Silibinin inhibits tumor growth in a murine orthotopic hepatocarcinoma model and activates the TRAIL apoptotic signaling pathway.

AIM

The present study investigated the molecular mechanism of silibinin-induced antitumoral effects in hepatocarcinoma Hep-55.1C cells in vitro and in a hepatocarcinoma model in mice.

MATERIALS AND METHODS

Cell death was analyzed by flow cytometry. The genetic expression of apoptotic and inflammatory biomarkers was assessed by quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR). Orthotopic grafting of Hep-55.1C cells into the liver of C57BL/6J mice was performed, and tumor growth was followed by micro-computed imaging.

RESULTS

Silibinin activated the extrinsic apoptotic pathway in Hep55.1C cells, as attested by the up-regulation of TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL Death receptor 5 (DR5) transcripts, and by the activation of caspase-3 and -8. After grafting of Hep-55.1C cells into mouse liver, the oral administration of silibinin at 700 mg/kg body weight for four weeks caused a significant reduction of tumor growth, associated with the down-regulation of inflammatory components [matrix metalloproteinase -7 and -9, (MMP-7, MMP-9), Interleukin-1 beta (IL1β)], the up-regulation of apoptotic mediators (TRAIL, DR5), and caspase-3 activation.

CONCLUSION

Silibinin treatment exerted important anticarcinogenic effects, including the activation of TRAIL death receptor apoptotic signaling pathway in Hep-55.1C hepatocarcinoma cells, both in vitro and in hepatocarcinoma grafts in mice.