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Annona muricata L. and Annona squamosa L. (Annonaceae): A review of their traditional uses and anticancer activities

Over the past century, research on cancer has increased due to the importance of the disease as sixth leading cause of mortality worldwide. Several medicines, methods and strategies have been used to cure the disease. However, the problematic of drug resistance faced by researchers and physicians before different cancer types remains a big challenge. Therefore, basic plant research has produced new bioactive compounds with promising prospects in this regard. Phytotherapy appears then as a potential alternative for the discovery of new drugs in the fight against cancer and its drug resistance.


Introduction
Sixth cause of death in human population since 2016 behind infections, cancer is one of the diseases that continues to progress statistically [1] . Radiation therapy, chemotherapy and surgery remain ineffective treatments while herbal remedies become the best mean because of their less harmful side effects on non-target human cells and the biological environment [2] . Traditional African medicines have aroused growing interest as potential sources of new medicines with a wide range of biological and pharmacological activities. In a pharmaceutical context, plants with high use in ethno-medicine are a rich source of active phytoconstituents known to improve health against a wide range of diseases and infections [3] . Plants that are used in traditional medicine include Annona muricata and Annona squamosa. Belonging to the Annonaceae family, they have been widely used in Beninese traditional medicine for the treatment of cancer and tumors [4] . In this review, we describe the botany, distribution and ethnomedicinal use of these plants. Then we summarize the phytochemistry, anticancer activities and possible mechanisms of actions of A. muricata and A. Squamosa against cancer.
Remember that plant stress lowers the active components of the plant. Plant stress is a condition considered to be detrimental to plant growth. Transporting the plants to the state of the goods produce many quantities of secondary metabolite, which are used as medicine.

Ethnomedicinal Uses
All parts of the A. muricata and A. Squamosa tree are widely used as traditional remedies for a range of human ailments and illnesses, in particular cancer and parasitic infections. The fruit is used as a natural medicine against cancer, neuralgia, malaria, diarrhea, dysentery, rheumatism, fever, arthritis, parasites, dysentery, rashes and worms. It is also consumed by mothers to improve postpartum milk production. The leaves are used to treat cystitis, diabetes, headaches and insomnia. The crushed seeds are said to have anthelmintic activities against worms, external and internal parasites. The leaves of A. Muricata are used as ethnomedicine for tumors and cancer [4] . The anti-inflammatory, hypoglycemic, sedative, relaxant effects of smooth muscles, hypotensive and antispasmodic are also accredited on the leaves, barks and roots of A. Muricata [5,7] . Aside from its ethnomedicinal use, the fruits are widely used for the preparation of drinks, candies, ice creams, shakes and syrups [12,13] .

Phytochemistry
Huge phytochemical assessments on different parts of the A. muricata plant have shown the presence of various phytoconstituents and compounds, including alkaloids (ALKs) [6,14] , megastigmanes (MGs) [15] , flavonoltriglycosides (FTGs) [16] , phenolics (PLs) [17] ,cyclopeptides (CPs) and essential oils [18,19] . However, Annona species, including A. muricata and A. Squamosa, have been shown to be generally the main source of acetogenin compounds (AGEs) [20] . The presence of different major minerals such as Fe, Ca, Na, Cu, K and Mg suggest that continuous consumption of the A. muricata fruit can help to provide nutrients and essential elements to the human body [21] . Phytochemical research reveals that acetogenins are the main components of the Annonaceae family. Over 100 annonaceae acetogenins reported have been isolated from the leaves, bark, seeds, roots and fruits [3] . AGEs are a distinctive class of secondary metabolites C-35/C37 obtained from long chain fatty acids (C-32/C34) in the polyketide pathway. They are normally characterized by a fusion of fatty acids with a C-2 2propanol unit which forms an α, βunsaturated methylsubstituted γ-lactone [22] . Since the discovery of Uvaria accuminata uvaricin in 1982, more than 500 AGEs have been characterized in different parts of the Annonaceae plants family [23,24] . Due to the special structures and extensive biological activities, AGEs have aroused significant scientific interest in recent years. Various biological activities have been reported for AGEs, including antimalarial, pest and pesticide activities [22,25] . However, the biological activities of AGEs are mainly characterized by toxicity against cancer cells and inhibitory effects against the mitochondrial complex I (NADH mitochondrial: ubiquinone oxidoreductase) [26,27] . Phytochemical examinations and biological research on various parts of the A. muricata plant have made it possible to identify a wide range of AGE compounds, as summarized in Table 2. The main chemical structures of the main acetogenins are illustrated in Figure 3.

