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Page 8 of 36 Dave et al. J Cancer Metastasis Treat 2020;6:46 I http://dx.doi.org/10.20517/2394-4722.2020.106

molecules. The situation is complicated because JNK1 and JNK2 have opposite effects in relation to cancer
cell survival. JNK1 promotes apoptosis while JNK 2 promotes cancer cell survival. The expression of p53 is
[91]
negatively regulated by JNK1 and positively regulated by JNK2 . EGCG attenuated reduced expression of
JNK1 and oxidative damage and, at the same time, inhibited JNK2, thereby augmenting apoptotic signaling
in cancer cells [87,92-94] .

p38/MAPK signaling pathway.
p38/MAPK is a third major signaling cascade in MAPK, playing a major role in controlling the process of
apoptosis. Activation occurs by several environmental factors such as stress and inflammatory cytokines.
[95]
p38 activates several downstream kinases that induce apoptosis . EGCG increases p38 levels and thereby
inhibits growth in leukemic cells, HCC cells, and U373MG cells [94,96,97] .

SULFORAPHANE
Chemical and pharmacological properties
Sulforaphane (1-isothiocyanato-4-methylsulfinylbutane) is an aliphatic hydrocarbon that is the major by-
[98]
product obtained during the hydrolysis of glucoraphanin . It was isolated in 1947 from radish. Later,
glucoraphanin was found to be present in larger quantities in cruciferous vegetables such as cauliflower,
[99]
broccoli, Brussel sprouts, and cabbage . It is generally found in broccoli and broccoli sprouts, yielding the
highest concentrations found in any plant source [100] . Broccoli and other cruciferous vegetables are widely
consumed throughout the world for various health benefits.

Hydrolysis of glucoraphanin occurs due to disruption of the plant cell and the subsequent activity of the
intrinsic enzyme myrosinase. Sulforaphane is not heat stable, but greater stability is retained when exposed
to light and acidic pH levels, rendering the compound useful under gastric pH conditions [99-101] . The
presence of epithiospecifier protein (ESP) disrupts the process of glucoraphanin hydrolysis, reducing the
bioavailability of sulforaphane and sulforaphane nitrile, with the nitrile form being less active in its binding
to pharmacological targets [102] . Since ESP is temperature insensitive, heating the broccoli at 60 ºC decreases
the formation of sulforaphane nitrile [103] . Once absorbed, sulforaphane is conjugated with glutathione
and metabolized by the meracaptopurine pathway; it is then excreted as N-acetylcysteine conjugates [104] .
Pharmacokinetic studies have demonstrated that the peak plasma levels of sulforaphane are relatively high
after oral administration of broccoli, for 1.6 to 6 h. with 95% elimination after 12 h [105] . In clinical studies,
the plasma concentrations of sulforaphane following oral consumption of broccoli are in the range of 0.02-
0.2 µmol/L [106] . With animal models, the consumption of broccoli has been found to exhibit protection
against cancer [107] .

Sulforaphane has also exhibited protective properties in the central nervous system by activating nuclear
factor (erythroid derivative)-like 2 (Nrf2) and reducing oxidative stress and inflammation in nerve cells [108] .
Further, the compound shows insulin-sensitizing and hepatoprotective effects in rats fed a high fructose
diet [109] . Patients with type 2 diabetes treated with broccoli sprout powder (5 to 10 g for 4 weeks) showed
reduced serum glucose levels and improved insulin levels [110] . Patients with deregulated type 2 diabetes
treated with 5 g of broccoli extract along with metformin (500 mg to 3000 mg) showed reduced HbA1c
levels and there was a reduction in glucose production [111] . In healthy male individuals, cholesterol and LDL
cholesterol levels were reduced; in women, HDL cholesterol levels increased significantly after consumption
of 100 g of fresh broccoli sprouts for 1 week [112] .

Sulforaphane reduced levels of iNOS with lipopolysaccharide (LPS) activated macrophages in a mouse
model [113] . Anti-inflammatory properties were further demonstrated in another study conducted with mice
treated with sulforaphane; cytokine production was reduced in a concentration-dependent manner by
activating the Nrf2 pathway. T-cell proliferation was also significantly inhibited [114] .