Phytosterol and stanol (or phytosterols) consumption reduces intestinal cholesterol absorption, leading to decreased blood LDL-cholesterol levels and lowered cardiovascular disease risk. However, other biological roles for plant sterols and stanols have also been proposed. The objective of this review is to critically examine results from recent research regarding the potential effects and mechanisms of action of phytosterols on forms of cancer. Considerable emerging evidence supports the inhibitory actions of phytosterols on lung, stomach, as well as ovarian and breast cancer. Phytosterols seem to act through multiple mechanisms of action, including inhibition of carcinogen production, cancer-cell growth, angiogenesis, invasion and metastasis, and through the promotion of apoptosis of cancerous cells. Phytosterol consumption may also increase the activity of antioxidant enzymes and thereby reduce oxidative stress. In addition to altering cell-membrane structure and function, phytosterols probably promote apoptosis by lowering blood cholesterol levels. Moreover, consumption of phytosterols by healthy humans at the recommended level of 2 g per day does not cause any major health risks. In summary, mounting evidence supports a role for phytosterols in protecting against cancer development. Hence, phytosterols could be incorporated in diet not only to lower the cardiovascular disease risk, but also to potentially prevent cancer development.
Plant sterols or phytosterols are structurally similar to cholesterol and exist in several forms in plants (Jones, 1999; Law, 2000; Katan et al., 2003; St-Onge and Jones, 2003; Abumweis et al., 2008a), including β-sitosterol, campesterol, stigmasterol and cycloartenol (Figure 1); Ostlund, 2002). Of these, sitosterol is the most abundant phytosterol, followed by campesterol (Ostlund, 2002; Ryan et al., 2007). Phytosterols possess a double bond at carbon-5, which can be saturated by enzymatic hydrogenation in plants or during food processing to form plant stanols (Bradford and Awad, 2007). Rich sources of phytosterols include grain legumes such as sesame, chickpeas, lentils and peas; cereal grains such as wheat, corn, millet, rye and barley (Ryan et al., 2007); vegetable oils including corn oil (Ostlund, 2002); and nuts such as pecans, pine, pistachio nuts, peanuts, cashew nuts and almonds (Ryan et al., 2006).
In a recent epidemiological study, Klingberg et al. (2008) have shown an inverse relation between phytosterol consumption and serum cholesterol in north Sweden. Calpe-Berdiel et al. (2009) have shown a better understanding of the molecular mechanisms of actions of plant sterols and stanols on cholesterol metabolism. Phytosterols have been shown to reduce blood cholesterol levels by interfering with the absorption of cholesterol from the gut (Jones, 1999; Hayes et al., 2004; Jia et al., 2007; Varady et al., 2007). Plant sterols have also been implicated to play an important role in mediating intestinal membrane-transport proteins such as ABCG5, ABCG8 and NPC1L1 and hence, reduce circulating cholesterol levels (Jones et al., 1997, 2007; Marinangeli et al., 2006).
In addition to their cholesterol-lowering actions, mounting evidence suggests that phytosterols possess anti-cancer effects (Choi et al., 2007) against cancer of the lung (Mendilaharsu et al., 1998), stomach (De Stefani et al., 2000), ovary (McCann et al., 2003) and estrogen-dependent human breast cancer (Ju et al., 2004). It has been speculated that phytosterols inhibit the production of carcinogens, cancer-cell growth, invasion and metastasis, and promote apoptosis of cancerous cells (Meric et al., 2006). These observations imply that phytosterols may be useful in prevention of both cardiovascular disease and cancer. Therefore, the objective of this review is to analyze results from recent studies on the effects of phytosterol consumption on cancer and describe the mechanisms involved.
