**4. Cancer prevention possibilities**

Polyphenols likely have many different mechanisms of how they can prevent proliferation and overall survival of cancerous cells. As mentioned in previous sections, there is substantial overlap among mechanisms. Due to this overlap, it is almost certain that multiple mechanisms are involved to provide the cancer prevention properties of polyphenols. It is therefore more convenient to present research based on some of the individual actions of polyphenols such as anti-oxidative properties, pro-oxidant activity, mediation of cellular signaling, and epigenetic modifications [41].

#### **4.1 Antioxidant properties**

The structure of polyphenols makes them great antioxidants due to the high availability of hydroxyl groups attached. The more hydroxyl groups present on the molecule, the greater the potential for antioxidant activity [41]. Cancer cells have been shown to increase greater amounts of reactive oxygen species (ROS) than non-cancerous cells. Through various different pathways, ROS have been shown to promote both tumorigenesis and the proliferation through mechanisms such as angiogenesis and the promotion of cell migration [42]. Flavonoids have been shown to lower the amount of ROS by scavenging free radicals, chelating of transition metals that help form further ROS, and regulating oxidative stress-mediated enzyme activity [43]. Research has shown that rats treated with epigallocatechin gallate (EGCG) had increased levels of antioxidant enzymes [44]. Lowering ROS levels results in the prevention of cancerous cells to undergo proliferation or migration.

#### **4.2 Pro-oxidant activity**

Effectiveness of cancer treatment can also be improved by modulating oxidative levels in the cells. Oxidative stress can damage cells and cancer cells have an increased capacity to handle oxidative damage. Taking advantage of this increased capacity, cancer cells can somewhat be recognized more specifically. Therapies involving polyphenols generally reduce oxidative damage, but in cancer cells the standard signaling is already modified, thus some polyphenols actually increase oxidative damage to a level in which apoptosis and therapeutic sensitivity increased. Research shows that cancer cells undergo changes to better handle the high levels of ROS in their environment such as generating higher levels of nicotinamide adenine dinucleotide phosphate (NADPH) [45–47]. This better equips cancerous cells to resist the effects of oxidative stress that can lead to apoptosis. However, this resistance is still able to be overcome by increasing the amount of ROS to a level more than the cells can handle.

#### *Therapeutic Potential of Dietary Polyphenols DOI: http://dx.doi.org/10.5772/intechopen.99177*

Many polyphenols have been shown *in vitro* to have pro-oxidant activity by utilizing transition metals already present in biological systems to create more ROS and overcome the natural resistance that cancerous cells possess [48–50]. Vitamin C has been shown in high doses to inhibit tumor growth as well as metastasis without harming non-cancerous cells present. Ascorbate as a standalone treatment has been shown to reduce both tumor growth and weight by 41–53% in Ovcar5, Pan02, and 9 L tumors. It was also shown to reduce the amount of metastases that were present in approximately 30% of 9 L glioblastoma control groups [51]. This shows promise, as a difficulty surrounding cancer treatment is the incidental harm of non-cancerous cells simultaneous to cancerous cells. Potentially utilizing natural polyphenols already present in biological systems may be a way to work around this issue. Another class of polyphenols, hydroxycinnamic acids, has shown the ability to damage DNA molecules in the presence of Cu(II) ions [52]. Further studies are crucial in determining the *in vivo* ability of polyphenols to replicate results shown *in vitro*.

## **4.3 Mediation of cellular signaling**

As mentioned in both the inflammation and metabolism sections, NF-κβ is an important component in the inflammatory nature of cancerous cells. It is believed that it is the primary factor responsible for inducing a variety of cancer molecules such as adhesion molecules, growth factors, angiogenic proteins, cell proliferation proteins and inflammatory cytokines [41]. NF-κβ also increases expression of inhibitors of apoptosis and suppresses the expression of genes involved in cell death [53]. Research has shown that polyphenols have the ability to interfere with NF-κβ's mechanisms specifically involved with cancer. Flavonoids disrupt inhibitors of kappa kinase (IKK), an activator of NF-κβ, as well as binding directly to NF-κB and preventing its binding to DNA [41, 54, 55]. The mediation of polyphenols in these pathways can provide valuable anti-inflammatory benefits that can both prevent the formation of cancerous cells and tumors, as well as removing the suppression of apoptosis that is caused by NF-κβ leading to cell death.

### **4.4 Epigenetic modifications**

Methylation of specific cancer genes has become a key predictor of both markers of cancer and cancer survival. One example of this is the methylation state of the BRCA1 promoter gene in ovarian cancer. Research showed that patients with a higher level of methylation on the gene, had a shorter median for disease free interval. It also showed that facilitating demethylation of the gene results in increased survival time and decreased occurrence rate [41, 56]. DNA methyltransferase (DNMT) is the enzyme responsible for methylation of genes. Polyphenols have been shown to decrease methylation by inhibiting DNMT. *In vitro*, DNMT was inhibited by EGCG at a concentration of 20 μmol/L [57]. The ability for polyphenols to inhibit DNMT and other methyltransferase enzymes makes them of interest for not only cancer prevention, but other disease states that are affected by an increase in methylation of DNA [41]. Research in this area should continue so a greater understanding of the ability for polyphenols to affect methyltransferase enzymes such as DNMT.

#### **4.5 Cancer treatment adjunctive therapy**

Cancer therapies are an ever changing area of interest as we better understand ways to induce cancer cell death as well as maintain the health of non-cancerous

cells in the body. Resistance to chemotherapies is also an area of concern making it difficult to achieve appropriate therapy and leading to more aggressive treatments which leads to an increase in harm to non-cancerous cells. One of the ways that cancer cells present resistance is in the increase of the multidrug resistant p-glycoprotein transporter. The p-glycoprotein transporter pumps the drugs out of the therapeutic intracellular location. Curcumin has been shown to suppress the action of the multidrug resistant p-glycoprotein transporter. Sulfasalazine, a specific substrate for the multidrug resistance protein ABCG2, was shown to have an increased Cmax concentration in the presence of a 400 mg/kg dose in mice. The change was 1230 ng/mL in the absence of curcumin and 3350 ng/mL with curcumin present [58]. This would in turn result in an increase in concentration of medication inside the cancer cell and therefore greater efficacy of the therapy making curcumin a good possibility for adjuvant therapy. Another issue arises during chemotherapy in the possible need to increase ROS to produce apoptosis of cancerous cells [59]. These ROS also negatively affect non-cancerous cells so the need to protect these cells is crucial to ensure appropriate chemotherapy can continue. As mentioned above, one of the mechanisms in how polyphenols can prevent cancer is through their antioxidant activity. Through this mechanism, polyphenols can provide valuable adjuvant therapy for patients allowing them to prolong their chemotherapy without increasing negative effects associated with the increase in ROS.
