**Background**
Familial hypercholesterolemia and various malignancies, including colorectal cancer and melanoma, present significant challenges in clinical medicine due to their complex metabolic and signaling pathways. The microsomal triglyceride transfer protein (MTP) and the mechanistic target of rapamycin complex 1 (mTORC1) are critical regulators of lipid metabolism and cell growth, respectively. Dysregulation of these targets often leads to elevated plasma LDL levels or uncontrolled tumor proliferation. Furthermore, neuroinflammation and oxidative stress play pivotal roles in the progression of cerebral ischemia/reperfusion injury. Given the need for agents that can modulate these diverse pathways, there is significant research interest in compounds with multi-target activity. In this context, we will introduce a versatile inhibitor – Lomitapide.
**Definition**
Lomitapide mesylate is an orally active MTP inhibitor and a selective mTORC1 inhibitor that exhibits lipid-lowering activity, blood-brain barrier (BBB) permeability, and HDAC inhibitory properties.
**In Vitro and In Vivo Studies**
According to the Lomitapide description, this compound acts as an ATP-competitive inhibitor of mTORC1, inducing AMPK-independent autophagic cell death. In terms of Lomitapide in vitro activity, Lomitapide mesylate (5 μM; 48 h) inhibits the proliferation of human HCT116, HT29, and SW480 colorectal cancer cells by reducing colony formation. It further induces autophagic cell death in HCT116 and HT29 cells (5 μM; 24 h), a process that can be reversed by autophagy inhibition. In patient-derived colorectal cancer organoids (CRC-01 and CRC-02), it potently inhibits growth (5-20 μM; 48-72 h), showing superior efficacy compared to 5-FU. Additionally, it provides neuroprotection by improving the survival rate of OGD-injured Neuro-2a cells and primary mouse cortical neurons (0.01-1 μM; 24 h) in a concentration-dependent manner.
Lomitapide in vivo studies demonstrate its broad therapeutic potential. In BALB/c nude mice, Lomitapide (10-50 mg/kg; i.p.; every 2 days for 10 days) potently inhibits colorectal cancer xenografts; at 20 mg/kg, HT29 tumor volume is reduced to 38% of the control. In C57B6/N mice, it inhibits MC38 colorectal cancer and B16-F10 melanoma growth (20 mg/kg; i.p.) while increasing CD8+ T cell infiltration. For neurological research, Lomitapide (0.5 mg/kg; p.o.; daily for 14 days) improves neurological function and reduces neuronal tissue loss by 41.05% in MCAO-induced ischemic stroke models. Furthermore, in obese LDLr−/− mice, oral administration (1 mg/kg/day; 2 weeks) improves cardiovascular function and reduces atherosclerotic plaque area. In conclusion, Lomitapide is a multi-functional agent that promotes Lomitapide Autophagy and inhibits lipid secretion, making it a valuable tool for cancer, stroke, and hypercholesterolemia research.
Keywords
Lomitapide, 202914-84-9, AEGR-733, BMS-201038, AEGR733, AEGR 733, BMS201038, BMS 201038, Microsomal Triglyceride Transfer Protein (MTP), mTOR, LDLR, Autophagy, Apoptosis, Mammalian target of Rapamycin, Low-density lipoprotein receptor
References
[1] Lee B, et al. Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR. Cell Death Dis. 2022;13(7):603. Published 2022 Jul 12.
[2] Zheng Y, et al. Lomitapide ameliorates middle cerebral artery occlusion-induced cerebral ischemia/reperfusion injury by promoting neuronal autophagy and inhibiting microglial migration. CNS Neurosci Ther. 2022;28(12):2183-2194.
[3] Munkhsaikhan U, et al. The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr-/- Mice with Obesity. Antioxidants (Basel). 2023;12(6):1287. Published 2023 Jun 16.
[4] Won JI, et al. Balancing Low-density Lipoprotein Cholesterol Reduction and Hepatotoxicity With Lomitapide Mesylate and Mipomersen in Patients With Homozygous Familial Hypercholesterolemia. Rev Cardiovasc Med. 2017;18(1):21-28.