Ferulic acid has been reported to improve glucose tolerance and lipid metabolism (El-Seedi et al. 2012; Ardiansyah et al. 2006). Recently, Wang et al. reported that ferulic acid administration alleviated high-fat and high-fructose diet-induced metabolic syndrome parameters, such as obesity, hyperglycemia, hyperlipidemia, and insulin resistance (Wang et al. 2015). Several studies have shown that ferulic acid acts as a potent antioxidant by scavenging free radicals in rats (Sudheer et al. 2005). Antioxidants are considered potential inhibitors of cancer by protecting critical cellular molecules from oxidative damages. Indeed, ferulic acid suppresses chemically induced colon (Kawabata et al. 2000), skin (Asanoma et al. 1994), and lung carcinogenesis (Lesca 1983) in animals.

Sesamin is a furofuran-type lignan in sesame seed oil, which has potential benefits for health promotion (Pathak et al. 2014). Studies have shown that sesamin plays a significant role in lipid metabolism through the downregulation of lipogenic enzymes (Peñalvo et al. 2006), sterol regulatory element binding protein-1 (SREBP-1), acetyl-CoA carboxylase, and fatty acid synthase (Ide et al. 2001) in animals. In addition, sesamin inhibits cholesterol absorption and biosynthesis in humans (Hirose et al. 1991; Hirata et al. 1996). These bioactivities may be beneficial for preventing the obesity and atherosclerosis. Sesamin showed anti-inflammatory activities through the inhibition of Δ5 desaturase, a key enzyme in arachidonic acid biosynthesis that leads to a lower level of pro-inflammatory mediators (Shimizu et al. 1991; Chavali et al. 1998). As inflammation plays an important role in carcinogenesis, sesamin could be a good candidate cancer preventive agent. Indeed, Hirose et al. reported that the administration of 0.2 % sesamin significantly reduced the number of 7,12-dimethylbenz[a]anthracene (DMBA)-induced palpable mammary cancers compared with control animals (Hirose et al. 1992).

Sesamolin has been demonstrated to increase the activity and mRNA level of various enzymes involved in hepatic fatty acid oxidation in rats (Lim et al. 2007). Sesamolin is also known as an antioxidant and has been shown to have a protective effect in neuronal cells against hypoxic and lipopolysaccharide (LPS)-induced toxicity or excitotoxicity in vitro and in vivo (Hou et al. 2003a, b; Cheng et al. 2006). In addition, Miyahara et al. reported that sesamolin inhibited proliferation and induced apoptosis in human lymphoid leukemia Molt 4B cells (Miyahara et al. 2001).

γ-Tocopherol, the most abundant tocopherol in sesame seed oil, showed a very broad range of medicinal properties (including anticancer, antidiabetic, anti-inflammatory, and anti-oxidative effects) not only in preclinical studies but also in human intervention studies (Jiang 2014). In a preclinical model, γ-tocopherol administration attenuated dextran sulfate sodium (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced colon tumorigenesis (Jiang et al. 2013), partly through the suppression of eicosanoids [prostaglandin (PG) E₂ and leukotriene B4] production (Ju et al. 2009). In addition, Takahashi et al. demonstrated that the supplementation of γ-tocopherol suppressed prostate tumor progression with the induction of apoptosis through caspase activation in the transgenic rats for adenocarcinoma of prostate (TRAP) model (Takahashi et al. 2009). Thus, γ-tocopherol exhibits strong anti-oxidative and anti-inflammatory effects in many studies, and it could be a good candidate as cancer preventive agent.

Sesamol is involved in the oil-soluble compartment as oil-soluble lignans. Sesamol possesses antioxidant (Hsu et al. 2006), anti-inflammatory (Chavali et al. 2001), and free radical scavenging activity (Parihar et al. 2006). As neutrophil-derived hydrogen peroxide (H₂O₂) plays an important role in the progression of inflammatory bowel disease (IBD), a previous report examined the sesamol protective effects on dinitrochlorobenzene (DNCB)-induced mucosal injury in a rat IBD model. Sesamol (100 mg/kg, po) treatment for 7 days significantly decreased the levels of myeloperoxidase, thiobarbituric acid reactive species, and nitrite in the colon tissue (Kondamudi et al. 2013). In a long-term animal experimental study, sesamol treatment at dietary levels up to 2 % for 2 years was shown to decrease the spontaneous development of preneoplastic hepatocytic foci in F344 rats (Hagiwara et al. 1996).

