Lomitapide is an inhibitor of microsomal triglyceride transfer protein (MTTP), with an IC50 value of 8nM[1]. Lomitapide targets MTTP to block the assembly of apolipoprotein B (Apo B) lipoproteins in the liver and gut[2]. Lomitapide has been widely used as an anticancer agent to inhibit tumor growth and to develop novel combination therapies[3].
In vitro, Lomitapide significantly inhibited the proliferation of SW1990, AsPC-1 and BxPC-3 cells after 72 hours of treatment, with IC50 values of 5.689μM, 7.293μM and 6.962μM, respectively[4]. Treatment with 2.5μM Lomitapide for 48 hours significantly inhibited the viability of HCT116 cells, resulting in a decrease in intracellular ATP levels and an increase in ROS levels, and promoting autophagy in the cells[5]. Treatment with 2μM Lomitapide for 24 hours significantly reduced the permeability of the outer mitochondrial membrane in multiple myeloma (MM) cells and induced mitochondrial dysfunction[6].
In vivo, Lomitapide treatment via intraperitoneal injection at a dose of 20mg/kg (every other day for 10 days) significantly reduced HCT116 xenograft growth in mice without affecting body weight[7]. Oral administration of 0.5mg/kg of Lomitapide daily for 14 consecutive days can improve the neurological recovery of mice with middle cerebral artery occlusion (MCAO) and reduce the loss of neural tissue[8].
References:
[1] Sulsky R, Robl J A, Biller S A, et al. 5-Carboxamido-1, 3, 2-dioxaphosphorinanes, potent inhibitors of MTP[J]. Bioorganic & medicinal chemistry letters, 2004, 14(20): 5067-5070.
[2] Wu H T, Wu B X, Fang Z X, et al. Lomitapide repurposing for treatment of malignancies: A promising direction[J]. Heliyon, 2024, 10(12).
[3] Ivanova A, Wilson T M, Ghannad-Zadeh K, et al. Lomitapide enhances cytotoxic effects of temozolomide in chemotherapy-resistant glioblastoma[J]. JCI insight, 2025, 10(17): e186703.
[4] Wang Y, Zhang S, He H, et al. Repositioning Lomitapide to block ZDHHC5-dependant palmitoylation on SSTR5 leads to anti-proliferation effect in preclinical pancreatic cancer models[J]. Cell death discovery, 2023, 9(1): 60.
[5] Zuo Q, Liao L, Yao Z T, et al. Targeting PP2A with lomitapide suppresses colorectal tumorigenesis through the activation of AMPK/Beclin1-mediated autophagy[J]. Cancer Letters, 2021, 521: 281-293.
[6] Zhang H, Wang H, Hu Y, et al. Targeting PARP14 with lomitapide suppresses drug resistance through the activation of DRP1-induced mitophagy in multiple myeloma[J]. Cancer Letters, 2024, 588: 216802.
[7] Lee B, Park S J, Lee S, et al. Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR[J]. Cell death & disease, 2022, 13(7): 603.
[8] Zheng Y, Hu Y, Han Z, et al. Lomitapide ameliorates middle cerebral artery occlusion‐induced cerebral ischemia/reperfusion injury by promoting neuronal autophagy and inhibiting microglial migration[J]. CNS neuroscience & therapeutics, 2022, 28(12): 2183-2194.
Lomitapide是一种微粒体甘油三酯转移蛋白（MTTP）抑制剂，IC50值为8nM[1]。Lomitapide通过靶向MTTP阻断肝脏和肠道中载脂蛋白B脂蛋白(Apo B)的组装[2]。Lomitapide目前已作为抗癌剂广泛应用于抑制肿瘤生长及开发新型联合疗法[3]。
在体外，Lomitapide处理72小时能显著抑制SW1990、AsPC-1和BxPC-3细胞增殖，IC50值分别为5.689μM、7.293μM和6.962μM[4]。使用2.5μM的Lomitapide处理HCT116细胞48小时，可显著抑制细胞活力，降低细胞内ATP水平，提高ROS含量，并促进细胞自噬[5]。用2μM的Lomitapide处理多发性骨髓瘤(MM)细胞24小时，能显著降低线粒体外膜通透性并诱导线粒体功能障碍[6]。
在体内，隔天腹腔注射20mg/kg剂量的Lomitapide连续10天，可显著抑制HCT116移植瘤在小鼠体内的生长，且不影响体重[7]。连续14天每日口服0.5mg/kg剂量的Lomitapide，能改善大脑中动脉阻塞(MCAO)小鼠的神经功能恢复，并减少神经组织损失[8]。