Leelamine (hydrochloride)

Leelamine hydrochloride is an orally active weakly basic amine that inhibits NPC1 and the androgen receptor AR-V7, and acts as a cannabinoid receptor agonist. Leelamine hydrochloride also functions as a lysosome affinity agent that blocks endocytosis, disrupts autophagic flux and cholesterol transport, thereby altering the RTK-AKT/STAT/MAPK signaling cascade. Leelamine hydrochloride induces cancer cell death and autophagosome accumulation, and can be used in research related to melanoma, castration-resistant prostate cancer and breast cancer^[1][2][3][4]. In Vitro:Leelamine hydrochloride (6, 10, 100 μM) potently inhibits the proliferation and induces apoptosis of UACC 903 and 1205 Lu metastatic melanoma cells, with IC₅₀ values of 1.35 μM and 1.93 μM for the two cell lines, respectively. Its mechanism of action involves disrupting cholesterol transport and inhibiting oncogenic signaling pathways^[1].
Leelamine hydrochloride (1, 2, 3, 4, 5 μM) induces dose-dependent apoptosis in MDA-MB-231, MCF-7 and SUM159 breast cancer cells without affecting normal MCF-10A mammary epithelial cells, and also inhibits the self-renewal of breast cancer stem cells^[1].
Leelamine hydrochloride (0.62-100 μmol/L; 72 h) potently kills UACC 903 and 1205 Lu melanoma cells, with IC₅₀ values of 1.35 μmol/L and 1.93 μmol/L, respectively; it shows weak activity against normal FF2441 fibroblasts, with an IC₅₀ of 8.91 μmol/L; its cytotoxic activity can be reversed by bafilomycin A1 or β-cyclodextrin^[2].
Leelamine hydrochloride (3, 5, 10 µmol/L; 24 h) induces caspase-independent cell death in UACC 903 and 1205 Lu melanoma cells at concentrations as low as 3 µmol/L, a process that is partially dependent on autophagic flux; BAX-knockout HCT116 cells exhibit increased resistance to it, whereas normal fibroblasts show reduced cell death activity at this concentration; this cell death can be blocked by vacuolar H⁺-ATPase inhibitors or cholesterol depletion via β-cyclodextrin^[3].
Leelamine hydrochloride (3.0-5.0 μmol/L; 24 h) dose-dependently inhibits autophagic flux in UACC 903 melanoma cells, which is confirmed by increased protein levels of p62 and LC3B following treatment with 3.0, 4.0, and 5.0 μmol/L for 24 h^[2].
Leelamine hydrochloride (3.0-5.0 μmol/L; 24 h) inhibits the PI3K/AKT, STAT3 and MAPK oncogenic signaling pathways in UACC 903 melanoma cells following 24 h of treatment at concentrations of 3.0, 4.0 and 5.0 μmol/L^[2].
Leelamine (3 µmol/L; 30-45 min) acts as a lysosome-targeting compound in UACC 903 melanoma cells, with an uptake rate of 60% within 30 minutes. At a concentration of 3 µmol/L, it reduces the uptake of LysoTracker Red DND-99, and its vacuolating activity is inhibited by vacuolar H⁺-ATPase inhibitors^[3]. In Vivo:Leelamine hydrochloride (80 mg/kg, administered via oral gavage) reduces the volume of melanoma xenografts in nude mice by 50%, inhibits tumor proliferation, and causes no obvious systemic toxicity^[1].
Leelamine hydrochloride (7.5 mg/kg; intraperitoneal injection; 5 times per week) inhibits the growth of orthotopic SUM159 breast cancer xenografts in female nude mice by 70% without obvious systemic toxicity^[1].
Leelamine hydrochloride (80 mg/kg; p.o.; daily; 3-4 weeks) inhibits tumor growth of xenografted melanoma in female athymic nu/nu mice with extremely low systemic toxicity^[2].
Leelamine hydrochloride (5-20 mg/kg) increases the activity of hepatic CYP2B enzyme by 4-fold in male mice and upregulates the protein level of CYP2B10^[1].