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glucopyranoside (Cy-g) in a dose-dependent manner by the activation of PKC and PI3K. Upon treating
HL-60 cells with Cy-g (200 µg/mL), differentiation characteristics were observed such as enhanced activity
of esterase, increased adhesion, and reduced expression of the oncogene c-Myc. When cells were treated
with PKC or PI3K inhibitors, the effect of differentiation induced by Cy-g was substantially decreased [152] .
Since the degree of differentiation correlates with the degree of tumor malignancy, it may be suggested
anthocyanins can act at the cancer formation stage by stimulating differentiation.

Anti-carcinogenic activities in the cancer development stage
Anthocyanins can induce apoptosis of cancer cells through the external death receptor pathway and the
internal mitochondrial pathway. It was determined that delphinidin could activate p38-FasL and the Bid
pathway, which is a pro-apoptosis protein that induces apoptosis with HL-60 cells, in a dose- and time-
dependent manner [153] . In vascular smooth muscle cells, delphinidin and cyanidin strongly inhibited the
expression of vascular endothelial growth factor (VEGF) (stimulated by platelet derived growth factor) by
repressing the JNK and p38-MAPK pathways [154] .

Pharmacological properties
Hydroxylation of nonreactive carbons is a major function of phase I cytochrome P450s and the mono-
oxygenase system [155] . Phase I hydroxylation of anthocyanins is noteworthy since hydroxyl groups
structurally distinguish this group of compounds. Even though flavonoids are reported to have low
bioavailability due to extensive metabolism, their metabolites may be present for a longer duration and
result in significant bioactivity. This can be the case with anthocyanins, since metabolites have been found
to retain basic structural characteristics, thereby preserving bioactivity [156,157] . The majority of the flavonoids
present in the urine and circulation as glycated, glucuronidated, sulfated, and methylated conjugates [158,159] .
Glucuronide conjugation is regarded as an important conjugation reaction in the metabolism of
flavonoid [158-162] . UDP-glucuronosyltransferases, which catalyzes the glucuronidation reaction, are observed
in high concentrations in the intestine, kidney, and liver [163,164] . However, in humans, following dietary
consumption, evidence suggests that the initial site for flavonoid glucuronidation is the intestine [159,165,166] .
Methylation is observed as the second major conjugation reaction of flavonoids [162] . O-Methylation is the
most common such reaction. Catechol-O-methyltransferase catalyzes O-methylation utilizing the cofactor
S-adenosyl methionine. The liver is a major organ responsible for methylation with the highest catechol-O-
methyltransferase activity [167] . The primary site of methylation is determined by the pattern of a flavonoid
ring structure. Some studies have shown low oral doses of quercetin in animals and humans undergo
extensive methylation [168] . Glycation or sulfation are common conjugation reactions that predominate
when low dose phenolic drugs are administered. Sulfotransferases are a small group of cytosolic enzymes
that are widely distributed in the body. They use phosphoadenosine-5’-phosphosulfate as a cofactor
and their recognized substrates include polyphenols (i.e., flavonoids), hydroxylamines, 4-nitrophenol,
iodothyronines, and phenols [168] .

Studies suggest that anthocyanins have very low bioavailability (< 1% in plasma), although some amount
has been found in the colonic tissues of patients, indicating the possibility of a local site of action [169,170] . It
is still unclear whether anthocyanins are effective against cancer in human beings and whether they can
function as metabolites or as parent molecules.

CURCUMIN
Chemical and pharmacological properties
Curcumin [(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is a yellow-colored
phytochemical obtained from Curcuma longa (turmeric), a member of the ginger family (Zingiberaceae).
It is commonly cultivated in the southwest Asia region and is popularly used as a spice for various
cuisines [171,172] . Curcumin is comprised of two o-methoxy phenolic rings which are connected by seven