and susceptibility) are needed to assess the benefits or risk of spices.

Spices may be a key to determining the balance between pro- and anticancer factors that regulate risk and tumor behavior (Figure 17.2). About 75% of U.S. households use dietary approaches to reduce their risk of diseases, including cancer (Sloan 2005). Americans between the ages of 36 and 55 are increasingly interested in adopting healthy eating behaviors and are gravitating toward ethnic cuisines based on perceived health benefits (Uhl 2000). Many of these ethnic foods are loaded with unique and flavorful spices; however, while dietary guidelines in several countries tend to support the incorporation of spices into diets, quantifiable recommendations for specific amounts have not yet been forthcoming (Tapsell et al. 2006).

FIGURE 17.2. Multiple factors may influence the need for spices for reducing the risk of cancer or changing the biological behavior of cancerous cells.

FIGURE 17.2

Multiple factors may influence the need for spices for reducing the risk of cancer or changing the biological behavior of cancerous cells.

Between 1970 and 2005, the overall per capita consumption of spices in the United States doubled, increasing from about 1.6 to 3.3 pounds per year (United States Department of Agriculture Economic Research Service, 2007). As expected, the consumption of some spices increased far more than others; for example, garlic consumption increased more than sixfold. According to a report by Buzzanell (1995) from the United States Department of Agriculture’s (USDA) Economic Research Service, the increasing domestic use of spices reflects a number of factors. Among these are the growing Hispanic and Asian populations within the United States, an increasing trend toward the use of culinary herbs and spices to compensate for less salt and lower fat foods and a general increase in the popularity of ethnic foods.

This chapter reviews culinary herbs and spices for their ability to modify several cellular processes that are linked to the risk of cancer and/or tumor behavior (Figure 17.3). The ability of spices to serve as inhibitors of carcinogen bioactivation, decrease free radical formation, suppress cell division and promote apoptosis in cancerous cells, suppress microbial growth, and regulate inflammation and immunocompetence will be discussed as plausible mechanisms by which selected spices may promote health and disease resistance. The low toxicity and wide acceptance of spices may make them particularly useful as a subtle personal dietary change that may decrease risk for several diseases. It is already appreciated that the addition of about 1 g/day of herbs to one’s diet can significantly contribute to total antioxidant intake (>1 mmol) and offers a better source of antioxidants than many food items (Dragland et al. 2003; see also Chapter 2 on antioxidants in herbs and spices). Because several spices are effective antioxidants, they may be particularly important in decreasing oxidative damage due to environmental stress, including excess calorie intake.

FIGURE 17.3. Multiple cancer-related processes may account for the ability of spices to inhibit experimentally induced cancers.

FIGURE 17.3

Multiple cancer-related processes may account for the ability of spices to inhibit experimentally induced cancers. While these processes are likely critical for determining the risk of cancer and tumor behavior in humans, only limited clinical evidence (more…)

More than 180 spice-derived compounds have been identified and explored for their health benefits (Aggarwal et al. 2008). It is beyond the scope of this chapter to deal with all herbs and spices that may influence the risk of cancer and tumor behavior. Therefore, a decision was made to review those with some of the more impressive biological responses reported in the literature, and a conscious effort was made to provide information about the amount of spices needed to bring about a response and thus their physiological relevance. When possible, recent reviews are included to provide readers with additional insights into the biological response(s) to specific spices and to prevent duplication of the scientific literature. Because there is a separate chapter devoted to curcumin (a bioactive component in turmeric) in this book and there are also several excellent reviews published about curcumin (Patel and Majumdar 2009; Aggarwal 2010; Bar-Sela, Epelbaum, and Schaffer 2010; Epstein, Sanderson, and Macdonald 2010), turmeric is not discussed in this chapter.

