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Page 22 of 36 Dave et al. J Cancer Metastasis Treat 2020;6:46 I http://dx.doi.org/10.20517/2394-4722.2020.106

growth factors, inflammation) and exogenous (e.g., radiation, chemical carcinogens, viruses, smoking, lack
of exercise, nutrient imbalance) risk factors, and typically long latency periods [273] . Further, cause-effect
relationships are often nebulous.

In the context of chemoprevention, it is likely that dietary phytochemicals currently play an important role
in cancer reduction or delay, but that role is difficult to quantify in a direct manner. Daily consumption
varies, as does the phytochemical content of the foods consumed. For a more predictable response,
especially for individuals at high risk for developing malignancies, a cocktail of chemopreventive agents
[8]
would be preferred . Development of such a cocktail needs to take into account the pleiotropic activities of
typical chemopreventive agents, as demonstrated by those described in this review and elsewhere. On one
hand, pleiotropic responses are considered a distinct advantage. On the other hand, the creation of a proper
preparation becomes a daunting task as a result of complexity. However, unique tools are now available
that can be put to use. For example, with agents know to function in a chemopreventive capacity, we can
take into account novel pathways uncovered utilizing primary -omics data (e.g., genomics, proteomics,
metabolomics) or data mining with publicly accessible biological data repositories (e.g., ChEMBL,
PubChem).

Consider resveratrol as an example. Based on literature reports describing individual actions of this
compound, we input human target proteins listed in ChEMBL (accessed on August 25 2020) [274] on STRING
(accessed on August 25 2020) [275] . As shown in Figure 9, the gene list with network edges is visualized with
enriched pathways (e.g., neuroactive ligand-receptor interaction, calcium signaling pathway, nitrogen
metabolism, serotonergic synapse, cAMP signaling pathway). Clearly, this is a more realistic view of the
action of resveratrol, relative to thinking of it as simply inhibiting or stimulating factor x, y or z. Now, if
we consider a second chemopreventive agent, and the network of factors modulated by that agent, and
overlay the two individual networks, it is easy to perceive the complexity of the actual response leading to a
chemopreventive response.

There is little doubt that the intrinsic response of a mammal exposed to a chemopreventive agent correlates
to some extent with the theoretical response shown in Figure 9. As an example, an area of great interest
for our group is the potential effect of grapes on health [276] , and the corresponding mechanisms. In a recent
study (unpublished) in which mice were provided diets with or without whole grape supplementation, RNA
expression data were examined. As shown in Figure 10, remarkable alterations were observed that would
likely relate to some of the beneficial properties. There is little doubt this modulation of genetic expression
results from the action of phytochemicals contained within the grape. Grapes have received great notoriety
for being a primary dietary source of resveratrol but, in actual fact, whole grapes contain over 1,600
[34]
phytochemicals . Thus, it is perhaps not surprising that such a profound effect on genetic expression was
observed. This provides a good illustration of the complexity of a real-life response and accentuates the
naivety of one drug-one target philosophy.

Indirectness
As noted above, the low bioavailability of phytochemicals may lead to discrepancies in effective doses
observed with in vitro models but required for in vivo responses. For example, the oral bioavailability of
resveratrol is reported as under 1% due to rapid metabolism in the intestine and liver [277] . As exemplified
in Figure 11, this has led to the exploration of technology designed to enhance bioavailability. Here, a map
was created based on bibliographic data (co-occurrence) of “resveratrol” from Web of Science, and words
such as “drug-delivery” and “encapsulation”, and highlighting using VOSviewer [278] .

Of course, metabolism of chemopreventive agents may have a major influence on efficacy. Several major
metabolites derived from the chemopreventive agents described herein are shown in Figure 12. In some