An overview of cancer development
Cancer represents a group of diseases characterized by uncontrolled growth of cells, which spreads from the original sites to other parts of the body, resulting in destruction of those areas (Meric et al., 2006). Cancers occur when genes controlling cell growth and apoptosis are damaged, resulting in altered production and/or activity of the proteins they code (Hanahan and Weinberg, 2000; Foijer and Te Riele, 2006). The damage to the genes is caused by various substances, such as reactive oxygen species produced by oxidatively stressed cells during the inflammation process (Romanowska et al., 2007). Several proteins regulate cell growth and apoptosis, including pro-inflammatory cytokines such as tumor necrosis factor-α; transcription factors, including nuclear factor-κB (Lu et al., 2006); mitochondrial membrane proteins, namely Bax (pro-apoptosis) and Bcl-2 (anti-apoptosis) (Hanahan and Weinberg, 2000) and Fas protein found on cell membranes (Guseva et al., 2002). Various enzymes such as cyclooxygenase, caspase and enzymes of the mitogen-activated protein kinase (MAPK) family, including extracellular-signal regulating kinase (ERK), p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, which are pro-apoptotic enzymes (Moon et al., 2007; Kralova et al., 2008), have a major function in cell multiplication, whereas anti-apoptotic enzymes such as phosphatidylinositol 3-kinase, protein kinase B (Akt) and p42/p44 MAPK (Rivas et al., 2008) largely influence cell death. Oxidative stress within cells leads to increased production of tumor necrosis factor-α, which activates nuclear factor-κB, resulting in the production of cyclooxygenase-2 (Lu et al., 2006). Cyclooxygenase-2 is involved in production of pro-inflammatory prostaglandins of series 2 (Liu et al., 2001; Larkins et al., 2006) and is overexpressed in cancer cells (Ohno et al., 2007). Cyclooxygenase-2 has been shown to be involved not only in activation of carcinogens (Wiese et al., 2001) but also in the promotion of cell growth and metastasis (Larkins et al., 2006); Masferrer et al. (2000) reported that cyclooxygenase-2 enhances angiogenesis. Caspase enzymes are involved in cell apoptosis (Park et al., 2007); their activities can be enhanced by extracellular stimuli through the Fas pathway or by internal stimuli through Bax (Guseva et al., 2002).
An overview of phytosterol metabolism
The overall metabolism and beneficial effects of phytosterols have been well defined (Ling and Jones, 1995; Law, 2000; Katan et al., 2003; Normen et al., 2006; Abumweis and Jones 2007; AbuMweis et al., 2008a, 2008b). Phytosterols occur naturally in plants either esterified with fatty acids in the cell membranes or in free form within the cells (Beck et al., 2007). After ingestion, phytosterols, like cholesterol and other lipids, are emulsified by bile salts secreted into the small intestine to form micelles for digestion. After micelle formation, the esterified phytosterols are hydrolyzed to free phytosterols probably by cholesterol esterase and pancreatic lipase enzymes (Normen et al., 2006). Free phytosterols are then absorbed into enterocytes by ATP-binding cassette transporters that are encoded by ABC G5 and G8 genes, which are also involved in cholesterol absorption (Igel et al., 2003). In the enterocytes, these compounds become esterified to fatty acids by acyl-CoA cholesterol acyltransferases, and combined with cholesterol, triacylglycerol and apolipoproteins to form chylomicrons (Gylling et al., 2006). The chylomicrons are secreted into the lymph and then transferred to the bloodstream, where they are transformed to chylomicron remnants after the uptake of triacylglycerol by cells and transported to the liver. In the liver, the phytosterols may either be used for synthesis of bile salts (Hamada et al., 2007) or be incorporated into very low-density lipoproteins and be secreted into the blood, from where they are converted to low-density lipoproteins and presented to cells for uptake (Sanders et al., 2000; Gylling et al., 2006; Hamada et al., 2007). In the tissues, phytosterols are incorporated into the cell membranes (Awad et al., 2004) and have been found to be highly concentrated in the lungs, adrenal cortex, intestinal epithelia and ovaries (Sanders et al., 2000). Phytosterols that are either not taken up by cells or secreted back into the blood by cells are transported to the liver, from where they are excreted into the bile (Sanders et al., 2000).
