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

Souad Bousserouel, Gaetan Bour, Henriette Kauntz, Francine Gossé, Jacques Marescaux, Francis Raul
Anticancer Research 2012, 32 (7): 2455-62

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.

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