17.2. ALLSPICE

The term “allspice” was coined in the 1600s by the English, who thought the herb combined the flavors of cinnamon, nutmeg, and cloves. Allspice is also referred to as “Jamaica pepper,” “kurundu,” “myrtle pepper,” “pimenta,” and “newspice.” Ground allspice is not a mixture of spices as some still believe, but arises from the dried unripe berries of the tree Pimenta dioica. This tree is native to the Greater Antilles, southern Mexico, and Central America. Today, P. dioica is cultivated in many warm areas throughout the world. Allspice is also available commercially as an essential oil.

Allspice is claimed to possess antimicrobial, antioxidant, anti-inflammatory, analgesic, antipyretic, anticancer, and antitumorigenic properties (Rompelberg et al. 1996; Al-Rehaily et al. 2002; Kluth et al. 2007). It contains a multitude of potential bioactive agents that may contribute to health promotion, including flavonoids, phenolic acids, catechins, and several phenylpropanoids (Al-Rehaily et al. 2002). Berries contain about 2-5% essential oils that include the following bioactive compounds: eugenol (60-75%), eugenol methyl ether, cineole (eucalyptol), phellandrene, and caryophyllenes (Kluth et al. 2007). The antioxidant and antimicrobial activities of allspice may be associated with eugenol (Rompelberg et al. 1996; Kluth et al. 2007).

Billing and Sherman (1998) reported that allspice was as effective as garlic and onions in suppressing microbial growth. The significance of its antimicrobial properties was recently highlighted by evidence that allspice and eugenol were effective in lowering the virulence of Escherichia coli O157:H7 (Takemasa et al. 2009). Nevertheless, there are concerns that allspice oil can be toxic and promote inflammation, nausea, and vomiting when consumed in excess.

The anticancer properties of allspice may be in part due to its ability to influence cytochrome P450 (CYP) activity and thereby influence carcinogen bioactivation. Kluth et al. (2007) cultured human liver carcinoma cells and human colon adenocarcinoma cells and studied the ability of the spice extract to activate mechanisms related to phase I detoxification enzymes. The allspice extract (3 mg/mL in dimethyl sulfoxide) did not activate pregnane X receptor (PXR) directly but did strongly activate the CYP3A4 promoter. Thus, the activation of transcription factors to bind to response elements seems like a plausible mechanism by which allspice, and potentially eugenol, function. There is specificity in the response to allspice and eugenol because gastrointestinal glutathione peroxidase (GPx), a phase II enzyme linked to removal of reactive oxygen species (ROS), was not influenced by allspice or eugenol (Kluth et al. 2007).

Inflammation is linked to increased risk of cancer (Dinarello 2010) and appears to be influenced by allspice consumption. Although controlled clinical interventions are not available, evidence in rodents suggests potency (Al-Rehaily et al. 2002). Providing an oral allspice suspension (500 mg/kg body weight) significantly inhibited carrageenan-induced paw edema and cotton pellet granuloma in rats. It also suppressed acetic acid-induced writhing and tail flick reaction time and decreased yeast-induced hyperpyrexia in mice. Interestingly, the suspension also appeared to have antiulcer and cytoprotective activity in rats by protecting gastric mucosa against indomethacin and various necrotizing agents, including 80% ethanol, 0.2 M sodium hydroxide (NaOH), and 25% sodium chloride (NaCl), suggesting that it might also have an impact on cyclooxygenase (COX) activity. It remains unclear what molecular target alteration(s) account for this response.

Evidence exists that allspice can alter the proliferation of several cultured cancerous cells. While cell viability was reduced about 50% when allspice extract was added to prostate cancer cells (LNCaP cells), it did not influence the viability of cultured human prostate cancer cell lines (DU145) or cervical epithelial carcinoma (HeLa) cells (Lee et al. 2007). The mechanism by which allspice leads to cellular growth depression remains largely unresolved. However, recent studies by Lee et al. (2007) suggest that epigenetics may be involved. A depression in histone acetyltransferase (HAT) activity may be involved. Androgen-induced HAT activity was decreased by 70% when allspice was provided at 100 μg/mL. Allspice also suppressed androgen receptor (AR) acetylation in LNCaP cells and significantly decreased histone H3 and H4 acetylation, indicating that a repression of AR-mediated transcription was induced due to shifts in histone and nonhistone acetylation. While these in vitro studies are intriguing, there is a need for controlled interventions in animal models before exploring allspice’s potential benefit as a dietary antitumorigenic agent.

