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were 31% and 69%, respectively. At the molecular level, the combination of indole-3-carbinol and silibinin
inhibited Akt and ERK activation and induced apoptosis [228] . Silibinin has also shown effects against cancer
stem cells (CSC) in lung cancer [229] . A model of acquired erlotinib resistance was established by growing
NSCLC cells with a TKI-sensitizing EGFR exon 19 deletion in the constant presence of high doses of
Erlotinib (Erlotinib-refractory PC-9/Erl-R cells). Treatment with silibinin (50-100 µg/mL) decreased
the amount of lung cancer spheres in this model. These results suggest the possibility of using silibinin
in combination with EGFR tyrosine kinase inhibitor Erlotinib to target CSC in EGFR-mutant NSCLC
patients [229] .

The anti-prostate cancer properties of silibinin have been investigated in various studies. The substance
has shown inhibition of androgen- and serum-stimulated PSA protein levels in LNCaP cells, and this is
[230]
associated with cell growth inhibition through G1 arrest in cell cycle progression . Treatment with 25 and
75 µg/mL of silibinin for 24 h showed 45% and 59% decreases in PSA secretion in the medium, respectively.
Silibinin has further shown up-regulation of insulin-like growth factor binding protein 3 expression and
suppression of androgen-independent prostate cancer (PC-3) cell proliferation [231] . With PC-3 cells in a
medium supplemented with 10% FBS, treatment with silibinin (2 and 20 µmol/L) reduced cell growth by
17.3% and 54%, respectively [231] .

Silibinin has been shown to suppress the adhesion and migration of human prostate adenocarcinoma (PC-3)
cells [232] , and the motility, migration, and invasion of ARCaPM prostate cancer cells [233] . However, the
response was weak with ARCaPM cells. When applied at a higher concentration (200 µmol/L), growth
inhibition was only 18.5% in ARCaPM cells, but in the case of LNCaP, PC-3 and DU145 cells, the growth
inhibition was found to be 48.7%, 60.0%, and 73.8%, respectively, after 48 hours of treatment. Moreover,
silibinin induced morphological reversal to the epithelial phenotype from epithelial-mesenchymal
transition (EMT), down-regulated MMP-2 and vimentin, and up-regulated cytokeratin-18. Also, silibinin
inhibited NF-κB p50 translocation by up-regulating I kappa B alpha (IκBα) protein, and down-regulating
the expression of two key EMT regulators, SLUG, and ZEB1 transcription factors [234] .

Several studies have demonstrated the activity of silibinin against colon cancer. Silibinin mediated apoptosis
in cultured human colorectal carcinoma LoVo cells, which was associated with high levels of cleaved PARP
and cleaved caspases (3 and 9). When LoVo cells were treated with silibinin (50-200 µmol/L) for 24 hours,
growth was reduced by 30%-49%. The substance also induced strong cell cycle arrest at the G1 phase, and
a minor although significant G2/M phase arrest, at the highest concentration tested. Moreover, silibinin
reduced the levels of cyclins (A, B1, D1 and D3), CDK1, CDK2, CDK4, and CDK6, and elevated the level
of CDKIs (p21 and p27) and phosphorylation of Rb protein [235] . Anti-angiogenic effects, such as a decrease
in inducible COX-1 and COX-2, NOS and NOS3, and VEGF and HIF-1α, were exhibited by silibinin [236] .
When administered along with TNF-related apoptosis-inducing agent (TRAIL), silibinin caused cell death
in primary tumor cells (SW480), as well as TRAIL-resistant metastatic cells (SW620). Finally, silibinin
induced up-regulation of death receptor 4 (DR4) and DR5, down-regulated the anti-apoptotic proteins
XIAP and Mcl-1, and synergistically activated the mitochondrial apoptotic pathway [237] [Figure 7].

LYCOPENE
Chemical properties lycopene
Lycopene is a lipophilic hydrocarbon carotenoid with red color due to a chromatophore with 11 conjugated
double bonds [238] . The antioxidant properties of lycopene derive from this conjugated polyene structure [239] .
Unlike α- and β-carotenes, lycopene is not provitamin A due to the absence of a β-ionone ring and its
acyclic structure [239] . Having been studied for many decades, lycopene is found in tomatoes, watermelon,
pink grapefruit, papaya, and other fruits [240] . Unlike other widely distributed carotenoids, however, lycopene
is mainly found in tomatoes and tomato products [241] . Unique structural and chemical features may
contribute to distinct biological properties [239] .