Annonacin

The herbs of Annona glabra

Annonacin, a mono-tetrahydrofuran acetogenin, arrests cancer cells at the G1 phase and causes cytotoxicity in a Bax- and caspase-3-related pathway.[Pubmed:12697268]

Life Sci. 2003 May 9;72(25):2853-61.

Annonaceous acetogenins are a group of potential anti-neoplastic agents isolated from Annonaceae plants. In this study, we purified Annonacin, a cytotoxic mono-tetrahydrofuran acetogenin, from the seeds of Annona reticulata and analyzed its biological effects. Herein, we have shown that Annonacin caused significant cell death in various cancer cell lines. T24 bladder cancer cells at the S phase were more vulnerable to the cytotoxicity of Annonacin. Furthermore, Annonacin activated p21 in a p53-independent manner and arrested T24 cells at the G1 phase. It also induced Bax expression, enhanced caspase-3 activity, and caused apoptotic cell death in T24 cells. In summary, these results suggest that Annonacin is potentially a promising anti-cancer compound.

Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons.[Pubmed:17634376]

J Neurosci. 2007 Jul 18;27(29):7827-37.

A neurodegenerative tauopathy endemic to the Caribbean island of Guadeloupe has been associated with the consumption of anonaceous plants that contain acetogenins, potent lipophilic inhibitors of complex I of the mitochondrial respiratory chain. To test the hypothesis that Annonacin, a prototypical acetogenin, contributes to the etiology of the disease, we investigated whether Annonacin affects the cellular distribution of the protein tau. In primary cultures of rat striatal neurons treated for 48 h with Annonacin, there was a concentration-dependent decrease in ATP levels, a redistribution of tau from the axons to the cell body, and cell death. Annonacin induced the retrograde transport of mitochondria, some of which had tau attached to their outer membrane. Taxol, a drug that displaces tau from microtubules, prevented the somatic redistribution of both mitochondria and tau but not cell death. Antioxidants, which scavenged the reactive oxygen species produced by complex I inhibition, did not affect either the redistribution of tau or cell death. Both were prevented, however, by forced expression of the NDI1 nicotinamide adenine dinucleotide (NADH)-quinone-oxidoreductase of Saccharomyces cerevisiae, which can restore NADH oxidation in complex I-deficient mammalian cells and stimulation of energy production via anaerobic glycolysis. Consistently, other ATP-depleting neurotoxins (1-methyl-4-phenylpyridinium, 3-nitropropionic, and carbonyl cyanide m-chlorophenylhydrazone) reproduced the somatic redistribution of tau, whereas toxins that did not decrease ATP levels did not cause the redistribution of tau. Therefore, the Annonacin-induced ATP depletion causes the retrograde transport of mitochondria to the cell soma and induces changes in the intracellular distribution of tau in a way that shares characteristics with some neurodegenerative diseases.

Annonacin in Asimina triloba fruit: implication for neurotoxicity.[Pubmed:22130466]

Neurotoxicology. 2012 Jan;33(1):53-8.

INTRODUCTION: The acetogenin, Annonacin, from the tropical annonaceous plant Annona muricata, is a lipophilic, mitochondrial complex I inhibitor reported to be more toxic than rotenone to mesencephalic neurons. The temperate annonaceous plant Asimina triloba (pawpaw) is native to the Eastern United States and products are available online. This study determined whether Annonacin is in the pawpaw fruit pulp and whether it or the crude ethyl acetate extract is toxic to cortical neurons. METHODS: Pawpaw extract was prepared by pulp extraction with methanol and liquid-liquid partitioning with ethyl acetate (EtOAc). Annonacin was isolated from the crude EtOAc extract via column chromatography using a gradient solvent system of increasing polarity. Mass spectroscopy, nuclear magnetic resonance and infrared spectroscopy were used to compare isolated material with synthetic Annonacin data and a natural Annonacin sample. Toxicity of isolated Annonacin and the total EtOAc extract was determined in primary rat cortical neurons using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. RESULTS: The average concentration of Annonacin in the fruit pulp was 0.0701+/-0.0305mg/g. Purified Annonacin (30.07mug/ml) and crude EtOAc extract (47.96mug/ml) induced 50% death of cortical neurons 48h post treatment. Annonacin toxicity was enhanced in the presence of crude extract. DISCUSSION: Pawpaw fruit contains a high concentration of Annonacin, which is toxic to cortical neurons. Crude fruit extract also induced neurotoxicity, highlighting the need for additional studies to determine the potential risks of neurodegeneration associated with chronic exposure to pawpaw products.

