Sensitive Tumor Cell Line for Annonaceous Acetogenins and High Therapeutic Efficacy at a Low Dose for Choriocarcinoma Therapy

Annonaceous acetogenins (ACGs) have attracted much attention because of excellent antitumor activity. However, the lack of selectivity and the accompanying serious toxicity have eventually prevented ACGs from entering clinical application. To decrease the side effects of ACGs, the cytotoxicity of ACGs on 10 types of tumor cell lines was investigated by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) test to identify one that was very sensitive to ACGs. Meanwhile, ACGs nanoparticles (ACGs-NPs) were prepared using poloxamer 188 (P188) as an excipient so as to solve the problem of poor solubility and the in vivo delivery of ACGs. ACG-NPs were 163.9±2.5 nm in diameter, negatively charged, and spherical with a high drug loading content (DLC) of 44.9±1.2%. MTS assays demonstrated that ACGs had strong cytotoxicity against JEG-3, HeLa, SiHa, MCF-7, A375, A2058, A875, U-118MG, LN- 229, and A431 cells, among which JEG-3 cell line was extremely sensitive to ACGs with a 50% inhibitory concentration (IC50) value of 0.26 ng/mL, a very encouraging discovery. ACGs-NPs demonstrated very good dose-dependent antitumor efficacy in a broad range of 45?1200 μg/kg on JEG-3 tumor-bearing mice. At a very low dose (1200 μg/kg), ACGs-NPs achieved a high tumor inhibition rate (TIR) of 77.6% through oral administration, displaying a significant advantage over paclitaxel (PTX) injections that are currently used as first-line anti-choriocarcinoma drugs. In the acute toxicity study, the half lethal dose (LD50) of ACGs-NPs was 135.5 mg/kg, which was over 100 times as of the effective antitumor dose, indicating good safety of ACGs-NPs. ACGs-NPs show promise as a new type of and potent anti-choriocarcinoma drug in the future.

An Overview of the Chemical Characteristics, Bioactivity and Achievements Regarding the Therapeutic Usage of Acetogenins from Annona cherimola Mill

Annona cherimola Mill., or the custard apple, is one of the species belonging to the Annonaceae family, is widely used in traditional medicine, and has been reported to be a valuable source of bioactive compounds. A unique class of secondary metabolites derived from this family are Annonaceous acetogenins, lipophilic polyketides considered to be amongst the most potent antitumor compounds. This review provides an overview of the chemical diversity, isolation procedures, bioactivity, modes of application and synthetic derivatives of acetogenins from A. cherimola Mill.

Annonaceous acetogenins mimic AA005 targets mitochondrial trifunctional enzyme a subunit to treat obesity

Obesity and related disease is a serious threat to people's health. However, currently available anti-obesity drugs couldn’t fully meet the clinic needs. We found annonaceous acetogenin mimic AA005 treatment could resist obesity in diet-induced obese mice and leptin-deficient (ob/ob) mice at non-cytotoxic dose. Then, with a bait of biotin labeled AA005, 44 proteins were captured as AA005 binding proteins using chemical proteomics. Alpha subunit of mitochondrial trifunctional protein (HADHA) showed the strongest affinity and its knockdown suppressed the fat accumulation in 3T3-L1 cells, identical to the effect of AA005. Pharmacokinetic analysis indicated that AA005 were mainly distributed in liver and fat tissue, and thus we constructed tissue-specific HADHA knockout mice of liver and fat. The obesities induced by high fat diet in these mice were significantly inhibited. Intriguingly, elevating energy expenditure and activated thermogenesis pathway were detected in AA005-treated as well as HADHA knockout mice. Thus, AA005 targeting HADHA may serve as novel therapeutic strategy for obesity.

