Cancer is a catastrophe of the frame of higher multicellular organisms consequential from the deviant growth of the cells. It is portrayed by modifications in the statement of copious amendments, prompting dysregulation of the conventional cell programming concerned with the cell division and cell separation. This upshot in an unevenness of cell replication and cell passing that promotes the development of a tumor cell population. The qualities that portray a lopsided growth of a malignant tumor are the competence to strike locally, to sweep to neighboring lymph nodes, and to metastasize far off organs in the body. Clinically, growth seems, by all accounts, to be an extensive assortment of diseases with various phenotypic attributes. As a cancerous growth ensues, genetic drift in the cell population forms cell heterogeneity in such physiognomies as cell antigenicity, invasiveness, metastatic potential, rate of cell proliferation, differentiation state, and response to chemotherapeutic agents. At the molecular level, all cancers have plentiful things in mutual, which implies that the ultimate biochemical lesions steering to malignant transformation and progression can be fabricated by a common but not analogous pattern of alterations of gene readout. In general, malignant cancers cause noteworthy morbidity and will be lethal to the host if not treated. Omissions to them give the marks to be concealed, laidback cancers that may remain clinically undetectable (or in situ), permits the host to have a standard life expectancy. There are over 100 diverse categories of cancer, and each is classified by the type of cell that is initially affected, and these include breast cancer, cervical cancer, skin cancer, leukemia, lung cancer, prostate cancer, and so on.
There have been researches done on the anti-cancerous properties of plants and recognized for centuries. The National Cancer Institute (NCI) has screened approximately 35,000 plant species for conceivable anticancer activities. Among them, about 3,000 plant species have established reproducible anticancer activity. Many studies have focused on the anticarcinogenic properties of plants such as Abrus precatorius , Albizzia lebbeck Alstonia scholaries Anacardium occidentale hepatoma, Asparagus racemosa , Boswellia serrata , Erthyrina suberosa , Euphorbia hirta , Gynandropis pentaphylla , Nigella sativa , Peaderia foetida , Picrorrhiza kurroa , Withania somnifera, Annona muricata to name a few. The current review focuses on the efficacy of the plant Annona muricata in inhibiting the various cancerous occurrences and growth.
Annona muricata, commonly called Soursop, is a tropical plant species variety renowned for its edible fruit which has selected restorative benefits, yet in addition particular toxicological impacts. This plant is a species of the genus Annona, of the Annonaceae family, order Magnoliales and Division Magnoliophyta. The genus Annona comprises over 70 species among which A. muricata is the most extensively grown. The soursop tree grows up to 5– 10 m tall and 15– 83 cm in breadth with low branches. It has a tendency to blossom and fruit a large segment of the year, however there are more characterized seasons relying upon the altitude. It is scattered in the tropical areas. Soursop organic product is an ovoid berry, dull green in shading. Each fruit may comprise 55–170 black seeds when fresh and they transform to light brown when dry. The flesh is white and creamy with distinctive aroma and flavor. Traditional medicinal benefits of leaves, bark, fruit and seed of A. muricata have been the emphasis of myriad medicinal routines. The most significantly used preparation in traditional medicine is the decoction of bark, root, seed or leaf and applications are wide-ranging. The ingestion of leaves decoction is used as analgesic and also it is used to cope with discomfort accompanying colds, flu and asthma; and to treat cutaneous (external) and internal parasites. The use of leaves to treat malaria is very substantial. The fruit is not only cherished as food, but the juice is used as galactogogue to treat diarrhea, heart and liver diseases, and against intestinal parasites. Customary therapeutic qualities of A. muricata have been recognized in tropical locales to ponder different afflictions, for example, fever, torment, respiratory and skin disease, bacterial infections, hypertension, aggravation, diabetes and cancer. There have been a number of reports on the ethno-medical uses of A. muricata leaves including treatments for hypertension, diabetes and cancer. Most parts of the A. muricata tree, similar to that of the other Annona species, namely A. squamosa and A. reticulata are widely used as local and habitual medicines contrary to a large number of human inflamations, infections and disorders. The pulp of the fruit is used as natural medicine for joint pains, dysentery, neuralgia, diarrhea, rheumatism, fever, malaria, parasites, skin rushes and worms, and also is eaten to increase mother’s milk after parturition. The leaves are used to control cystitis, , body aches and diabetes. Additionally, the administration of the leaf’s decoction is thought to display anti-rheumatic and neuralgic effects. In addition, the cooked leaves are topically used to treat abscesses and rheumatism that was reported by de Sousa OV and colleagues.(9)