17.3. BASIL

Basil (Ocimum basilicum) is a culinary herb prominently featured in Italian and Southeast Asian cuisines. While many varieties of basil exist, sweet basil is one of the most predominant and most frequently examined herbs for its health benefits. Basil is originally native to Iran, India, and other tropical regions of Asia, but now it is widely available throughout the world. Basil’s antioxidant, antimutagenic, antitumorigenic, antiviral, and antibacterial properties likely arise from a variety of components including linalool, 1,8-cineole, estragole, and eugenol (Muller et al. 1994; Chiang et al. 2005; Makri and Kintzios 2007). Similar to most culinary spices, far more information is needed about the variation in content of constituents as a function of plant varietal, growing conditions, and processing.

The essential oil of basil possesses antimicrobial properties (Wannissorn et al. 2005). Moghaddam, Karamoddin, and Ramezani (2009) investigated the effect of basil on Helicobacter pylori and found that methanol, butanol, and n-hexane fractions of basil demonstrated antagonistic activity against the bacteria (MIC = 39-117 μg/disk). While not as potent as amoxicillin, its effectiveness raises possibilities of using individual or multiple spices as potent antimicrobials, especially in areas where commercial antibiotics are in limited supply (Moghaddam, Karamoddin, and Ramezani 2009).

The effects of basil are not limited to its antimicrobial properties because evidence indicates that it also can lower oxidative damage in animal models (Dasgupta, Rao, and Yadava 2004). Feeding mice 200 and 400 mg/kg body weight with a hydroalcoholic extract of basil leaves for 15 days markedly increased GPx (1.22-1.4 fold), glutathione (GSH) reductase (1.16-1.28 fold), catalase (1.56-1.58 fold), and superoxide dismutase (1.1-1.4 fold; Dasgupta, Rao, and Yadava 2004). The change in activity in one or more of these enzymes may explain the decrease in lipid peroxidation caused by basil in studies by Dasgupta, Rao, and Yadava (2004). Drăgan et al. (2007) examined the effects of balsamic vinegar–enriched extracts from several herbs (rosemary, sage, and basil) in soups and salads on oxidative stress and quality of life measures in women with stage IIIB and IV breast cancer. While there was a decrease in oxidative stress, the complexity of the dietary intervention made it impossible to determine the component(s) that led to improvements.

Several studies provide evidence that basil is an antimutagenic spice (Kusamran, Tepsuwan, and Kupradinun 1998; Stajkovic et al. 2007). Stajkovic et al. (2007) studied the antimutagenic effects of basil on mutagenicity in Salmonella typhimurium TA98, TA100, and TA102 cells in the presence or absence of liver microsomal activation. The essential oil of basil, at concentrations ranging from 0.5 μL/plate to 2.0 μL/plate, inhibited mutations from ultraviolet irradiation (dose = 6 J/m2) by 22-76%. Mutations caused by 4-nitroquinoline-N-oxide (0.15 μg/plate) were decreased by 23-52%, and those from 2-nitropropane (14.9 mg/plate) by 8-30%. These findings are consistent with studies by Jeurissen et al. (2008), who demonstrated that 50 μg/mL basil largely blocked DNA adduct formation caused by 1′-hydroxyestragole in the human hepatoma (HepG2) cell line, possibly by promoting phase II enzymes and thereby conjugation and elimination of this carcinogen. These findings likely explain the ability of basil to decrease the mutagenicity of aflatoxin B1 (AFB1) and benzo(a)pyrene (B(a)P) (Stajkovic et al. 2007). The mutagenicity of AFB1 was inhibited by >30% by the presence of 1-2 mg/plate of a hexane-based basil extract and 0.5-1 mg/ plate of chloroform- and methanol-based basil extracts. Because B(a)P mutagenicity was only inhibited by chloroform- and methanol-based basil extracts at doses of 2-5 mg/plate, multiple constituents might be responsible for basil’s antimutagenic activities.