The transport of phytosterols from the lumen into intestinal enterocytes is lower than that of cholesterol and is dependent on the structure of the phytosterol (Ostlund et al., 2002). For instance, Ostlund et al. (2002) observed 0.512, 1.89, 0.0441 and 0.155% absorption for sitosterol, campesterol, sitostanol and campestanol, respectively, in humans, whereas Sanders et al. (2000) observed 27, 4, 13, 1 and 2% absorption for cholesterol, sitosterol, campesterol, sitostanol and campestanol, respectively. These data suggest that absorption of campesterol is higher than that of sitosterol, and that absorption of phytosterols is in general higher than that of the corresponding stanols.
Effect of phytosterol intake on cancer development in humans and animals
Consumption of phytosterols has been shown to inhibit various forms of cancer. Mendilaharsu et al. (1998) carried out a case–control study with 463 subjects with newly diagnosed primary lung cancer and 465 hospitalized controls in Uruguay to determine the effect of phytosterol intake on lung carcinogenesis within 3 years. Phytosterol consumption was associated with reduced risk of the cancer by approximately 50%, after correcting for factors including tobacco smoking, vegetables, fruits and antioxidant substances, known to be confounders. High consumption of phytosterols and low consumption of other factors that were also found to reduce the risk of lung cancer, including carotene and flavonoids, resulted in reduced risk of the cancer by 38%.
Moreover, De Stefani et al. (2000) investigated the effects of plant sterol intake on gastric-cancer prevalence in 120 patients confirmed to have stomach cancer, and 360 controls. Results showed an inverse relationship between total phytosterol intake and stomach cancer. In a case-control study, McCann et al. (2003), on investigating female patients with confirmed ovarian cancer, also reported a reduced risk of developing ovarian cancer at higher intakes of stigmasterol (>23 mg per day) compared with a lower intake of the same plant sterol (<12 mg per day) (odds ratio 0.42, 95% confidence interval, 0.20–0.87). However, Normen et al. (2001), working in a cohort study in the Netherlands with 3123 subjects with colon and rectal cancer risks, observed no relation between phytosterol intake and a low risk of colon and rectal cancers after 6.3 years of monitoring.
The effects of phytosterol consumption on cancer development have also been investigated in animals. Ju et al. (2004) examined the action of phytosterols (9.8 g per kg diet) on growth of estrogen-dependent human breast cancer cells in ovarectomised mice implanted with or without 17β-estradiol. β-Sitosterol consumption did not affect the growth of the breast cancer cells in 17β-estradiol-untreated mice, but reduced tumor growth in 17β-estradiol-treated mice by 38.9%. Similarly, Choi et al. (2007) determined the effect of campesterol at 10–20 μg/ml on basic fibroblast growth factor-induced angiogenesis in the chorioallantoic membrane of fertilized chicken eggs and reported reduced vascularization in the membrane in a concentration-dependent manner. Quilliot et al. (2001), however, failed to observe any effect of phytosterol ingestion (24 mg per rat per day) on colon cancer in rats fed a diet with normal or high saturated fatty acids.
From these studies, it is apparent that phytosterols alleviate various cancers in humans and animals except colon cancer. The lack of effect of phytosterol on colon cancer risk in vivo could be because of its inhibitory effect on cholesterol absorption in the small intestine, which resulted in increased flow of cholesterol to the colon, where it may induce and promote cancer development as suggested by Normen et al. (2001). More research is required to further probe the effect of phytosterols and cholesterol on colon cancer.
Mechanism of action of phytosterols against carcinogenesis
Effect of phytosterols on production of carcinogens
Reactive oxygen species produced by oxidatively stressed cells can damage DNA, resulting in carcinogenesis. Vivancos and Moreno (2005) reported that β-sitosterol increased the activities of antioxidant enzymes, superoxide dismutase and glutathione peroxidase in cultured macrophage cells with oxidative stress induced by phorbol 12-myristate 13-acetate, indicating that phytosterols can protect cells from damage by reactive oxygen species. In a study by Awad et al. (2004), cultured lipopolysaccharide-activated macrophage cells were treated with β-sitosterol and campesterol at 8 and 16-μM concentrations. Results showed decreased production of prostaglandin E and prostaglandin I of series 2, by 68 and 67% (for sitosterol), and by 55 and 52% (for campesterol), respectively. These studies suggest that phytosterols can alleviate cancer development by reducing the production of carcinogens.
