Silibinin: Source, metabolism, bioavailability and anti-cancer efficacy

Silibinin: Source, metabolism, bioavailability and anti-cancer efficacy

The standardized milk thistle extract contains approximately 70–80% of the defined flavonoids and flavonolignans (together known as ‘silymarin’), and approximately 20–30% chemically undefined fractions, compromising mostly of polyphenols and aliphatic fatty acids (---). Silibinin is the main component of silymarin complex and constitutes about 50–60% of it depending upon the formulation [60]. Silymarin is considered to be primarily conjugated and excreted into bile and urine and appears to have minimal phase I metabolism; however, limited data exist suggesting the role for phase II metabolic pathways and transporters [61–63]. Pharmacokinetic analysis of silymarin (where silibinin is the major active constituent) given to healthy volunteers has revealed that flavonoids present therein are rapidly metabolized to their conjugates such as sulfates and glucuronides, and can be detected in the human plasma [61]. It is also observed that conjugated silibinin metabolites had slower elimination as compared to free silibinin [61]. Now it is confirmed that silibinin is composed of 1:1 mixture of two diastereoisomers silybin A and silybin B [60]. Recent metabolic studies illustrated that silybin B is more efficiently glucuronidated compared to silybin A suggesting a stereoselectivity in their metabolism [61].

Silibinin is known to have poor bioavailability because of two main reasons, namely it has multi-ring structure (Fig. 2) that is too large to be absorbed by simple diffusion and that silibinin has poor miscibility with oils and other lipids, severely limiting its ability to cross the lipid-rich outer membrane of the enterocytes of the small intestine [64]. Therefore, there have been several efforts to prepare silibinin formulations to increase its bioavailability [65–67]. In this regard, silibinin has been complexed with phosphatidylcholine, this formulation is known as ‘Silipide’ (trade name ‘Siliphos’). Pharmacokinetic studies in healthy subjects have clearly shown the higher absorption of silibinin in the plasma and liver from siliphos compare to conventional silibinin [65,68]. Siliphos tested in prostate cancer patients and colon cancer patients also revealed high plasma bioavailability [55,56,69]. Comparative analyses of two clinical studies revealed high bioavailability of silibinin in the colon tissue but a poor levels into prostate tissue [55,69], suggesting the organs specific differences in the silibinin bioavailability following oral administration. Recently, the bioavailability of silibinin was reported to be significantly enhanced when administered in beagle dogs as silibinin-nanosuspensions [67]. This study also suggests that uptake and bioavailability of silibinin could be further enhanced through altering the nanoparticle size [67]. Overall, recent efforts toward increasing the bioavailability of silibinin are promising and encouraging.

The anti-cancer efficacy of silibinin is clearly evident from the published reports against various cancers in last two decades, which were mainly through targeting proliferation, apoptosis, inflammation, angiogenesis and cancer cell metabolism (summarized in Table 1). Silibinin is known to activate cellular-check points and cyclin-dependent kinase inhibitors (CDKIs), decrease the levels of both cyclins and CDKs, and to induce strong cell cycle arrest in cancer cells [70–72]. Silibinin also targets CDK-CDKI interaction, CDK kinase activity, Rb phosphorylation, and E2Fs in cancer cells [70,71,73]. Silibinin treatment stimulates apoptotic machinery (both extrinsic and intrinsic) and induces apoptotic death in various cancer cells [74–78]. Silibinin has also been reported to possess remarkable anti-angiogenic efficacy through targeting VEGF, VEGF receptors and iNOS [79–81]. Additionally, silibinin is reported to target an array of cellular signaling pathways and molecules including EGFR, MAPKs, AP1, HIF-1α, STATs, PI3K/Akt, β-catenin, IGF-IGFBP3, NF-κB, COX2 etc; and these molecular alterations contribute toward most of silibinin’ biological effects [82–89]. Recent studies have clearly shown that silibinin also possesses strong anti-invasive and anti-metastatic efficacy against various cancers, and these studies along with mechanistic details are discussed next.