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Page 6 of 16 Yeger et al. J Cancer Metastasis Treat 2020;6:26 I http://dx.doi.org/10.20517/2394-4722.2020.61
[57]
note that ITCs are promising chemopreventives for bladder cancer . In other words, routes of metabolism
and elimination may be key sites for their biological activity in certain cancers. Aside from these 3 main
natural compounds, more than 20 natural and synthetic ITCs have been studied for their anti-carcinogenic
potential and properties [25,58,59] . In clinical trials conducted or in progress on a variety of cancers, ITCs
[58]
are showing positive outcomes on different biological parameters . Importantly the efficacy has varied
considerably dependent upon the test system, target tissues, type of carcinogen involved, the particular
ITC, dose, and dosing regimen. In a limited series of experiments in humans, activation of a carcinogen
was blocked supporting the idea of chemoprevention. High performance liquid chromatography has
afforded a reliable means of measuring ITC levels and kinetics.

From the perspective that ITCs might be consumed during cancer therapy, and in trying to understand
normal tissue/organ chemoprotection, the following biochemical pathway has received great attention. The
ITCs are potent inducers of the phase 2 enzymes, the Nrf2-Keap1 pathway mentioned above, involved in
detoxification of carcinogens, mutagens and a larger variety of toxins constituting the protective system in
[60]
[39]
cells, both normal and cancerous . However, there is thinking that this complexly regulated pathway ,
being upregulated by ITCs, may counter chemotherapeutic efficacy compromising the therapeutic outcome.
[40]
On the other hand, the evidence that ITCs can potentiate the efficacy of chemotherapeutics , their rapid
metabolism and elimination may actually interfere with the Nrf2 pathway based detoxification scenario.

It is well recognized and known, that tumor cells can invoke other mechanisms of drug resistance of
greater impact. Also consider that ITCs have reliable documented broad effects on cell cycle progression,
proliferation, apoptosis, and multiple cell survival signaling pathways supporting interference in tumor
progression in many cancers and in a dose dependent manner. Concomitantly, the induction of phase 2
[39]
enzymes by ITCs may also play a significant role in protecting normal tissues against cytotoxics .

Epigenetics play a significant role in cancer. Relevant to epigenetic regulation, ITCs are weaker but still
[35]
effective inhibitors of histone deacetylases, histone deacetylases , and although changes in histone
[61]
acetylation may be minimal, some of their potency may involve modulation of cell activity epigenetically .
In fact, combinations of SFN (and likely other ITCs) with other phytochemicals (e.g., genistein) could
operate with enhanced epigenetic activity [62,63] and via mechanisms involving inhibition of non-coding
[64]
RNAs (e.g., miRNAs) . Since epigenetic therapy inhibits metastases by disruption of the metastatic
niche, i.e., the tumor microenvironment , ITCs may be advantageous at multiple steps in the malignant
[65]
process. In skin, evidence exists that ITCs can normalize epigenetic marks altered during tumorigenesis
[66]
while inhibiting melanoma growth and survival . PEITC also modulates epigenetic writers and erasers
[58]
to restrict tumor development . Regulation of the epigenetic machinery may be a major function of ITCs
in chemoprevention and perhaps chemoprotection of normal tissues. Whether the mechanism involves
favorably rebalancing miRNAs is still to be determined.

Interestingly, ITCs target mitochondria and the electron transport chain to provoke cancer cell-selective
death programming. ITCs incur mitochondrial disruption of electron transport generation to trigger
[67]
apoptosis as chemopreventives . The mechanism here for SFN is thought to be targeting critical
mitochondrial cysteine residues in complex III but also complex I-II by SFN; it should be noted that
ITCs (with the highly reactive R-N=C=S moiety) in general are reactive with accessible cysteine residues
in proteins, thus possibly able to inactivate multiple key signaling proteins favoring cancer growth
[68]
and survival . As a primary example, SFN suppresses the growth of the very aggressive glioblastoma
tumor cells, the stem-cell like spheroids (the CD133 fraction) and xenografts through multiple signaling
[69]
pathways, with a lessor effect on normal brain cells . This study also demonstrated it can cross the blood-
brain barrier and so may have versatility in enhancing other therapeutics. Despite this ability our own
xenograft studies did not show any toxicity to the mice and obviously higher consumption of cruciferous