MULTICELLULAR TUMOR SPHEROIDS (MCTS) AS AN IN VITRO MODEL FOR STUDYING SORAFENIB (SFB) RESISTANCE IN HEPATOCELLULAR CARCINOMA (HCC): EFFECT OF THE SIRTUINS 1/2 INHIBITOR EX-527 (EX) ON CELLULAR VIABILITY

PALMA NICOLÁS FRANCISCO; LIVORE, VERÓNICA INÉS; CHARES LAURA G; FERRETTI, ANABELLA, C; COMANZO, CARLA G; VERA, MARINA C; ALVAREZ, MARÍA DEL L.; MOTTINO, ALDO DOMINGO; CARRILLO, MARÍA CRISTINA; QUIROGA, ARIEL DARÍO; CEBALLOS MANCINI, MARÍA PAULA

Mar del Plata

Congreso; REUNIÓN ANUAL 2022 DE LA SOCIEDAD ARGENTINA DE FISIOLOGÍA (SAFIS); 2022

Sociedad Argentina de Fisiología

It is essential to count with more relevant preclinical models to studypossible chemotherapy strategies for HCC. Tumors are 3D structures and their inner stromal cells contribute to cancer progressionand chemoresistance (CR). MCTS composed of cancer and stroma cells provide reliable results in vitro since they mimic featuresof in vivo tumors. CR counteracts the efficacy of SFB, a first-linedrug used for HCC, and better therapies are still missing. Sirtuins1/2 promote cancer progression and CR. Aim: to study the effectof EX addition during SFB treatment in MCTS composed of Huh7or SFB-resistant Huh7 (Huh7-SR) cells together with stromal cells.Methods: Huh7-SR cells were established after incubating Huh7cells for 6 months with increasing doses of SFB. Resistance wasevaluated in 2D cultures (MTT; Western Blot). MCTS of Huh7 orHuh7-SR, endothelial (EA.hy926) and hepatic stellate (LX-2) cellswere obtained and treated for 72 h with different doses of SFB, EX,SFB+EX or DMSO (control group). Cell viability was studied (acidphosphatase assay) and IC50 and combination index (CI) valueswere determined (CompuSyn). Results and discussion: Huh7-SRcells presented with a higher IC50 value for SFB (6.7µM*) comparedto Huh7 cells (2.7µM) as well as more PCNA, cyclin D1, P-gp andMRP3 protein levels, confirming SFB resistance. SFB and EX reduced MCTS viability in a dose-dependent manner compared to theABSTRACTS 275control group. Huh7-SR-formed MCTS were more resistance to SFBthan Huh7-formed MCTS (IC50: 11µM* and 7µM, respectively). Different SFB+EX combinations decreased MCTS viability comparedto the individual treatments (synergistic effect; CI