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Michael Lokant
English 305 Process Description
September 25, 2014
Phloretin as a Chemopreventive Agent
Chemopreventive Agents
Chemopreventive agents are substances that have the ability to either lower the risk of
developing cancer or slow its progression. The process of chemoprevention may even be able to
reverse the development of cancer. Although it is sometimes associated with the use of
chemotherapeutics, chemoprevention is not meant to be used as a treatment for cancer. It is
typically used by those who are at a higher risk of developing cancer. Both drugs and naturallyoccurring chemicals can act as chemopreventive agents. Sometimes a combination of substances
is required in order to elicit a chemopreventive change (American Society of Clinical Oncology,
2012). Table 1 below lists a select few chemopreventive agents, their sources, and their major
chemopreventive effect.
Table 1. Select examples of chemopreventive agents, their source or drug classification, and one
of their chemopreventive effects are shown below (Dorai & Aggarwal, 2004; Saunders &
Wallace, 2010).
Chemical
Source/Drug Type
6-Gingerol
Ginger
Catechins
Green Tea
Curcumin
Ellagic Acid
Tumeric
Pomegranate
Berries, Peanuts, Red
Grapes
NSAID
Resveratrol
Sulindac
Chemopreventive Effect
Inhibits NF-kB, affecting regulation of genes
involved in cell proliferation
Suppresses AP-1 activation, affecting regulation of
genes involved in cell proliferation
Induces caspase-mediated apoptosis
Eliminates reactive oxygen species
Interferes with cell replication cycle
Inhibits an COX-2, alleviates inflammation and pain
Phloretin
Phloretin is a substance found commonly in apples that acts as a chemopreventive
agent. It belongs to the structural class known as polyphenols as it contains two phenol groups,
as well as a carbonyl group (Fig. 1). Phloretin is mostly known for its ability to obstruct the
active transport of glucose into cells by inhibiting sodium/glucose co-transporters and glucose
transporters. It also inhibits the both absorption and re-absorption of glucose in the intestines
(Yang et al. 2009).
Figure 1. The structure for phloretin contains two phenol groups, a carbonyl, and two hydroxyl
groups (Kundu, Chun, Chae, & Kundu, 2014).
Figure 2 lists many examples of the chemopreventive effects phloretin has on the body
and what proteins or processes are involved in inducing those effects. The process described
below will illustrate one of the numerous chemopreventive mechanisms phloretin initiates,
apoptosis of cancerous cells. Apoptosis is programmed cell death. Phloretin can induce cell
death by activating the protein p53. Once active, p53 plays a major role in initiating several
different diverging and converging pathways leading to apoptosis. Activation of the specific
proteins or genes by p53 in response to phloretin will be described below.
Figure 2. The various chemopreventive effects of phloretin and what biochemical changes
cause these effects to occur are illustrated in the diagram (Kundu, Chun, Chae, & Kundu, 2014).
Phloretin-induced Cell Death
Activation of p53
Although the exact mechanism has not yet been uncovered, results from several studies
indicate that phloretin does up-regulate p53. The p53 protein is a well-known tumor suppressor.
It can activate several different processes, each with their own contribution to the death of the
cell. Most of the time p53 is bound to its inhibitor Mdm2, keeping it inactive. This tumor
suppressor is typically activated in response to cellular stress signals, such as DNA damage,
insufficient oxygen levels, or issues with cell division or replication (Fridman & Lowe, 2003).
However, phloretin is able to activate p53 without causing any sort of cellular stress. It is
important to note that phloretin only activates existing p53 proteins; it does not induce
transcription of the p53 gene, which would lead to the production of more p53 proteins (Kundu,
Chun, Chae, & Kundu, 2014).
BAX and Bcl-2
In addition to activating p53, phloretin exposure leads to decreased levels of the B-cell
lymphoma 2 (Bcl-2) protein and increased levels of the Bcl-2-associated X protein (BAX)
protein (Kundu, Chun, Chae, & Kundu, 2014). The changes in these protein levels are not
directly due to phloretin, but to active p53. As a tumor suppressor, p53 plays a major role in
controlling the transcription of pro-apoptotic genes. These genes encode for proteins, such as
BAX, that induce cell death. When p53 binds to its specific region on the DNA strand it
activates the transcription of several genes, including that for BAX. This produces an mRNA
template that is read in the process of translation in order to produce the BAX protein. One role
of BAX is to bind and inhibit Bcl-2. Bcl-2 is known as an anti-apoptotic protein as it is active in
pathways that strive to keep the cell alive. When BAX inhibits Bcl-2, Bcl-2 loses its antiapoptotic abilities. With these proliferation pathways disabled, apoptotic pathways initiated by
p53 can be carried out largely unopposed. The other role of BAX facilitates cell death through
its association with the mitochondria by leading to the activation of caspases. Caspases are
essential to cell death as they can degrade proteins (Fridman & Lowe, 2003).
This pathway works with a wide variety of others, all leading towards the end-goal of
programmed cell death. This specific pathway is summarized in Figure 3.
Figure 3. The words in black denote molecules while the blue words denote cellular locations.
Black lines indicate stimulatory pathways while the red line indicates an inhibitory pathway.
Active p53 and caspases, and inactive Bcl-2 lead to cell death.
Summary
One way in which phloretin acts in chemoprevention involves activation of the tumor
suppressor protein p53. Active p53 can increase the levels of BAX, which can bind and
inactivate Bcl-2, an anti-apoptotic protein. This mechanism combined with others leads
cancerous cells to undergo a programmed death. Understanding how chemopreventive agents
like phloretin work can be very important for future cancer treatment. Although they are not
currently used as treatments, chemopreventive agents may hold the key to cancer prevention.
Fighting as vicious a disease as cancer simply by eating an apple would provide an ideal option
for cancer treatment.
References
American Society of Clinical Oncology. (2012). Chemoprevention. Retrieved from
http://www.cancer.net/navigating-cancer-care/prevention-and-healthyliving/chemoprevention
Dorai, T., & Aggarwal, B. (2004). Role of Chemopreventive Agents in Cancer Therapy. Cancer
Letters, 215 (2), 129-140. doi: 10.1016/j.canlet.2004.07.013
Fridman, J. S., & Lowe, S. W. (2003). Control of apoptosis by p53. Oncogene, 22, 9030-9040.
doi: 10.1038/sj.onc.1207116
Kundu, J., Chun, K. S., Chae, I. G., & Kundu, J. K. (2014). Phloretin: An Apple Polyphenol with
Cancer Chemopreventive Potential. Archives of Basic and Applied Medicine, 2 (1), 1723. Retrieved from http://archivesbam.com/ojs/index.php/abam/article/viewFile/35/65
Saunders, F. R., & Wallace, H. M. (2010). On the Natural Chemoprevention of Cancer. Plant
Physiology and Biochemistry, 48 (7), 621-626. doi: 10.1016/j.plaphy.2010.03.001
Yang, K., Tsai, C., Wang, Y., Wei, P., Lee, C., Chen, J., Wu, C., & Ho, Y. (2009). Apple
Polyphenol Phloretin Potentiates Anticancer Actions of Paclitaxel Through Induction of
Apoptosis in Human Hep G2 Cells. Molecular Carcinogenesis, 48 (5), 420-431.
doi: 10.1002/mc.20480