Effect of phytosterols on cell growth and multiplication
Studies on the effect of phytosterols on cell growth and multiplication have shown a negative relationship between phytosterols and cancer development and progression at various concentrations ranging from 8 to 32-μM concentrations (Awad et al., 2007; Moon et al., 2007; Park et al., 2007). Park et al. (2007) reported that β-sitosterol treatment of leukemia cells at 15 and 20 μM for 72 h decreased cell viability by 37 and 33%, respectively. β-Sitosterol treatment of prostate (Awad et al., 2005) and breast cancer cells (Awad et al., 2007) at 8 and 16 μM has been observed to reduce the cell growth by at least 9 and 50%, respectively. Moon et al. (2007), while investigating the effect of β-sitosterol on proliferation of mouse fibrosarcoma cells, also reported that cell viability reduced to 63 and 39% because of β-sitosterol treatment at 16 μM and 32 μM, respectively, compared with that of untreated fibrosarcoma cells.
Effect of phytosterols on cellular apoptosis
Phytosterols have been shown to promote apoptosis (programmed cell death), an important mechanism in the inhibition of carcinogenesis. (see Figure 2). Awad et al. (2005) observed increased apoptosis of prostate cancer cells by 73% on β-sitosterol treatment at a dosage of 16 μM. Park et al. (2007) similarly reported that treatment of human leukemia cells with β-sitosterol at varying concentrations for 72 h increased the percentage of apoptotic cells in a dose-dependent manner.
The mechanism by which β-sitosterol promotes apoptosis has recently been investigated by Park et al. (2007, Moon et al. (2007) and Awad et al. (2007). Park et al. (2007) reported that treatment of human leukemia cells with β-sitosterol at various concentrations ranging from 5 to 20 μM, resulted in an increased activity of caspase-3 in a dose-dependent manner, with increase in the activity at 20 μM being three fold. The addition of z-DEVD-fmk (50 μM), a caspase-3 inhibitor, to β-sitosterol-treated leukemia cells resulted in two-fold decrease in caspase-3 activity and in decreased cell apoptosis, indicating that β-sitosterol induces apoptosis by activation of caspase-3. Overexpression of Bcl-2, reduced the β-sitosterol-induced caspase-3 activation, suggesting that β-sitosterol increases the activity of caspase-3 through downregulation of Bcl-2. Similarly, Moon et al. (2007) observed increased caspase-3 activity in mouse fibrosarcoma cells because of β-sitosterol treatment for 48 h. In their study, these investigators also observed increased activities of pro-apoptosis enzymes of MAPK family, specifically ERK and p38 mitogen activated protein kinase, and reduced activity of anti-apoptosis enzymes of the same family (phosphatidylinositol 3-kinase and Akt), which are activated by extracellular signals and are involved in activation of caspase.
Rubis et al. (2008) showed increased activity of caspase-3 by more than 60% because of treatment of human endothelial cells with β-sitosterol in vitro. The Fas pathway will activate caspase if Bcl-2 pathway is inactivated (Guseva et al., 2002). Therefore, the reduction in expression of Bcl-2 protein, as reported by Park et al. (2007), and the increased activity of pro-apoptosis MAPK enzymes, as reported by Moon et al. (2007), suggest that the activation of caspase because of phytosterol could be mediated by extracellular signals that are complemented by mitochondrial pathways. Moon et al. (2008) have analyzed various mechanisms of the anti-carcinogenic effects of β-phytosterol at 20 μM on U937 and HL60 leukemia cells. The authors showed that β-phytosterol causes inhibition of the cell growth, G2/M arrest, and triggers apoptosis. β-Sitosterol also induces endo-reduplication and apoptosis by involving phosphatidylinositol 3-kinase/Akt and ERK-independent pathways.
