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Page 4 of 16 Yeger et al. J Cancer Metastasis Treat 2020;6:26 I http://dx.doi.org/10.20517/2394-4722.2020.61
[20]
changes in dietary habits . In order to translate the MedDiet to a multiethnic population, for example in
Australia, there is a need for a consistent definition of the MedDiet to ensure the key elements are captured
[21]
and translated so that the translated MedDiet model retains authenticity . Translating the MedDiet to
non-Mediterranean populations with different cultural food habits and cultural customs has been discussed
[22]
as rather challenging .

On the other hand, there are other diets that are also more plant based and can be equally effective and
[23]
advantageous like the Jiangnan diet in China and the Japanese traditional (Washoku) diet characterized
by the high consumption of fish and soybean products and low consumption of animal fat and meat. This
diet uses the umami taste to enhance palatability . As vegetarian and vegan diets appear to be rising in
[24]
popularity one might envision a positive reversal in dietary trends going forward. However, as changing
dietary habits tends to be difficult to adapt in many ways we stress the necessity to identify key dietary
derived compounds that could be easily and cheaply integrated as inexpensive supplements into the most
basic of diets.

THE DIETARY CRUCIFEROUS FAMILY OF ITCS
The cruciferous family of plants, that provide ITCs, includes the brassica species (cabbage family) garden
cress, watercress, radish, white mustard and papaya. This class of compounds has been investigated for
anti-carcinogenic, chemoprotectant, chemopreventive, and anti-cancer activities, in vitro and in animal
models, over the past several decades. A number of excellent detailed reviews and perspectives have been
published [25-30] . Key members of the ITC family found in the diet, SFN, phenethylisothiocyanate (PEITC),
and benzyl isothiocyanate (BITC), show antitumor efficacy, perhaps selectively, against a variety of different
cancers [31] and thus have received the greatest attention. These authors have reviewed the molecular
mechanisms for individual ITCs and emphasized roles for nuclear factor (erythroid-derived 2)-like 2,
(Nrf2) and nuclear factor-kappa beta modulation. In addition, another common and widely studied ITC,
allylisothiocyanate (AITC) also possesses anti-inflammatory and antioxidant properties that can improve
oxidative stress in pathological processes . Singh et al. reviewed the key features of the ITC, erucin
[30]
[32]
(4-methylthio butyl isothiocyanate; 4-MTB-ITC) closely related to SFN, and studied in rodent models of
cancer, showing mechanisms of chemopreventive and anticancer effects including apoptosis and cell-cycle
arrest, and also enhancing the phase II metabolizing enzymes, suppressing phase I metabolizing enzymes,
with enhancement of Nrf-2 that leads to enhanced antioxidant activity.

The known basic structured compound of the ITC family, SFN, derived through digestion or other means,
has been well studied and demonstrated by many groups to possess chemopreventive and ant-tumor
activities [25,29,32-36] . The association with cancer chemoprevention has also been established in animal models
[27]
[3]
and minimally yet in humans . Metabolic phenotypes can have a modulatory role . For example, the
glutathione-S-transferase T1 phenotype in particular appears to be relevant in how humans physiologically
respond to ITCs. Not surprisingly, this speaks to the concept of metabolizer phenotypes for many
metabolites (and drugs) in the human population . Nevertheless, dissecting the mechanism of action
[37]
of the different ITCs has become an important area of investigation and their negative effects on several
[25]
key cancer survival and growth pathways have been documented showing commonalities . SFN itself
has been identified as a prime example of a compound that triggers the drug detoxification Nrf2-Keap1
(Kelch-like ECH-associated protein 1) pathway in cells [38,39] . As a result there is also the caveat that the SFN
[39]
induced Nrf2 pathway could protect tumor cells against cytotoxic chemotherapeutics . On the other hand,
there are several examples of drug potentiation published. Addition of SFN to taxanes enhanced the anti-
[40]
tumor efficacy against triple negative breast cancer . SFN can synergize with cisplatin to suppress human
[42]
ovarian cancer , and as a component with other anti-tumor phytochemicals . Studies from our lab have
[41]
noted the potent anticancer effects of SFN for both pediatric and adult cancers [35,43,44] . Our approach for
therapeutic targeting of several cancers (bronchial carcinoids, bladder cancer, and neuroblastoma) was