Limonin (Synonyms: di-δ-lactone Limonoic Acid)

Limonin is a natural tetracyclic triterpenoid compound, which widely exists in Euodia rutaecarpa (Juss.) Benth., Phellodendron chinense Schneid., and Coptis chinensis Franch ^[1]. Limonin has pharmacological effects in anti-tumor, anti-inflammatory and analgesic, anti-bacterial and anti-virus, anti-oxidation, nerve protection, liver protection, and blood lipid regulation. Modern pharmacological effects indicate that limonin has value in the prevention and treatment of certain diseases, including cancer, enteritis, hepatitis, hemorrhoids, osteoporosis, obesity, anaphylactic reaction, and brain aging ^[2].

Limonin has an anti-hepatocarcinoma effect. In vitro, limonin inhibited the growth of hepatocellular carcinoma cell line (SMMC-7721) cells (IC50 = 24.42 μg/mL) in a concentration and time-dependent manner ^[3]. Limonin has certain cytotoxicity to human colon cancer (Caco-2) cells ^[4]. Limonin has a good antiproliferative effect on lung cancer cells A549 (IC50 = 82.5 uM) ^[5].

In vivo, limonin (200 mg/kg) diets inhibited cell proliferation and promoted apoptosis through suppressing the levels of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in azoxymethane (AOM)-injected rats, therefore, it was considered that limonin has the effect of inhibiting colon cancer ^[6]. Limonin (50 mg/kg) has excellent antioxidant and therapeutic effects on N-nitroethylenediamine (DEN)-induced hepatocarcinoma rats by suppressing lipid peroxidation (LPO) and oxidative stress-mediated free radicals generation, and through modulating antioxidants` defense mechanism ^[7]. Limonin significantly decreased the levels of tumor necrosis factor-α (TNF-α), interleukin (IL-1β and IL-6), and inhibited the expression of inflammatory factors in lipopolysaccharide (LPS)-induced acute lung injury mice ^[8].

References:
[1].Fan S, Zhang C, Luo T, et al. Limonin: A review of its pharmacology, toxicity, and pharmacokinetics[J]. Molecules, 2019, 24(20): 3679.
[2].Gualdani R, Cavalluzzi M M, Lentini G, et al. The chemistry and pharmacology of citrus limonoids[J]. Molecules, 2016, 21(11): 1530.
[3].Zhang J J, Luo G, He R L, et al. Inhibiting effects of limonin on human hepatocarcinoma cells SMMC-7721 in vitro[J]. Sichuan J. Physiolog. Sci, 2007, 29: 157-160.
[4].Qian P, Jin H W, Yang X W. New limonoids from Coptidis Rhizoma–Euodiae Fructus couple[J]. Journal of Asian natural products research, 2014, 16(4): 333-344.
[5].Bai Y, Jin X, Jia X, et al. Two new apotirucallane-type isomeric triterpenoids from the root bark of Dictamnus dasycarpus with their anti-proliferative activity[J]. Phytochemistry Letters, 2014, 10: 118-122.
[6].Vanamala J, Leonardi T, Patil B S, et al. Suppression of colon carcinogenesis by bioactive compounds in grapefruit[J]. Carcinogenesis, 2006, 27(6): 1257-1265.
[7].Langeswaran K, Kumar S G, Perumal S, et al. Limonin–A citrus limonoid, establish anticancer potential by stabilizing lipid peroxidation and antioxidant status against N-nitrosodiethylamine induced experimental hepatocellular carcinoma[J]. Biomedicine & Preventive Nutrition, 2013, 3(2): 165-171.
[8].WANG D, ZHANG H, FANG J, et al. Effects of limoninon on LPS-induced acute lung injury in mice[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(1): 8.