The effects of β-sitosterol at 8 and 16 μM concentrations on the apoptotic pathway in MCF-7 and MDA-MB-231 breast cancer cells were examined by Awad et al. (2007). Results showed an increased β-sitosterol content in the cell membrane by approximately 50 μg/mg after treatment with 16 μM of β-sitosterol. Treatment with β-sitosterol also caused an increase in Fas protein content and caspase activity in breast cancer cells. These researchers suggested that the increased caspase activity after β-sitosterol administration could be due to the alteration of structure and function of cancer cell membranes as a result of β-sitosterol incorporation into the membranes. Phospholipids have been reported to interact more strongly with cholesterol than with phytosterols, indicating that the incorporation of phytosterols in the membranes can alter the structure of the membranes (Hac-Wydro et al., 2007). Cell-membrane lipid rafts, in which sterols are highly concentrated, regulate cellular phosphorylation cascades that arise from external stimuli (Zhuang et al., 2005). Therefore, incorporation of phytosterols into lipid rafts, altering their structure, may result in beneficial changes in signal transduction.
An additional mechanism through which phytosterols can act in promoting apoptosis is by lowering blood cholesterol levels. Reductions in blood cholesterol level could result in increased apoptosis. Three areas of evidence associate cholesterol with cancer. First, high intakes and elevated blood concentrations of cholesterol are associated with cancer. For instance, Chang et al. (2007) observed lower serum levels of HDL-cholesterol and apolipoprotein A–I, and higher serum levels of VLDL-cholesterol in women with breast cancer compared with normal women, whereas Oadir and Malik (2008) reported that in women with breast cancer, plasma levels of triglycerides, cholesterol and LDL-cholesterol are higher than those in normal women. Also, Lucenteforte et al. (2008) found an association between cholesterol intakes and endometrial cancer in women.
Second, increases in level of cholesterol in blood result in its increased accumulation in cell membranes. For example, Zhuang et al. (2005) reported that increased levels of blood cholesterol in mice, effected by feeding hypercholesterolemic diets, resulted in increased cholesterol content in lipid rafts in prostate cancer cells.
Third, an increase in level of cholesterol in cell membranes could result in increased survival and reduced apoptosis of the cells. Oh et al. (2007) reported increased apoptosis of prostate cancer cells, and increased activity of caspase-3 and reduced Akt and ERK signal transduction in the same cells in vitro because of cholesterol depletion in their lipid rafts due to treatment with hydroxypropyl-β-cyclodextrin. These authors attributed the increased apoptosis to increased activity of caspase-3 and reduced Akt and ERK signal transduction due to absence of cholesterol in lipid rafts. Li et al. (2006) indicated that cholesterol depletion in breast and prostate cancer cells using methyl-β-cyclodextrin results in increased apoptosis due to increased activity of caspase-3 and reduced activity of Akt. In their study, replenishment of lipid rafts with cholesterol reversed the activity of these two enzymes and cell viability. Zhuang et al. (2005) similarly observed increased activity of Akt in lipid rafts in prostate cancer cells because of increased cholesterol content in the same cells. From these studies it thus seems that by lowering blood cholesterol level, phytosterols could reduce the incorporation of cholesterol in the lipid rafts of cancer cells and hence promote the apoptosis of cancer cells by reduction in anti-apoptotic signal transduction.
