The sirtuins inhibitor cambinol reverses sorafenib resistance in human hepatocellular carcinoma HepG2 cells

DELPRATO, CB; FERRETTI, AC; QUIROGA, AD; CARRILLO, MC; LIVORE, VI; LUCCI, A; ALVAREZ, ML; CEBALLOS, MP; CARMELI BARBERIS, E; COMANZO, CG; MOTTINO, AD

Congreso; SAFIS Reunión anual 2019; 2019

Sorafenib (SFB) is the only approved drug forhepatocellular carcinoma (HCC) treatment but it onlyprolongs patients? median survival by nearly 3 months.The main reason underlying the impaired sensitivity to SFBis multidrug resistance (MDR). MDR often results fromupregulation of ABC transporters, like P-glycoprotein (Pgp)and multidrug resistance-associated protein 3 (MRP3).Sirtuins 1 and 2 (SIRTs1/2) are overexpressed in HCC andare associated with tumoral progression and MDR.Previous results from our group showed that the SIRTs1/2inhibitor cambinol (CAMB) diminished P-gp and MRP3expression in HepG2 cells and exacerbated the effects ofSFB on cellular viability and migration in 2D and 3Dcultures of these cells. Aim: to analyze whether SIRTs1/2activities blockage overcomes MDR during SFB treatment.Methods: 2D and 3D cultures of the HepG2 cell line weretreated for 72 h with SFB (2 μM) in presence or absence ofCAMB (50 μM). Proliferation (2D: PCNA-western blot; 3D:Ki67-immunofluorescence), apoptosis (2D and 3D:CellEventCaspase 3/7 reagent), invasion (2D: transwell assay) and ABC expression (2D: P-gp and MRP3-westernblot) were assayed. Results: In 2D and 3D cultures, cellstreated with SFB and CAMB showed a greater fall incellular proliferation (2D: SBF -17%, SFB+CAMB -98%*#)and presented with more apoptosis than cells treated withSFB alone. In 2D cultures, treatment with SFB and CAMBdiminished invasion compared to SFB treatment (SBF -70%*, SFB+CAMB -85%*#). Whereas SFB induced ABCexpression in 2D cultures (P-gp: +154*, MRP3: +92*)treatment with CAMB+SFB reduced ABC protein levels (Pgp:-50*#, MRP3: -44*#) compared to control cells.*p