The anticancer properties of basil in preclinical studies are mixed. In studies with Sprague-Dawley rats fed with an AIN-76 diet with or without high concentrations of basil (6.25% and 12.5%), there was no clear indication of a decrease in 9,10-dimethyl-1,2-benzathracene (DMBA)-induced mammary cancer. It is unclear whether the quantity of the procarcinogen examined, the simultaneous induction of both phase I and II enzymes, or some other factors accounted for the lack of protection by adding basil to the animals’ diet (Kusamran, Tepsuwan, and Kupradinun 1998). Nevertheless, there is evidence that basil can decrease DMBA-induced carcinogenesis. Providing Swiss mice with a diet containing 150 or 300 mg/kg body weight of basil extract decreased DMBA-induced skin tumors (12.5% reduction and 18.75% reduction for lower and higher doses, respectively), and lowered the tumor burden per mouse. Compared to the average number of tumors per mouse in the controls, the tumor burden was approximately 2.4 times lower (p < .01) in the low-dose basil group and 4.6 times lower (p < .001) in the high-dose basil group (Dasgupta, Rao, and Yadava 2004). It is unclear whether differences in the response between mice and rats reflect the species, the cancer site, or the dietary or procarcinogen exposures.

DNA methyltransferase (MGMT) is a critical repair protein in the cellular defense against alkylation damage. MGMT is highly expressed in human cancers and in tumors resistant to many anticancer alkylating agents. Niture, Rao, and Srivenugopal (2006) examined the ability of several medicinal plants to upregulate O6-methylguanine adducts. Both ethanol and aqueous extracts of basil increased MGMT protein levels in HT29 human colon carcinoma cell lines 1.25-fold compared to controls after 72-hours incubation. Compared to the control, basil increased glutathione-S-transferase (GST) protein activity 1.33-fold after 12 hours of incubation; after 24 hours, GST activity increased 1.68-fold compared to the control, which declined to 1.47-fold after 72 hours incubation. Because MGMT is one of the body’s first lines of defense against alkylation DNA damage, a small increase (two- to threefold) in this enzyme may protect against mutagenic lesions (Niture, Rao, and Srivenugopal 2006).

The anticancer properties of basil may also relate to its ability to influence viral infections. Individuals with hepatitis B are recognized to be at increased risk for hepatocellular carcinoma (Fung, Lai, and Yuen 2009; Ishikawa 2010). Chiang et al. (2005) evaluated the antiviral activities of basil extract and selected basil constituents in a human skin basal cell carcinoma cell line (BCC-1/ KMC) and a cell line derived from hepatoblastoma HepG2 cells (2.2.15) against several viruses, including hepatitis B. Impressively, Chiang et al. (2005) found that the aqueous extract of basil, along with apigenin and ursolic acid, displayed greater anti-hepatitis B activity than two commercially available drugs, glycyrrhizin and lamivudine (3TC). Overall, these studies raise intriguing questions about the merits of using commercially available spices to retard viruses and potentially cancer. Undeniably, much more information is needed to clarify the amounts and durations needed to bring about a desired viral response and the mechanism by which a response occurs.

It should be noted that there are concerns about excess basil exposure. Estragole, a suspect procarcinogen/mutagenic found in basil, raises questions about the balance between benefits and risks with the use of this and other spices (Muller et al. 1994). Now, the majority of evidence points to the antimutagenic effects of basil outweighing the potential adverse effects associated with estragole-induced cell damage (Jeurissen et al. 2008).

Read more… http://www.ncbi.nlm.nih.gov

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