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Page 10 of 16 Yeger et al. J Cancer Metastasis Treat 2020;6:26 I http://dx.doi.org/10.20517/2394-4722.2020.61

Keeping hormetic effects in mind, and the fact that such compounds can accumulate in cells and tissues,
would bioavailability still remain a true physiological limitation?

As with many phytochemicals ingested daily over a lifetime, maintenance of a lower plasma concentration
and eliminating excess, may be of real benefit since ITCs are also beneficial for normal organ functions
[60]
as fully evident . What is of concern is whether humans would maintain dietary practices that could
provide the necessary amounts of phytochemicals, like the ITCs, to serve for chemoprevention and
chemoprotection. Furthermore, as the evidence for additive and synergistic positive effects amongst a
[70]
variety of phytochemicals is compelling , one would hope that ideal combinations of phytochemicals
could be uncovered to provide supplements that could be included in products acceptable to the general
populations. One could envision incorporating such combinations in everyday desirable foods sought by
most.

Finally, keeping an open mind, one might envision combining ITCs with other natural related compounds,
e.g., curcumin, showing potent anti-tumor and anti-inflammatory activity as well as having positive
physiological effects that could provide a better chemoprotective environment. In addition, in light of the
metabolic reprogramming of the cancer microenvironment [104] the widely used drug for treatment of type
2 diabetes (T2D), metformin, a biguinide, derived almost a century ago from parent compound galengin
found in French lilac, has shown anti-tumor effects perturbing glucose metabolism in tumor cells [105] . When
considering that hormesis also includes mitohormesis perhaps adding metformin (or a phytochemical
equivalent) to the ITCs regimen could prove more effect in targeting tumor evolution or progression in
the earliest stages. This of course is only speculative but it does invite supporting further research on this
subject. Another factor is that if ITCs from food have limiting bioavailability/absorption could this be
balanced out by the beneficial kinetics of hormesis? Since many phytochemicals operate with the kinetics
of hormesis, in order to keep the dosage within the positive optimal low dose range, it may be necessary to
obtain necessary pharmacokinetic information from acute, intermittent and chronic administration (i.e.,
ingestion). One might surmise that this strategy would not constitute a burden on lifestyle as many people
have their morning coffee (or tea, both with touted health benefits) with little thought to daily frequency.
Many folks are also cognizant of the antioxidant value of phytochemicals, however it should also be
recognized that phytochemicals operate as anti-cancer agents through multiple mechanisms [106] .

It would bode well for all global communities to re-examine their diets and realign them more effectively
with a more uniform country-wide distribution of foods that could attain the goal of improving health
in concert with increased longevity. As discussed before many regions of the world can identify diets
that constitute wholly or partially the basic components and endorse appropriate supplementations in a
cost effective form containing the ITCs, polyphenolics, and healthy fats found in vegetables and fruits.
Therefore, the MedDiet may emerge as a medical prescription able to win against unhealthy eating habits
from other areas of the globe [107] . A major global challenge is overriding the wave of obesity in many
cultures [108] with links to the growing rise in T2D [109] . Therefore it is reasonable to raise the progressive
idea of supplementing reasonably balanced diets with the beneficial compounds found in the MedDiet,
when bulk produced to lower costs, and deriving the optimal concentrations. Adding an optimal dose of
chemoprevention/chemoprotection to the morning coffee or tea, if pre-formulated and not altering taste,
etc., would not raise any concerns if proven beneficial. Addressing this aspect Yagishita et al. [110] reviewed
the current state of knowledge regarding the different aspects of formulations, bioavailability and efficacy and
[111]
what might be needed to implement a public health paradigm for global application. Quirante-Moya et al.
also question whether bioactive compounds from Brassica species are being studied in the right way given
the lack of solid clinical trial data thus far. Moreover, ITC containing plant species are present in cold and
hot climates thus permitting global acquisition and evaluation.