Anticancer activities 5.1 Annona muricata
Several studies have reported significant antiproliferative effects of different isolated plant extracts and AGEs to various cancer cell lines [28 -30]. However, few of these studies have explained the underlying mechanism of action ( Table 1). Recent in vitro studies have been performed to determine the mechanism of action of ethyl acetate extract from A. Muricata leaves against colon cancer cells (HT-29 and HCT-116) and lung cancer cells (A549). The leaf extract could activate apoptosis in colon and lung cancer cells via the mitochondriamediated pathway. This antiproliferative effect was associated with stopping the cell cycle in the G1 phase [31,32] . In addition, the migration and invasion of cancer cells from the colon were significantly inhibited by the leaf extract. Activation of caspase 3 by the ethanolic extract of the leaves has also shown an apoptosis-inducing effect in K562 myeloid leukemia cells [30] . George VC et al., in 2012, also confirmed the presence of pharmacologically active antineoplastic compounds in the n-butanol leaf extract of A. muricata [30] . Another research focused on fractionation guided by the bioactivity of the leaves of A. muricata L. (Annonaceae) resulted in the isolation of two new Annonaceous acetogenins, muricoreacin (1) and murihexocin C (2). Compounds 1 and 2 showed significant cytotoxicity against six human tumor cell lines with selectivities for the prostate adenocarcinoma (PC-3) and pancreatic carcinoma (PACA-2) cell lines [33] . Rieser MJ et al., have shown that cis-announacin extracted from seeds of A. Muricata was selectively cytotoxic against colon adenocarcinoma cells (HT-29) and was 10,000 times more potent than adriamycin [34] . The components extracted from the leaves of A. Muricata were tested against the HeLa and PC3 cell lines. The HeLa cells treated with 75 μg of crude leaf extract of A. Muricata have shown 80% inhibition of cancer. A. Muricata has a wide range of powerful anti-cancer agents called acetogenins, which play a key role in different types of cancer. Acetogenins are powerful inhibitors of NADH oxidase from the plasma membrane of cancer cells [35] . A 2011 study demonstrated that a A. Muricata fruit extract significantly regulates the expression of the epidermal growth factor receptor (EGFR) gene and inhibits the growth of breast cancer cells [36] . A. Muricata extracts have been effective against the growth of adriamycin resistant human breast adenocarcinoma (MCF-7 / Adr) by blocking cancer cell access to ATP and inhibiting the actions of the glycoprotein in plasma membrane [37] . It also inhibited the expression of HIF-1α, NF-κB, glucose transporters and glycolytic enzymes, resulting in a decrease in glucose absorption and ATP production in pancreatic cancer cells [38] . The phenolic compounds in A. Muricata have also demonstrated the potential for free radical recovery from human breast carcinoma cells [30] and promyelocytic leukemia cells [39] . The muricin acetogenin isolates J, K and L have antiproliferative effects against human prostate cancer cells, with the strongest effect of muricin K [40] .
In the colon and lung cancer cell lines, the ethanolic extract of graviola caused the cell cycle to be stopped in the G1 phase by upregulating the Baxand downregulating the Bcl-2 proteins [41,42] . Recent in vitro and in vivo studies have been performed using the A. muricata aqueous leaves extract against the benign prostatic hyperplasia (BPH-1) and rat prostate cell line. The results demonstrated a suppressive effect on BPH-1 cells with an IC50 value of 1.36 mg / mL after 72 h with upregulation of Bax and downregulation of Bcl-2 at the mRNA level. The size of the rat's prostate was reduced after two months of treatment with a dose of 30 and 300 mg / mL ofthe extract [43] . This promising anti-tumor effect also reported an in vivo study on cell proliferation induced by 7,12-dimethylbenzene anthracene (DMBA) in the mammary tissues of mice. The protective effect against DNA damage induced by DMBA indicates that oral administration of the A. muricata leaves may have protective effects on the development of breast carcinogenesis [44] . The leaves, even at the low dose of 30 mg / kg, inhibited the initiation and promotion stage of cutaneous papilloma genesis in mice, activated respectively by DMBA and croton oil [45] .
Moghadamtousi et al, [46] have also studied the in vivo chemo preventive potential of ethyl acetate extract from the A. muricata against foci of azoxymethane-induced colonic aberrant crypt foci (ACF) in rats. Oral distribution of the extract at two doses (250 and 500 mg / kg) for 60 days substantially reduced ACF formation in rats, as evidenced by the methylene blue staining of the colorectal samples. The authors justified the use of A. muricata sheets in ethnomedicine against cancer and highlighted annomuricin E as one of the compounds contributing to anticancer activity.
An immunohistochemical examination showed that this activity was accompanied by an upregulation of Bax and a downregulation of Bcl-2. This significant decrease in ACF formation has also been reported for the ethanolic extract of the leaves against colon cancer triggered by 1,2dimethylhydrazine (DMH) [47] . Another research was followed by an in vitro study guided by biological tests against HT-29 cells, which led to the isolation of annomuricin E. This EFA showed mitochondrial-dependent apoptosis activity against colon cancer cells with an IC50 value of 1.62 ± 0.24 μg / mL after 48 h [46] . Anti-cancer research on A. muricata was not only limited to in vitro and in vivo analysis. A case study of a 66-year-old woman with metastatic breast cancer found that taking boiled leaves in water and Xeloda had stabilized the disease [48] . These important anti-cancer and anti-tumor activities indicated for the A. muricata leaves have led to tablet formulations of the ethyl acetate-soluble parts of the leaves, which contain ACGs that can be used as adjuvant therapy for cancer [49] .

