Microsomal triacylglycerol transfer protein (MTP) inhibition, by hypocholesterolemic drug lomitapide, favors tumor development

COMANZO, CARLA GABRIELA; VERA, MARINA CECILIA; LUCCI, ALVARO; HEIT BARBINI, FRANCISCO J.; SAMBLAS J; LORENZETTI, FLORENCIA; FERRETTI, ANABELA CECILIA; CEBALLOS, MARÍA PAULA; ALVAREZ, MARÍA DE LUJÁN; CARRILLO, MARÍA CRISTINA; QUIROGA, ARIEL DARÍO

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Congreso; REUNIÓN DE SOCIEDADES DE BIOCIENCIAS 2020. LXV Reunión Científica Anual de SAIC.; 2020

Microsomal triacylglycerol transfer protein (MTP) locates in the lumenof the endoplasmic reticulum and participates in the secretionof lipids from the liver as very low density lipoproteins. There is evidencethat MTP might be involved in other cellular processes, including the pathogenesis of different diseases; however, no studieswere performed yet to evaluate whether MTP plays a role in cancer.The MTP inhibitor lomitapide binds directly to MTP thereby inhibitingthe synthesis of triglyceride-rich VLDL in the liver. Therefore, the objectiveof this work was to study the effect of MTP inhibition on tumordevelopment. Adult male C57BL/6 mice were subjected to a modelof chemical hepatocarcinogenesis. Animals were randomly dividedinto two groups (5 mice/group). One group (Control) received vehicle(methylcellulose, gastric probe) and another group received5 mg/kg bw/day lomitapide (gastric probe) for 3 weeks. At the endof the treatment, mice were sacrificed, livers were excised andweighed and tumors on the liver surface were counted. After treatment,lomitapide-treated mice showed increased liver/body weightsratio (2-fold) and higher number of tumors (2-fold) than control mice.As expected, plasma levels of triacylglycerol and ApoB-100 weredecreased (-40% and -60%, respectively) in lomitapide-treated micecompared to control mice. Liver histology analysis showed no differencesbetween groups on tissue and tumor architecture; however,lomitapide-treated mice presented less remaining normal liver parenchyma.Conclusion: these studies represent the first steps in theevaluation of the role of MTP in cancer development, and demonstratethat MTP may be participating in tumor growth.