The crushed seeds are thought to have anthelmintic activities antaagonistic to external and internal worms. In tropical Africa, the plant is employed as an astringent pesticide, and insecticide; along this it is used to treat coughs, pain and skin diseases. In India, the fruit and flower are used as remedies against catarrh, while the root-bark and leaves are well known to have an anti phlogistic and anthelmintic activities which was worked upon by Adewole SO, Ojewole J.(2)
In Malaysia, the crude extract of A. muricata and A. squamosa is used as a syrup on the head to buffer from fainting. In South America and tropical Africa, including Nigeria, leaves of A.muricata are implemented as an ethnomedicine opposed to tumors and cancer. Moreover, the smooth muscle relaxant, hypotensive hypoglycemic,, anti-inflammatory, sedative, and antispasmodic effects accredit to the leaves, barks and roots of A. muricata. Moreover along with the ethnomedicinal uses, the fruits are widely employed for the preparation of beverages, ice creams,and syrups (3, 21, 23, 26)
There are more than 200 chemical compounds that have been documented and isolated from this plant; the foremost being the alkaloids, phenols, flavonoids and acetogenins. Based on the in vitro studies, extracts and phytochemicals of A. muricata have been sorted out as anti-microbial, anti-inflammatory, anti-protozoan, antioxidant, insecticide, larvicide, and cytotoxic to tumor cells. Studies on the extracts and isolated compounds of A. muricata showed contraceptive, antitumor, anti-ulceric, , wound healing, hepato-protective, anxiolytic, anti-stress, anti-inflammatory, anti-icteric and hypoglycemic activities. Furthermore, there have been clinical studies carried out in order to boost the hypoglycemic activity of the ethanolic extracts of A. muricata leaves. Mechanisms of action of a few pharmacological activities have been explicated, such as cytotoxic, antioxidant, antimicrobial, anti-nociception and hypotensive activities. Nonetheless, some phytochemical compounds isolated from A. muricata have shown a neurotoxic effect in vitro and in vivo. Thus, these crude extracts and isolated compounds requires further studies to define the magnitude of the effects, optimal dosage, long-term safety, and potential side effects.(32)
Constant examinations on diverse parts of the A. muricata have shown the occurrence of varieties of phyto constituents and compounds, including flavonol triglycosides (FTGs) alkaloids (ALKs), phenolics (PLs), megastigmanes (MGs), cyclopeptides (CPs) and essential oils. The existence of various minerals such as Ca, Na, Fe, K, Cu and Mg imply that regular intake of the A. muricata fruit can help furnish essential nutrients to the human body. However, Annona species, including A. muricata, have been shown to be a vital source of annonaceous acetogenin compounds (AGEs). Almost all the parts inclusive of the fruits, leaves, stems and roots of this plant are known to be rich in flavonoids, isoquinoline alkaloids and annonaceous acetogenins. (23,25,26,28,35,42)
Acetogenins are a unique category of C-35/C37 secondary metabolites obtained from long chain (C-32/C34) fatty acids in the polyketide pathway. They are basically illustrated by combining fatty acids with 2-propanol unit at C-2 that gives a methyl-substituted ?, ?-unsaturated ?-lactone. Starting with the discovery of uvaricin from Uvaria accuminata in 1982,there have been several acetogenins that are identified. About 500 have been reported from numerous parts of the plants in the Annonaceae family. Because of the exceptional structures and broad spectrum of biological activities, AGEs have drawn significant scientific interest of late. The active annonaceous acetogenins have shown to be successful in inducing death in cancer cells that are resistant to even chemotherapeutic drugs. Besides their remarkable anti proliferative efficacy, these annonaceous acetogenins have been endorsed to debilitating side effects such as neurotoxicity suggesting that these components can easily traverse the blood–brain barrier and are known to cause atypical Parkinson’s disease, thus restricting their development as new drug entities. Various biological activities have been reported for AGEs, including antimalarial, anti-parasitic and pesticidal activities. However, the physiological activities of AGEs are initially characterized by the toxicity against cancer cells and inhibitions of the mitochondrial complex I. (11)
There are plentiful reports that signify anti-proliferative effects of various extracts of the plant and isolated AGEs towards various cancer cell lines. In a study performed by Jaramillo MC et al., the mechanism of action of ethyl acetate extract of A. muricata leaves against colon cancer cells (HT-29 and HCT-116) and lung cancer cells (A549) has been illustrated. The leaf extract was proficient to induce apoptosis in colon and lung cancer cells through the mitochondrial-mediated pathway. This anti-proliferative effect was alongside with cell cycle arrest in the G1 phase.(20) However, the migration and invasion of colon cancer cells were profoundly inhibited by the leaf extract.
