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Page 16 of 36 Dave et al. J Cancer Metastasis Treat 2020;6:46 I http://dx.doi.org/10.20517/2394-4722.2020.106

by targeting cancer stem cells [such as A549 and H2170 (NSCLC cell lines)], down-regulating cyclin D1
and increasing the expression of p21 [199] . There is also evidence of involvement of curcumin in suppressing
[200]
glioma growth and inducing apoptosis by AKT and signal regulated kinase pathway in U87-MG cells .
In T-cell acute leukemia malignant cells, curcumin causes de-phosphorylation of active AKT, FOXO, and
releases cytochrome c, which activates caspase-3. This leads to inhibition of cell proliferation [201] .

SILIBININ
Chemical properties of silibinin
Silibinin is a key constituent of silymarin, which is a polyphenolic flavonoid obtained from milk thistle
seeds [202] . It is constituted as two isomers, silybin A and silybin B, in the ratio of 1:1, functions as a
weak acid in aqueous form, and is especially stable in the presence of acids and unstable in a basic
environment [203] . Silibinin is a major component of the silymarin complex, constituting 50%-60%,
depending on the formulation [204] . Many studies have demonstrated that silibinin has strong antioxidant
properties, scavenging both reactive oxygen species and free radicals, which can lead to the enhancement
of cellular antioxidant defense mechanisms [205-209] . Notably, silibinin can affect cancer development by
various modes of action, including modulation of oxidative stress, proliferation, inflammation, metastasis,
and angiogenesis [210-212] . Some studies have indicated a beneficial effect on toxicity due to short- and long-
term exposure to radiation treatment and chemotherapy [213] .

Pharmacokinetics of silibinin
Silymarin is primarily conjugated and excreted into bile and urine and seems to undergo insignificant phase
I metabolism; inadequate data exist concerning the role for phase II metabolism and transporters [214,215] .
Silymarin (where silibinin is an active constitute) pharmacokinetic analysis was done with healthy
volunteers. There was rapid metabolism, forming conjugates such as glucuronides, that were detected in
plasma [214] . Also, it was found that conjugated silibinin metabolites are eliminated slowly as compared to
free silibinin [214] . Factors such as inefficient intestinal absorption, low water solubility, elevated metabolism,
and rapid excretion, significantly decrease the serum concentration of silibinin, thus reducing its ability
to reach target organs and consequently therapeutic efficiency is reduced [216-218] . There have been many
efforts to produce formulations to increase the bioavailability of silibinin [219,220] . For example, silibinin that
is complexed with phosphatidylcholine is known as “silipide”. In pharmacokinetic studies conducted with
healthy subjects, it was shown that silibinin derived from silipide has greater absorption in plasma and liver
as compared with conventional silibinin [221,222] . Silipide, when tested in cancer patients, demonstrated high
plasma bioavailability [223-225] . A comparative study revealed high bioavailability of silibinin in colon tissue
but relatively poor levels in prostate tissue [223-225] . This suggests organ specificity may be anticipated as a
result of bioavailability following oral administration.

Chemoprevention mechanism of silibinin
Several studies suggest that silibinin may be effective against lung cancer. Silibinin reduced the production
of matrix metalloproteinase-2 and urokinase-plasminogen activator when metastatic A549 lung cancer
cells were treated with different concentrations, up to 100 µmol/L [226] . Silibinin has been shown to
reduce the development of human NSCLC, such as large cell carcinoma cells (H1299 and H460) and
bronchioalveolar carcinoma cells (H322) [227] . Silibinin treatment of cultured cells (10-75 µmol/L) has been
shown to target cell-cycle progression leading to a G1 arrest and altered protein levels of cyclins (D1, D3,
and E), CDKIs (p18/INK4C, p21/Cip1, and p27/Kip1) and cyclin-dependent kinases (CDKs) [227] . Inhibitory
effects of silibinin (75 µmol/L) were shown in both a human large-cell lung cancer cell line and human
lung adenocarcinoma A549 cells [228] . A combination of silibinin and indole-3-carbinol showed greater anti-
proliferative effects than the single compounds alone. A549 cells, when treated with 100 µmol/L of indole
3-carbinol and 75 µmol/L of silibinin, or 200 µmol/L of indole-3-carbinol plus 75 µmol/L of silibinin, for
24 h, showed a reduction in proliferation by 40% and 62%, respectively. With H460 cells, the responses