Annonacin, a natural lipophilic mitochondrial complex I inhibitor, increases phosphorylation of tau in the brain of FTDP-17 transgenic mice.[Pubmed:24389273]

Exp Neurol. 2014 Mar;253:113-25.

Both genetic and environmental factors likely contribute to the neuropathology of tauopathies, but it remains unclear how specific genetic backgrounds affect the susceptibility towards environmental toxins. Mutations in the tau gene have been associated with familial tauopathies, while Annonacin, a plant-derived mitochondrial inhibitor, has been implicated in an environmental form of tauopathy. We therefore determined whether there was a pathogenic synergy between Annonacin exposure and the expression of the R406W-tau mutation in transgenic mice. We found that Annonacin exposure caused an increase in the number of neurons with phosphorylated tau in the somatodendritic compartment in several brain areas in R406W(+/+) mice as opposed to mice that had only the endogenous mouse tau (R406W(-/-)). Western blot analysis demonstrated a concomitant increase in total tau protein without increase in tau mRNA, but reduced proteasomal proteolytic activity in R406W(+/+), but not R406W(-/-) mice, upon Annonacin-treatment. Phosphorylated tau levels exceeded the increase in total tau protein, along with increased levels of different tau kinases, foremost a striking increase in the p25/p35 ratio, known to activate the tau kinase Cdk5. In summary, we observed a synergistic interaction between Annonacin exposure and the presence of the R406W-tau mutation, which resulted in reduced degradation, increased phosphorylation and redistribution of neuronal tau.

Annonacin induces cell cycle-dependent growth arrest and apoptosis in estrogen receptor-alpha-related pathways in MCF-7 cells.[Pubmed:21840388]

J Ethnopharmacol. 2011 Oct 11;137(3):1283-90.

ETHNOPHARMACOLOGICAL RELEVANCE: Tamoxifen resistance is common in estrogen receptor-alpha (ERalpha)-positive breast cancers. Pawpaw and soursop are anticancer annonaceous plants in complementary medicine. Thus, we studied the effects of Annonacin, an annonaceous acetogenin, in breast cancer cells. MATERIALS AND METHODS: Cell growth and ERalpha-related pathways were studied. The effects of Annonacin were tested in MCF-7 xenografts in nude mice. RESULTS: In ERalpha-positive MCF-7 cells, Annonacin (half-effective dose ED(50) = 0.31 muM) and 4-hydroxytamoxifen (ED(50) = 1.13 muM) decreased cell survival whereas Annonacin (0.5-1 muM) increased cell death at 48 h. Annonacin and 4-hydroxytamoxifen were additive in inhibiting cell survival. Annonacin (0.1 muM) induced G(0)/G(1) growth arrest while increasing p21(WAF1) and p27(kip1) and decreasing cyclin D1 protein expression. Annonacin (0.1muM) decreased cyclin D1 protein expression more than 4-hydroxytamoxifen (1 muM). Annonacin (0.1 muM) increased apoptosis while decreasing Bcl-2 protein expression. The combination of Annonacin (0.1 muM) and 4-hydroxytamoxifen (1 muM) decreased Bcl-2 protein expression and ERalpha transcriptional activity more than Annonacin (0.1 muM) did alone. Annonacin, but not 4-hydroxytamoxifen, decreased ERalpha protein expression. Moreover, Annonacin decreased phosphorylation of ERK1/2, JNK and STAT3. In nude mice, Annonacin decreased MCF-7 xenograft tumor size at 7-22 days. Moreover, Annonacin decreased ERalpha, cyclin D1 and Bcl-2 protein expression in the xenograft at 22 days. CONCLUSIONS: Annonacin induced growth arrest and apoptosis in ERalpha-related pathways in MCF-7 cells. Annonacin and 4-hydroxytamoxifen were additive in inhibiting cell survival and ERalpha transcriptional activity. Moreover, Annonacin attenuated MCF-7 xenograft tumor growth while inhibiting ERalpha, cyclin D1 and Bcl-2 protein expressions in nude mice.

Annonacin is an Acetogenin and promotes cytotoxicity via a pathway inhibiting the mitochondrial complex. Annonacin is the active agent found in Graviola leaf extract to act as an inhibitor of sodium/potassium (NKA) and sarcoplasmic reticulum (SERCA) ATPase pumps.

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