The in vivo chemo preventive potential of the ethyl acetate extract of the A. muricata leaves against azoxymethane-induced colonic aberrant crypt foci (ACF) in rats was examined by Moghadamtousi and colleages. There was a significant reduction in ACF formation in rats because of the oral administration of the extract at two doses (250 and 500 mg/kg) for 60 days, as gaged by methylene blue staining of colorectal specimens. The down-regulation of PCNA and Bcl-2 proteins and the up-regulation of Bax protein after the administration of EEAML compared with the cancer control group was depicted in the Immunohistochemistry analysis. In addition, an increase in the levels of enzymatic antioxidants and a reduction in the malondialdehyde level of the colon tissue homogenates were found, suggesting the suppression of lipid peroxidation. The growth of HT-29 cells with an IC50 value of 1.62 ± 0.24 ?g/ml after 48 h was inhibited by Annomuricin E. The cytotoxic effect of annomuricin E was supplementarily substantiated by G1 cell cycle arrest and early apoptosis induction in HT-29 cells. Annomuricin E activated mitochondria-initiated events, comprising the dissipation of the mitochondrial membrane potential and caused the leakage of cytochrome c from the mitochondria. Preceding these events, annomuricin E activated caspase 3/7 and caspase 9. Further annomuricin E, induced a time-dependent upregulation of Bax and downregulation of Bcl-2 at the mRNA and protein levels.Thus, these findings verify the usage of A. muricata leaves in ethnomedicine against cancer and emphasize annomuricin E as one of the contributing compounds in the anticancer activity of A. muricata leaves. Furthermore, Moghadamtousi and colleagues examined that ethyl acetate extract of Annona muricata leaves (EEAM) exerted a striking cytotoxic effects on HCT-116 and HT-29 cells as determined by MTT and LDH assays. After 24 h of treatment, EEAM showed the IC50 value against HT-29 and HCT-116 cells. Flow cytometric analysis illucidated the cell cycle arrest at G1 phase and also the externalization of phosphatidylserine acting as an indicator of the induction of apoptosis. EEAM treatment activated excessive accumulation of ROS followed by disruption of MMP, cytochrome c leakage and activation of the initiator and executioner caspases in both colon cancer cells. Immunofluorescence analysis portrayed the up-regulation of Bax and down-regulation of Bcl-2 proteins while treated with EEAM. Furthermore, EEAM conspicuously blocked the migration and invasion of HT-29 and HCT-116 cells (29,31).
In colon cancer cells, Graviola leaves also have significant effects on cell survival potential via mitochondrial-mediated apoptosis associated with the G1 cell cycle arrest. Graviola elicits apoptosis by generating reactive oxygen species ROS and down-regulating the anti-apoptotic Bcl-2 protein, while up-regulating pro-apoptotic Bax protein. These processes subsequently steer to attenuation of mitochondrial membrane potential (MMP) and cytochrome c release. Release of cytochrome c activates apotosome and the intrinsic caspase cascade that triggers execution of apoptosis through DNA fragmentation. (30).
The effect of Graviola extract against the prostate cancer cell lines has also been expounded in vitro. The experiments performed to show that Graviola initiates necrosis in PC-3 cells through inhibition of cellular metabolism and tumor mobility. Further evaluation depicted the downregulation of the expression of the hypoxia-related factors and glycolytic factors following treatment in PC cells with Graviola (41).
