Annonacin is a mitochondrial complex I inhibitor that induces features of tau pathology[1]. Annonacin elicits the redistribution of abnormally phosphorylated tau from neurites to cell bodies in striatal neuronal cultures and contributes to degenerative Caribbean atypical parkinsonism (CAP) by modulating the production of tau and α-synuclein pathogenic protein assemblies[2]. Annonacin has been widely used in preclinical models to regulate cellular energy metabolism and kill tumor cells[3].
In vitro, Annonacin treatment for 48 hours significantly inhibited the viability of ES2, A2780, IOSE-80, and liver MIHA cells, with IC50 values of 15.12µM, 10.21µM, 15.48µM, and 28.92µM, respectively[4]. Incubation with 10µg/ml Annonacin for 24 hours induced apoptosis in T24 cells, arrested the cells at the G1 phase, and markedly enhanced the expression of p21[5]. Treatment with 25nM Annonacin for 48 hours reduced the proliferation of LUHMES cells, leading to an increase in the mRNA expression of the tau protein 4R subtype and a decrease in the expression of the splicing factor SRSF2[6].
In vivo, Annonacin treatment via intraperitoneal injection at a dose of 50mg/kg/day for 21 days reduced tumor growth in the MCF-7 xenograft tumor mouse model, accompanied by decreased expression of ERα, cyclin D1, and Bcl-2 proteins[7]. Continuous subcutaneous injection of Annonacin at a dose of 9mg/kg/day for 3 consecutive days enhanced tau protein levels in the brains of R406W+/+ tau transgenic mice[8].
References:[1] Costa M F D, Rösler T W, Höglinger G U. Exploring the neuroprotective potential of Nrf2-pathway activators against annonacin toxicity[J]. Scientific reports, 2024, 14(1): 20123.
[2] González‐Lizárraga F, Boluda S, Hidalgo J R, et al. Protein coaggregation in Caribbean atypical parkinsonism: The contribution of annonacin[J]. Neuropathology and applied neurobiology, 2025, 51(4): e70026.
[3] das Chagas Lima N N, Faustino D C, Allahdadi K J, et al. Acetogenins from Annonaceae plants: potent antitumor and neurotoxic compounds[J]. PharmaNutrition, 2022, 20: 100295.
[4] He Y, Tong J, Li Z, et al. Anticancer and chemo-sensitizing effects of annonacin via p53-mediated DNA damage in ovarian cancer[J]. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2025, 1871(7): 167971.
[5] Yuan S S F, Chang H L, Chen H W, et al. Annonacin, a mono-tetrahydrofuran acetogenin, arrests cancer cells at the G1 phase and causes cytotoxicity in a Bax-and caspase-3-related pathway[J]. Life Sciences, 2003, 72(25): 2853-2861.
[6] Bruch J, Xu H, De Andrade A, et al. Mitochondrial complex 1 inhibition increases 4-repeat isoform tau by SRSF2 upregulation[J]. PloS one, 2014, 9(11): e113070.
[7] Ko Y M, Wu T Y, Wu Y C, et al. Annonacin induces cell cycle-dependent growth arrest and apoptosis in estrogen receptor-α-related pathways in MCF-7 cells[J]. Journal of ethnopharmacology, 2011, 137(3): 1283-1290.
[8] Yamada E S, Respondek G, Müssner S, et al. Annonacin, a natural lipophilic mitochondrial complex I inhibitor, increases phosphorylation of tau in the brain of FTDP-17 transgenic mice[J]. Experimental neurology, 2014, 253: 113-125.