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Yeger et al. J Cancer Metastasis Treat 2020;6:26 I http://dx.doi.org/10.20517/2394-4722.2020.61 Page 5 of 16

to exploit the anti-tumor properties of SFN in combination with targeting of carbonic anhydrase (CA)
with acetazolamide, a pan CA inhibitor to perturb the pH regulation necessary for metastatic progression.
Results in vitro and in xenograft models showed a potent anti-tumor inhibition of growth and survival.
Whether this combination could similarly inhibit other cancers has yet to be explored. Our studies also
raised the possibility that the Nrf2-Keap1 pathway might actually be functionally deficient in certain
[35]
cancers thereby negating the presumed cancer chemoprotection effect . Whether this happens to be the
more general case in cancer patients still has to be determined but the low plasma concentrations exhibited
by phytochemicals may actually limit or negate tumor cell chemoprotection. An additional interesting
aspect revolves around whether Nrf2 activating compounds like SFN could target senescent cancer cells, a
[45]
[45]
potential nidus for metastasis . Malavolta et al. studied 15 Nrf2 activating compounds including ITCs
in the context of adjuvant therapy since these could display senolytic activity.
The growing evidence for ITCs as potent anticancer agents has placed greater recognition on SFN (e.g.,
being prevalent in broccoli and cabbage, and highly consumed) but it invites speculation that the MedDiet
might be advantageous since a number of potent anticancer agents could act cooperatively in all phases of
the neoplastic process. It should be noted that a complexity of ITCs are ingested in the MedDiet or other
phytochemical diets. The question in terms of cancer prevention is whether dietary factors such as these
are introduced in sufficient amounts during development of the fetus, as sourced from the mother, or
only appear later in life in the diet, to be maximally beneficial. Phytochemicals with epigenetic modifier
properties, such as ITCs, could help to counter environmental toxins exposed to the developing fetus
[46]
and prenatally . There is indeed the caveat that this ITC family of dietary plants, for various reasons
(e.g., bitterness, pungency), is often voiced as not favored by or agreeing with children and even adults
[47]
due to digestive disturbances . However, it should be recognized that other, less known members of the
cruciferous family are indeed popular and are regularly consumed at higher amounts, for example, in diets
[48]
in Asia (in cooked form) . Thus one would need to determine how specific ITCs could be otherwise
administered to achieve the greatest therapeutic benefit.

The essential information on ITCs can be viewed as follows. The three key ITCs, SFN, PEITC, and BITC,
are generated from glucosinolates (b-thioglucoside N-hydroxysulfates) by the enzyme myrosinase that
is located on the external surface of plant cellsthat becomesactivated and is exposed to the substrates
[49]
after mastication and cooking or insect damage. ITCs are particularly active via thiocarbamoylation .
Many phytochemicals exhibit both anti-oxidant and pro-oxidant activities dependent on dose and thus
phytochemicals via reactive oxygen species (ROS) induction and in combination with chemotherapeutics
compromises tumor cell survival or can be chemopreventive . In addition, ITCs like PEITC can tie up
[50]
glutathione (GSH) thereby raising ROS levels that can compromise tumor cell survival and in particular
cancer stem cells (CSCs) . Liskova et al. having gleaned the literature emphasize the significant
[51]
[52]
anti-cancer effects of dietary phytochemicals on CSCs in a wide range of cancer types via influencing
multiple signaling mechanisms. Targeting of CSCs speaks to the ability to suppress tumor progression
from first initiation through malignant progression towards metastasis. Elimination of CSCs or tumor
initiating cells would therefore constitute the ideal targets in chemoprevention and anti-tumor targeting
during progression. There are documented studies showing targeting of tumor stem cells with good
evidence [38,40,43,53] . Furthermore, considering all the hallmark features of cancer originally elaborated by
[55]
[54]
Hanahan and Weinberg and now reviewed and expanded on by Girotti et al. , who describe how
galectins can affect tumor progression, it is obvious that ITCs can have a significant impact on all of
[56]
these, including galectins . Thus it is not surprising that there is a building literature on the cancer
chemoprevention and anti-tumor progression by ITCs.

ITCs are metabolized in the liver by the mercapturic acid pathway and thereafter eliminated in the urine
being detected after consumption of glucosinolates. From the perspective of elimination it is interesting to