Potential Mechanisms of Chemoprevention

Cancer is a highly complex disease, underpinned by a wide variety of mechanisms and signaling pathways which collectively result in tumor initiation, development, progression, and metastases. Although there are over 200 different types of cancers relating to the various organs and tissues in the body that can become affected, it is now' known that all cancer cell types possess a number of common traits known as the “Hallmarks of Cancer” (see Chapter 1). These include high proliferation potential, and the ability to attract blood vessels (e.g., angiogenesis) and to metastasize. These characteristics have been used to design anticancer therapies that can selectively target cancer cells. Therefore, it is possible that some chemopreventive agents may act on similar processes and pathways to suppress the initiation and development of cancer. The most likely of these possibilities are described in Sections 12.2.1-12.2.11.

However, it is important to appreciate the magnitude of the challenge in trying to understand the details of how a particular chemopreventive agent or its close analogues may inhibit the transition of a healthy cell into a tumor cell, or the growth and development of a small tumor once it is established. To illustrate this challenge, it is instructive to look at the literature relating to the flavonols, a group of reported chemopreventive compounds containing the 3-hydroxy-2-phe- nylchromen-4-one core, key members of which included quercetin, kaempferol, casticin, and galangin (Figure 12.2). Although all flavonols contain the 3-hydroxyflavone backbone, family members vary depending on the position of phenolic -OH groups. Flavonols of this type are found in a variety of vegetables such as onions, tomatoes, and broccoli, with an estimated intake in Western diets averaging 20-50 mg per day, and are also present in some fruits.

Studies have showrn that their chemopreventive activity may be due to several different mechanisms. A recent literature review (up to mid-2020) of in vitro and in vivo studies involving flavanols such as quercetin, kaempferol, casticin, and galangin highlighted a multitude of both up-regulation and dow'n-regulation effects on a large number of signaling pathways as summarized in Table 12.1. These results indicate effects on processes including inflammation, apoptosis, cell cycle, cellular proliferation, invasion and metastasis, angiogenesis, epigenetics, and the metabolism of carcinogens and

Chemical structures of the parent flavonol structure, and the family members quercetin, kaempferol, casticin, and galangin

FIGURE 12.2 Chemical structures of the parent flavonol structure, and the family members quercetin, kaempferol, casticin, and galangin.

estrogen modulation. Clearly, it will take a significant amount of research work to elucidate the most significant mechanism (or mechanisms) of action for chemopreventive agents of this type, and it is entirely possible that many different mechanisms will be identified as key. This is important because, if chemopreventive agents based on natural products such as the flavanols are to be eventually licensed by regulatory bodies such as the FDA and EMA for chronic administration to healthy individuals, it would be preferable for a limited number of mechanisms to be operative that could be accurately measured and related to biological effect.

Effect on Metabolic and Other Enzymes

For some xenobiotics from the diet or environment, Phase I metabolism, which normally involves the addition of functionalities such as hydroxyl groups to increase polarity and water solubility to promote elimination through the kidneys

TABLE 12.1

Cellular Processes and Signaling Pathways Affected by the Flavonols Quercetin, Kaempferol, Casticin, and Galangin (See Figure 12.2) (Summarized from the Literature up to mid-2020)


Signaling Pathways Down-regulated

Signaling Pathways Up-regulated

Reduction of Inflammatory


TLR-4. NF-кВ. IL-ip/-6, COX-2, TNF-ct, Nrf2. кВа/p. IFN-y

IL—8. PARP. MCP-1. survivin

Induction of Apoptosis

Bcl-2. Bcl-xL. c-MYC. PI3K/Akt. PLK-1. IRS-1, survivin, XIAP

AMPK/mTOR, p38MAPK. p53, caspase-3/-7/-8/-9, DR5. TGF-pRI/II. JNK. ERK1/2, SIRT-2. p21. FasL/l. FADD. BID. Bax, Bad, PARP, ATM, cytochrome c

Induction of Cell-Cycle Arrest

Cyclins A/В 1/D1/D3/E. cdc2/25A/4. CDK1/2/4/6. Chk2. Rb

p21. p27, p53.Chk2.AMPK

Inhibition of Cellular Proliferation

p-S6.4EBPI. STAT3. GSK-3p. Wnt/p-catenin. Akt-CSN6-MYC

p38MAPK. ERK1/2. cathcpsin B/D, MEK1/2. ELK1. PTEN. caspase-3, TRA1LR

Inhibition of Invasion and Metastasis

p-catenin, vimentin, TGF-p, N-cadherin, E-cadherin, SNAIL, Slug, Rho, Rac, Twist, MMP-2/-9. STAT3. Smad6/7

JAKl, ATM. Smadl/2/3/4. Bcclinl

Inhibition of Angiogenesis



Epigenetic Modifications


Histone H3 phosphorylation

Metabolism of Carcinogens



Estrogen Modulation



or gut (via the liver), can activate an undesirable pharmacological activity. For example, some compounds, known as pro-carcinogens, are not inherently carcinogenic but can be transformed into carcinogenic molecules through Phase I metabolism or related metabolic processes. Other enzymes such as mono-oxygenases, cytochrome P450s, flavin adenine dinucleotide (FAD), or flavin adenine mononucleotide (FMN) can also carry out bio-transformations that may activate pro-carcinogens. Therefore, some chemopreventive agents may work by inhibiting this activation process.

On the other hand, Phase II enzymic transformations, also known as conjugation reactions, facilitate the attachment of small polar molecules (e.g., sugars) to xenobiotics or intermediate Phase I metabolites to produce less biologically active and/or or more water-soluble molecules that can be eliminated more easily. A wide variety of enzymes participate in this process, including glutathione-S-transferases (GSTs), sulfotransferases, UDP-glucuronosyltransferases (UGT), N-acetyltransferases (NATs), and methyltransferases (MTs). Some chemopreventive agents may work by enhancing the Phase II metabolism of pro-carcinogens or carcinogens thus facilitating their elimination from the body.

Also, for electrophilic carcinogens, the activity of enzymes such as GST, glutathione peroxidase (GPO), and glutathione reductase (GR) can conjugate the electrophilic center of the carcinogen to thiol-containing moieties thus reducing their ability to covalently interact with biological nucleophiles such as DNA and reducing their carcinogenic. Some chemopreventive agents may work by facilitating this process.

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