Resveratrol induced inhibition of cholangiocarcinoma cell growth is transglutaminase dependent

INTRODUCTION/OBJECTIVES: Cholangiocarcinoma is a tumour with a poor prognosis. An efficient therapy is unavailable in unoperable patients and new drugs are widely requested. Resveratrol (RES) is a natural molecule with a well known anticancer effect proved on different tumour cell lines. Previous studies demonstrated the cytotoxic effect of RES on cholangiocarcinoma cell cultures [1] and the related increase of transglutaminase type 2 (TG2), which is involved in carcinogenesis and apoptosis. AIMS & METHODS: Aim of the present study was to evaluate if the cytotoxic effect of RES on cholangiocarcinoma cell lines could be abolished by TG inhibition. Cholangiocarcinoma cell lines (SK-CHA-1 and MZ-CHA-1), growth in a three dimensional cell culture systems, have been treated for 72 hours with RES (32, 64 microM) alone or combined with three different TG2 inhibitors: cystamine and the selective inhibitors B003 and T101. At the end of the treatments we investigated: (1) cells viability (clonigenic test); (2) cell morphology with light microscopy on histological sections and electron microscopy (TEM); 3) TG2 activity (colorimetric technique). RESULTS: RES treatment induced a significant inhibition of cell growth (90% and 62% vs 100% controls). The cotreatement RES/TG2 inhibitors prevented these growth inhibition in both cell lines; the cell growth for MZ-CHA-1 at higher dose of RES was respectively (cystammine, B003 and T101) 50%, 60% and 90% vs. 100% controls; for SK-CHA-1 (cystammine, B003 and T101) was 55%, 60% and 80% vs. 100% controls. Histological sections and TEM results demonstrated a partial protection with both cystammine and B003/T101 inhibitors. The normalization of cell growth was associated to an inhibition of TG2 activity both in MZ-CHA-1 (60% with cystamine, 80% with B003 and 90% with T101 vs. 100% controls) and SK-CHA-1 (20% with cystammine, 40% with B003 and 60% with T101 vs. 100% controls). CONCLUSION: Our data demonstrated that the cytotoxic effect of RES in SK-CHA-1 and MZ-CHA-1 is TG2 mediated. REFERENCE(S): [1] Roncoroni et al. Liver Int. 2008;10:1426−36. Disclosure of Interest: None Declared.