Inhibition of angiogenesis and metastasis by phytosterols
Angiogenesis plays a vital role in cancer cell growth and multiplication as these cells require nutrients for growth (Prescott, 2000), whereas metastasis is the major cause of death due to cancer (Awad et al., 2001a). Choi et al. (2007) determined the effect of campesterol on basic fibroblast growth factor-induced angiogenesis in endothelial cells isolated from human umbilical vein, and observed reduced proliferation of the cells on campesterol treatment. Awad et al. (2001a) reported reduced invasiveness and adhesiveness of breast cancer cells in vitro on β-sitosterol treatment by 78 and 15%, respectively, compared with the control. This group also reported reduced metastasis of murine cancer cells of the lungs and lymph nodes by 62 and 33%, respectively, after inoculating the mice with prostrate cancer cells and feeding them diets containing 2% phytosterols. Awad et al. (2001b) have also reported that phytosterol treatment of breast cancer cells in vitro resulted in reduced invasiveness of the cells by reducing their adhesiveness. Results from these studies thus suggest that phytosterols can inhibit angiogenesis and metastasis.
However, Moon et al. (1999) have observed that β-sitosterol isolated from aloe vera possesses angiogenic property and have recommended their use for management of chronic wounds. Results of Choi et al. (2002) showing that β-sitosterol possesses a good angiogenic property in ischemia/reperfusion-damaged brain of Mongolian gerbils also support this assertion. Therefore, more research is required to establish the anti-angiogenic property of phytosterols.
Safety of phytosterols
The recommended dose of phytosterols for lowering blood cholesterol level is 2 g per day; higher levels result in little further reduction in blood cholesterol levels (AbuMweis et al., 2008a). As discussed earlier, phytosterols are poorly absorbed, and the little that is absorbed seems to inhibit cancer development. However, the controversy on whether increased plasma phytosterol levels exist as a risk factor for coronary heart disease in individuals without phytosterolemia remains to be elucidated (Sudhop et al., 2002). Lizard (2008), in reviewing the possible toxicity effects of phytosterols, concluded that a better knowledge of the effects of plant sterols in high concentration is important to ensure any presence of adverse effects. A number of investigations with different study designs have shown that plasma phytosterol levels have no association with the risk of coronary heart disease (Windler et al., 2009); Kritchevsky and Chen, 2005; Sudhop et al., 2002; Wilund et al., 2004; Pinedo et al., 2007).
Although phytosterol consumption reduces the absorption of β-carotenes and α-tocopherols (Richelle et al., 2004), these negative effects can be alleviated either by increasing dietary intake of carotenes or by consuming phytosterols with other food components that enhance carotene absorption. For instance, Noakes et al. (2002) reported that consumption of at least five servings of vegetables and fruits by individuals fed with phytosterols alleviated the adverse effects of phytosterols on β-carotene, whereas Jones et al. (2007) observed no effect of phytosterols on β-carotene absorption in hypercholesterolemic individuals when the phytosterols fed were esterified to fish oil, but not to sunflower oil. Thus, there is a need to develop a feeding strategy, which enhances the absorption of β-carotenes and α-tocopherols. Recently we have shown that consumption of 1.8 g per day of plant sterols distributed over the day yields optimal cholesterol-reducing effect rather than one large dose (Abumweis et al. 2008a, 2008b).
Summary and conclusions
Phytosterols seem to inhibit the development of various cancers mainly by inhibiting growth and promoting apoptosis of cancer cells by the activation of caspase enzymes. The increased activity of caspase enzymes could be attributed to the fact that incorporation of phytosterols into cell membranes results in changes in their membrane structure and function, and that these changes increase the activities of proteins involved in extra- and intracellular signal-transduction pathways that activate caspase enzymes. Phytosterols could also inhibit cancer development by lowering blood cholesterol as high blood cholesterol level and hence the concentration of cholesterol in lipid rafts of cell membranes are associated with reduced apoptosis of cancer cells. This combined evidence strongly supports an anticarcinogenic action of phytosterols and hence advocates their dietary inclusion as an important strategy in prevention and treatment of cancer.
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Contributors: TAW contributed in literature and data collection and in preparation of the paper. VRR contributed in the preparation of the paper and critical review. PJHJ also contributed in preparation of the paper and critical review.
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Woyengo, T., Ramprasath, V. & Jones, P. Anticancer effects of phytosterols. Eur J Clin Nutr 63, 813–820 (2009). https://doi.org/10.1038/ejcn.2009.29
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