Annona squamosa
Annona squamosa L. (Annonaceae), commonly known as an English apple, mainly used for its edible fruit, is also recognized for its many medicinal properties [9].Four new announced acetogenins (ACGs), squamocin-I (1), II (2) and III (3) and squamoxinone-D (4), as well as seven known ACGs (5-11), were isolated from the seeds from A squamosa. Compounds 1-4 were analyzed for their cytotoxicity against the human cancer cell lines Hep G2, SMMC 7721, BEL 7402, BGC 803 and H460. Compound 1 demonstrated better potency than the positivecontrol, while compound 3 showed selective cytotoxicity against H460 with an IC50 value of 0.0492 μg / ml [50] . Wang et al. focused on the anticancer potential of the organic and aqueous extracts of leaf of A. Squamosa L. The crude and ethyl acetate extracts were found to possess significant anticancer activity only against human epidermoid carcinoma KB-3-1 and colon cancer HCT-116 cell lines [2] . In a study to identify promising plant candidates against adult human T-cell leukemia / lymphoma, 245 extracts from 182 plants belonging to 61 families were tested against two T-cell lines infected with HTLV-I (MT-1 and MT-2). Extracts from the aerial parts of A. Reticulata and A. Squamosa have shown the most potent inhibitory activity [51] .

Toxicology
Mycotoxins are secondary fungal metabolites that can cause harmful effects in humans and animals. In 1999, research published in the Lancet Journal examined the possible relationship between the consumption of tropical fruits and the impact of atypical parkinsonism in the French West Indies [57] . Hence, AGEs are proposed as environmental neurotoxins responsible for neurodegenerative disorders, including atypical Guadeloupe parkinsonism. Research by Bonneau et al. have shown that the fruit of A. muricata with annonacin as the primary AGE may be a potential risk factor for neurodegeneration [59] . In rat striatal neurons, annonacin decreases the ATP reserve and interrupts the transport of mitochondria to the cell, which causes cellular disturbances in the tau protein and leads to a number of characteristics similar to neurodegenerative diseases [58] . It is estimated that if someone ingests a soursop fruit or its nectar daily, after one year, the total amount of annonacin consumed is sufficient to trigger brain damage in rats by intravenous infusion [60] . Globally, there are more than 300 mycotoxins [56] , but none of them have been associated with the use A. Muricata and A. Squamosa. However,, the intake of products from Annonaceae species must be done with caution to avoid any neurotoxic damage. Chemical structures of some compounds isolated from Annona muricata [3] .

Conclusion
A. muricata and A. Squamosa are highly coveted tropical trees with a long history of traditional use and a wealth of phytochemical investigations. In addition to being an important source of food and an indigenous medicinal plant, they have been shown to have a wide range of biological activities. Among all the studies on these plants, the most promising activities happen to be their anticancer activity. New in vitro, in vivo and clinical studies on the biological activities of A. muricata and A. Squamosa are necessary in order to better understand how these herbal medicines can serve as a starting point of the bioprospecting for new anticancer lead compounds.

Author's contribution
All manuscript was written through the contribution of all the authors and they have given approval to the final version.