STUDY OF THE EFFECT OF SIRTUINS 1 AND 2 INHIBITORS ON THE SURVIVAL AND MIGRATION OF HEPATOCELLULAR CARCINOMA CELLS UPON SORAFENIB TREATMENT CONDITIONS

ANGEL, A; COMANZO, CG; LIVORE, VI; LUCCI, A; FERRETTI, AC; QUIROGA, AD; ALVAREZ, ML; MOTTINO, AD; CARRILLO, MC; CEBALLOS, MP

Congreso; Sociedad Argentina de Investigaciones Clinicas; 2018

Sorafenib (SFB) is the only approved drug for hepatocellular carcinoma(HCC) treatment but it only prolongs patients? median survivalby nearly 3 months. The main reason underlying the impairedsensitivity to SFB is the multidrug resistance (MDR). Sirtuins 1 and2 (SIRTs1/2) are overexpressed in HCC and are associated withtumoral progression and MDR. Nowadays there is no second-linetreatment for patients who fail to respond to SFB therapy. Aim: to analyzewhether SIRTs1/2 activities blockage overcomes MDR duringSFB treatment. Methods: HepG2 and Huh7 cells were treated for72 h with SFB (2 μM) in presence or absence of the SIRTs1/2 inhibitorscambinol (Camb, 50 μM) or EX-527 (EX, 20 μM). Cell survival(2D culture: MTT, clonogenic assay, Annexin V-IP; 3D culture:spheroid growth delay and acid phosphatase assays) and migration(2D: wound healing; 3D: spheroid migration assay) were assayed.Results: In 2D cultures, cells treated with SFB and SIRTs1/2 inhibitorsshowed a greater fall in cellular viability (Huh7: SBF -24%*,SFB+CAMB -62%*#, SBF+EX -52%*#; **), number of colonies andcellular migration compared to cells treated with SFB alone. In thesame way, cells treated with SFB and SIRTs1/2 inhibitors presentedwith more apoptosis than cells treated with SFB alone (Huh7:SBF +202%*, SFB+CAMB +337%*#, SBF+EX +306%*#; **). In 3Dcultures, treatment with SFB and SIRTs1/2 inhibitors significantlydiminished spheroid growth (volume), viability and migration comparedto SFB treatment. 3D culture was less sensitive to drugs than2D culture. *p