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Mel928 mice but remained unaffected in ß-catenin-
inactivated Mel1011 mice (33). Swiss albino mice were
utilized in one study where the anti-proliferative potential
of hesperetin (HSP) was investigated against
benzo(a)pyrene induced lung carcinogenesis. Pre- and
post-treatment with HSP alleviated Lipid peroxidation,
increased the level of antioxidants and decreased the
expression of NF-?B, PCNA and CYP1A1 (34). Luteolin
is a flavone that is found in a number of plant foods and is
thought to possess anti-cancer activity. Cook et al (2016)
demonstrated the ability of luteolin to suppress progestin-
accelerated mammary tumors. Both low (1 mg/kg) and
high (25 mg/kg) doses of luteolin considerably reduced
progestin-dependent upsurges in tumor prevalance, while
increasing tumor inactivity and decreasing the incidence of
large (>300 mm3) mammary tumors. Immuno
histochemical examination of tumor tissues showed that at
all concentrations levels of VEGF were considerably
reduced within the tumors (35). Chromatin acetylation is
linked with epigenetics that play a crucial role in how
people respond to drugs with relevance to gene expression
in normal and diseased conditions. Luteolin, a flavonol,
was found to inhibit this acetylation. The underlying
mechanism was determined to be the competitive binding
of luteolin to the acetyl CoA binding that inhibited p300
acetyltransferase. Effects of luteolin were seen at multiple
levels i.e. at the level of gene expression as well as at the methanol, chloroform and hexane on three different cell
level of miRNA processing. Tumor model of head and
neck squamous cell carcinoma (HNSCC) was used. This
xenografted model was treated with luteolin which led to a
reduction in the size of the tumor within 4 weeks along
with a decrease in the acetylation of histones (36).
3.3. Anti-oxidant effects
Anti-oxidants regulate the cellular levels of reactive
oxygen species thereby preventing or reducing oxidative
damage. Oxidative stress is the underlying cause for a
number of diseases including cancer. Irregular levels of
free radicals generated inside a cell can activate a number
of signaling cascades that lead to cell-proliferation, cell
cycle progression, inflammation and thus cancer.
Flavonoids have been known to have anti-oxidant activity
whereby they exert a protective effect on cells. A number
of mechanisms are employed by flavonoids by which they
reduce or prevent oxidative damage.
1. Direct scavenging of ROS.
2. Inhibition of superoxide anion production by
inhibiting oxidases.
3. Activation of anti-oxidant enzymes.
4. Chelation of free metals; involved in oxygen
metabolism.
5. Alleviation of oxidative stress caused by nitric oxide
(37).
3.3.1. In vitro studies
In a recent study published in the journal of
photochemistry and photobiology, anti-oxidant activity of
extracts from Galinsoga species was determined. The anti-
300
Ebtesam A Al-Suhaimi et al.
oxidant activity was examined by determining the
scavenging property of these species. ROS scavenging is
one of the mechanisms by which flavanoids exert their
anti-oxidant activity. This activity was determined against
two radicals generated in cell-free systems; O2- and
H2O2. It was seen that ethanolic extracts from the herb
exerted cytotoxic effects while the aqueous extracts
exerted protective effects by inhibiting ROS generation.
The aqueous extracts can therefore be labeled as effective
photoprotectors (38). In a similar study conducted by Sung
et al (2015), free-radical scavenging assays were used to
determine the anti-oxidant activity of a perennial herb,
Humulus japonicas. Extracts from this herb contain a
number of bioactive compounds comprising luteolin,
luteolin 7-glycoside, quercetin and quercitrin which
effectively caused scavenging of ROS in in vitro and
intracellular systems. Furthermore, experiments also
demonstrated the upregulation of longevity-related
proteins, sirtuin 1 and AMP-activated protein kinase. Thus
it is safe to conclude that these flavanoids can be used as
effective anti-aging and anti-oxidant compounds (39).
Ashraf et al (2016), demonstrated the antioxidant
activity of three extracts of Psidium guajava leaf;
lines (KBM5, SCC4 and U266). The hexane extract
completely inhibited activation of TNF-a and Nf-kb
activation in KBM5 cells and hence had antitumor and
cytotoxic activity. All the extracts had different phenolic
and flavonoid contents (40).
3.3.2. In vivo studies
Animal models have also been used to further
determine the protective activity of different flavonoids
although present in vivo studies are very limited. Wedelia
chinensis is a traditional herb known to have
hepatoprotective properties. This herb was seen to have
neuroprotective effects in mice models by inhibiting
oxidative stress- induced damage. Extracts from this herb
contain luteolin that has been shown to have anti-cancer
properties in multiple studies (41).
Drug resistance during chemotherapy is one of the
many hurdles that lead to poor prognosis in cancer
patients. Isorhamnetin (IH), which is a metabolite of
quercitin, was evaluated for its attenuating effect against
chemoresistance. IH was administered along with
capecitabine to enhance its efficacy in gastric cancer. Nude
mice were used as tumor models. The results showed that
IH enhanced the apoptotic effects of capecitabine and
inhibited activation of the transcription factor Nf-kB.
Whether administered alone or together with capecitabine,
it showed anti-tumor activity and negatively regulated Nf-
kB and various other oncogenic biomarkers (42).
4. CONCLUSION
Many plant-derived and natural products are being
tested for their anti-cancer activities. Several of these
agents are in clinical trials all over the world such as taxol,
vinblastine, vincristine, etoposide etc (14). Other
flavonoids that show great promise include quercitin,
@Real Academia Nacional de Farmacia. Spain