In our experiments, among the four sesame seed constituents (ferulic acid, sesamin, sesamol, and sesamolin), 100 μM sesamol treatment in a human colon cancer cell line, DLD-1 cells, for 48 h suppressed basal cyclooxygenase-2 (COX-2) promoter transcriptional activity as detected by a β-galactosidase reporter gene system (Mutoh et al. 2000; Shimizu et al. 2014). COX-2 is an inducible enzyme to produce PGE₂, and both COX-2 expression and PGE₂ levels are increased in colon carcinoma tissues compared with that of normal colonic mucosa. Accumulating evidence suggests that COX inhibitors suppress colon carcinogenesis in animal experiments and human trials (Komiya et al. 2013; Mutoh et al. 2006). It has also been reported that COX-2 gene knockout results in the reduction of intestinal polyp development in a model of human familial adenomatous polyposis, Min mice (Oshima et al. 1996). Thus, it is likely that agents that can suppress COX-2 expression at the transcriptional level may also suppress colon carcinogenesis in animal experiments and human trials.

We have shown the suppressive potential of sesamol on intestinal polyp development in Min mice (Shimizu et al. 2014). The administration of 500 ppm sesamol reduced the total number of intestinal polyp development compared with that of the untreated group. When the small intestine is divided into three parts, the proximal, middle, and distal parts, sesamol decreased the number of polyps in the middle part.

In the polyp parts of Min mice, sesamol suppressed COX-2 mRNA expression levels. Sesamol treatment also reduced cytosolic prostaglandin E synthase (cPGES) mRNA expression levels. Moreover, a tendency of suppression in the expression levels of PGE₂ receptor subtypes EP1 and EP2 in the polyp parts was observed. We confirmed the effect of sesamol on human EP1 and EP2 mRNA levels in DLD-1 cells and found that sesamol significantly suppressed EP1 and EP2 mRNA levels. PGE₂ receptor subtype-knockout mice have demonstrated that EP1, EP2, and EP4 are promotive receptors in colorectal carcinogenesis, and EP3 plays suppressive roles (Mutoh et al. 2006). Unfortunately, there are a few inhibitors for PGE₂ receptor subtypes. Thus, the novel potential of sesamol may be worthwhile from the aspect of developing chemopreventive agents.

In addition, we performed a preliminary experiment using intestinal polyp samples of Min mice to examine effects of sesamol on the expression levels of oxidative-related factors. We obtained the data showing a tendency toward the reduction of NOX1 mRNA by sesamol as described in the next section.

Cancerous tissue is known to be under oxidative stress conditions. Distinct amounts of ROS are produced as a by-product from the mitochondrial respiratory chain, and a large amount of superoxide anion radical (O₂ ⁻) is often generated by cancer cells due to a complex I dysfunction in mitochondria. The initial step in ROS formation is the generation of O₂ ⁻ and then proceeds to H₂O₂ and the hydroxyl radical (OH), which causes strong damage to cells (Halliwell 1978). At low ROS concentrations, intracellular signaling is initiated, whereas at high ROS concentrations, oxidative stress is induced. Extensive studies over the years have determined that high ROS conditions contribute to the progression of various human diseases, especially cancer. ROS targets regulate proliferation, including cellular signaling (phosphatases, AP1 and NF-κB) and cell cycle (CDC25, cyclin D, and forkhead proteins; G1, G2, respectively) proteins.

Another enzyme that generates ROS is NOX. Membrane-integrated NOX family oxidases, such as NOX1 and Duox2, are known to produce O₂ ⁻ or H₂O₂ (Sumimoto 2008). NOX is a multicomponent enzyme, which is formed of a complex, membrane-associated component (Nox1-5, Duox1, 2, and p22^phox), cytosolic components (p47 ^phox, Noxo1 (homologue of p47 ^phox), Noxa1 (homologue of p67 ^phox), and p40 ^phox), and the small GTP-binding protein Rac (Vulcano et al. 2004; Li and Shah 2001; Muzaffar et al. 2008; Brandes and Schroder 2008).

Correlating with activating mutations in K–ras, NOX1 is overexpressed in human colon cancers (Laurent et al. 2008). Other factors are also elevated in cancer cells and have been suggested to play an important role in carcinogenesis. The function of NOX2 and NOX3 in cancer is not well known. NOX4-generated ROS has been suggested to induce resistance of pancreatic cancer cells to apoptosis (Mochizuki et al. 2006), and its inhibition suppresses melanoma cell growth (Yamamura et al. 2009). On the other hand, Duox1 and Duox2 are remarkably suppressed in lung cancer cells due to the hypermethylation of CpG-rich regions of their promoters (Luxen et al. 2008).

As described in a previous section, many studies have indicated that the NOX family of genes appears to be required for survival and growth of a subset of human cancer cells. Thus, the NOX family should be a focus of attention in cancer etiology and cancer prevention studies (Kamata 2009). The significance of NOX in carcinogenesis has been shown in experiments using NOX inhibitors. NOX functional inhibitors are classified as (1) small molecule chemical NOX inhibitors and (2) biological inhibitors for NOX, such as neopterin and gp91ds-tat. In this section, we will review and discuss the relationship between NOX inhibitors (apocynin, diphenylene iodonium, vanillin, and methyl-vanillin) and carcinogenesis.