EFFECT OF SIRTUIN 1 (SIRT1) INHIBITORS ON CELLULAR VIABILITY AND APOPTOSIS IN HEPATOCELLULAR CARCINOMA (HCC) CELL LINES. POSSIBLE ASSOCIATION WITH THE EXPRESSION OF ABC TRANSPORTERS

DECANDIDO, G; QUIROGA, AD; ALVAREZ, ML; PARODY, JP; LAMBERTUCCI, F; MOTTINO, AD; CARRILLO, MC; CEBALLOS, MP

Congreso; LXI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2016

Multidrug resistance (MDR) in patients with HCC frequentlyresults from upregulation of ABC transporters. SIRT1 deacetylaseis overexpressed in this pathology and is associated with tumoralprogression and MDR by inducing the expression of the ABCtransporter p-glycoprotein (p-gp). Inprevious studies we found adose dependent cytotoxic effect of the SIRT1 inhibitors Cambinol(Camb) and Ex527 (Ex) in HepG2 and Huh7 cell lines, with Huh7showing the highest response. Aim: to analyze if SIRT1 activityblockage could be beneficial during HCC therapy. Methods: HepG2and Huh7 cells were treated for 72 h with 50 μM Camb (Camb50)or 40 μM Ex (Ex40) and viability (MTT), apoptosis (FITC AnnexinV) and protein levels of p-gp and MRP3 (western blot) were assayed.Results: SIRT1 inhibitors significantly reduced viabilityonly in Huh7 cells (Camb50: -35%*, Ex40: - 7%*). Camb50 didnot modify apoptosis in HepG2 cells but significantly increasedearly (+65%*) and late (+45%*) apoptosis in Huh7 cells. Ex40induced early apoptosis in both cell lines (HepG2: +168%*, Huh7 :+118%*). Only Camb50 generated a significant fall in p-gp levels(-66%*) in HepG2 cells, whereas both drugs downregulated MRP3(Camb50: -40%*, Ex40: -37%*) in this cell line. In Huh7 cells,Ex40 significantly reduced MRP3 levels (-30%*) while Camb50significantly increased its expression (+135%*). Lastly, a significantraise was observed in p-gp levels with Camb50 (+711%*) andEx40 (+277%*) in Huh7. *p