INHIBITION OF MICROSOMAL TRIACYLGLYCERIDE TRANSFER PROTEIN (MTP) BY LOMITAPIDE FAVORS TUMOR GROWTH IN MICE

COMANZO, CG; VERA, MC; LUCCI, A; HEIT-BARBINI, FJ; LORENZETTI, MF; FERRETTI, AC; CEBALLOS, MP; CARRILLO, MC; ALVAREZ, ML; QUIROGA, AD

Congreso; Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2021

Microsomaltriacylglycerol transfer protein (MTP) locates in the lumen of the endoplasmicreticulum and participates in the secretion of lipids from the liver as verylow-density lipoproteins (VLDL). The MTP inhibitor lomitapide binds directly toMTP inhibiting the synthesis of VLDL in the liver. The objective of thiswork was to study the effect of MTP inhibition on tumor growth. Adult male Balb/cnude mice were subjected to a xenograft model where Huh7 cells (5x106/mouse)were injected subcutaneously into the right flank of mice. After 4 days, micewere divided into 2 groups. Control group received vehicle (methylcellulose, gavage)and another group received 5 mg/kg bw/day lomitapide (gavage) for 15 days.Tumors were monitored using a caliper and volumes were estimated based on theformula “1/2 x l x w x h”. At the end, mice were sacrificed, and tumors excisedand weighed. Lomitapide-treated mice showed higher tumor volume and weight (2-fold)than control mice. Plasma levels of triacylglycerol and cholesterol weredecreased (-30%, and -40%, respectively) in lomitapide-treated mice compared tocontrol mice. Tumor histology showed no differences between groups on tissuearchitecture; however, lomitapide-treated mice presented with accumulation ofcytosolic lipid droplets. Analysis of proliferation by immunoblotting in total tumorhomogenates showed that lomitapide-treated mice presented with increasedexpression of proliferation cell nuclear antigen (PCNA) (+58%). In line,positive Ki-67-stained nuclei were increased in tumor sections fromlomitapide-treated mice. Conclusion: these studies demonstrate that MTP inhibition,blocking lipid secretion from the liver, could lead to increased tumor growth,and represent the first steps in the evaluation of the role of MTP in cancerdevelopment.