Evaluation of Annona muricata Acetogenins as Potential Anti-SARS-CoV-2 Agents Through Computational Approaches

Annona muricata, a tropical plant which has been extensively used in ethnomedicine to treat a wide range of diseases, from malaria to cancer. Interestingly, this plant has been reported to demonstrate significant antiviral properties against the human immunodeficiency virus, herpes simplex virus, human papilloma virus, hepatitis C virus and dengue virus. Additionally, the bioactive compounds responsible for antiviral efficacy have also shown to be selectively cytotoxic while inhibiting tumorigenic cell growth without affecting the normal cell growth. Annonaceous Acetogenins are a class of bioactive compounds exclusive to the Annonaceae family at which the plant A. muricata belongs. In the current study, we have created a library of Acetogenins unique to the plant, comprising of Annomuricin A, Annomuricin B, Annomuricin C, Muricatocin C, Muricatacin, cis-Annonacin, Annonacin-10-one, cis-Goniothalamicin, Arianacin and Javoricin, for in silico and theoretical evaluations against the SARS-CoV-2 spike protein in an attempt toward promotion of plant based drug development for the current pandemic of coronavirus disease 2019 (COVID-19). We found that all the Acetogenins showing in silico spike protein significantly docking with good binding affinities. Moreover, we envision A. muricata Acetogenins can be further studied by in vitro and in vivo models to identify potential anti-SARS-CoV-2 agents.

A Review of Recent Studies on The Phytochemical and Pharmacological Activity of Annona Muricata

Medicinal plants have been used to treat illness and disease for thousands of years. Bioactive principles present in medicinal plants attribute to the therapeutic efficacy and it can be incorporated into modern medicine systems for the development of newer drug formulation for therapeutic ailments. Even now they are economically important, being used in the pharmaceutical, cosmetic, perfumery, and food industries. Screening of medicinal plants for antimicrobial activities and phytochemicals is important for finding potential new compounds for therapeutic use. In the present review, an attempt has been made to congregate the traditional, phytochemical, and pharmacological studies done on an important medicinal plant Annona muricata. Cyclo hexapeptides, acetogenins, annonaceous acetogenins were the major phytochemical compounds studied from this medicinal plant. The fruit is of economic value and hence cultivated and used widely as edible food. The plant possesses the major pharmacological activities includes Anti-viral activity, Anti-oxidant Activity, Larvicidal activity, Anti-inflammatory activity, Antipediculicidal activity, Anti-bacterial activity, and wound healing. It also has an anti-carcinogenic and cytotoxic effect.

The future potential of Annona muricata L. extract and its bioactive compounds as radiation sensitizing agent: proposed mechanisms based on a systematic review

Despite technological advances in cancer treatment, especially in radiotherapy, many efforts are being made in improving cancer cell radio-sensitivity to increase therapeutic ratio and overcome cancer cell radio-resistance. In the present review, we evaluated the anticancer mechanism of Annona muricata L. (AM) leaves extract and its bioactive compounds such as annonaceous acetogenins, annomuricin, annonacin, or curcumin; and further correlated them with the potential of the mechanism to increase or to reduce cancer cells radio-sensitivity based on literature investigation. We see that AM has a promising future potential as a radio-sensitizer agent.

Bio-Guided Isolation of Acetogenins from Annona cherimola Deciduous Leaves: Production of Nanocarriers to Boost the Bioavailability Properties

Annonaceous acetogenins (ACGs) are lipophilic polyketides isolated exclusively from Annonaceae. They are considered to be amongst the most potent antitumor compounds. Nevertheless, their applications are limited by their poor solubility. The isolation of ACGs from Annona cherimola leaves, an agricultural waste, has not been reported to date. Molvizarin (1) cherimolin-1 (2), motrilin (3), annonacin (4) and annonisin (5) are isolated for the first time from A. cherimola deciduous leaves. Annonacin was found to be four- and two-times more potent in tumoral cells (HeLa, 23.6% live cells; IGROV-1, 40.8% live cells for 24 h) than in HEK-293 at 50 µM (24 h, 87.2% live cells). Supramolecular polymer micelles (SMPMs) were synthesized to encapsulate the major ACG isolated, annonacin, in order to improve its solubility in aqueous media. The bioavailability of this compound was increased by a factor of 13 in a simulated human digestive system when compared with free annonacin and an encapsulation efficiency of 35% was achieved. In addition, the cytotoxic activity of SMPMs that hosted annonacin (100 µM, 24 h, 5.8% live cells) was increased compared with free annonacin in water (100 µM, 24 h, 92% live cells). These results highlight the use of by-products of A. cherimola, and their pure compounds, as a promising source of anticancer agents. The use of SMPMs as nanocarriers of ACGs could be an alternative for their application in food field as nutraceutical to enhance the administration and efficacy.