The activity of the water extract of leaves of A. muricata against the benign prostatic hyperplasia (BPH-1) cell line and rats prostates was examined where the the anti-proliferative effects with an IC50 of 1.36 mg/mL was indicated. Bax gene was up regulated, while Bcl-2 was suppressed. Normal histology of all the other testes was observed. Seminal vesicle was significantly reduced in test groups (P < .05) and showed marked atrophy with increased cellularity and the acinii, empty of secretion. Prostate of test groups were abridged with epithelial lining showing condensation, pyknotic nucleus and marginalization of the nuclear material as the characteristic of apoptosis of the glandular epithelium. Furthermore, inadequate prostatic secretion with flattening of acinar epithelial lining was observed. Thus was concluded that Annona muricata has anti-proliferative effects on BPH-1 cells and deduces the prostate size, possibly through apoptosis (5). This promising antitumor effect was also reported in an in vivo study on 7,12-dimethylbenzene anthracene (DMBA)-induced cell proliferation in the breast tissues of mice. Oral administration of the A. muricata leaves probably have protective effects towards the development of breast carcinogenesis was shown by DMBA as it induced a protective effect against DNA damage. The leaves, even at a low dosage of 30 mg/kg suppressed the initiation and promotion stage of skin papillomagenesis in mice that was induced by DMBA and croton oil, respectively (27). In xenografts studies, the oral administration of 100mg/kg bw GLE show tumor growth-inhibition in human prostate tumor. This study also validates the synergy amongst the components of Graviola leaf extract (GLE) equated to its acetogenin-enriched (AEF) fractions and flavonoid-enriched (FEF) (22).
In the conclusions made by, Constant Anatole Pieme and others A. muricata exhibited anti proliferative effects on HL-60 cells by promoting loss of cell viability, morphology changes, loss of membrane mitochondrial potential and G0/G1 phase cell arrest. Their reports confirmed the efficacy of A. muricata as an agent of chemotherapeutic and cytostatic activity in HL-60 cells (7). Studies have revealed that the extracts have selective inhibition of breast cancer cells via EGFR downregulation. An oncogene, the epidermal growth factor receptor (EGFR) is that is often overexpressed in breast cancer (BC), along with its overexpression has been associated with poor prognosis and drug resistance. EGFR is therefore a rational target for BC therapy development. In addition, experiments showed that Graviola fruit extract (GFE) reduces the growth of BC cells utilizing xenografts mouse model studies. Moreover, GFE selectively restrained the growth of EGFR-overexpressing human BC (MDA-MB-468) cells but not in non-tumorigenic human breast epithelial cells (MCF-10A). These studies strengthen the evidence that Graviola has selective anti-growth effects between cancer and non-cancer cells (8).
Another report on breast cancer cells by Yu-Min Koa and colleagues supported that Graviola endorses apoptosis in ER-related pathways. Moreover, Graviola subsided MCF-7 tumor growth while hindering ER-cyclin D1 and Bcl-2 protein expressions in nude mice (44). It has been analyzed that Graviola also seemed to have anti-proliferative effects of HL-60 cells via loss of cell viability, loss of MMP, G0/G1 phase cell arrest and morphological apoptotic changes. It was authenticated and confirmed that Graviola does indeed have anti-proliferative and cytostatic activity in HL-60 cells by these findings (7).
Overexpression of anti-apoptotic proteins is archetypal in many forms of cancer. In the study performed by Priya Antony and Ranjit Vijayan, there were conclusions on the insights on how a potential Bcl-Xl-selective inhibitors of cancer where molecular docking and simulations may be used to identify potential lead compounds from A. muricata that could be inhibitors of these anti-apoptotic proteins can be designed from acetogenins of A. muricata . The results depicted that the acetogenins namely annomuricin-D-one, annomuricin A, annohexocin, muricatocin A, , and muricatetrocin A/B showed higher docking score in Bcl-Xl but not in Bcl-2 and Mcl-1. Structural and interaction analysis presented that these molecules through large lipophilic interactions bound stably in the active site of Bcl-Xl. In comprehensive docking studies, using natural and synthetic inhibitors of Bcl-Xl, acetogenins indicated better binding scores and intermolecular interactions. When the protein–ligand complexes were rescored using frames from MD simulations, docking scores were also significantly upgraded suggesting that the water molecules play a crucial role in the binding site interaction (39).
Further studies by Yang C et, .al have shown that the Graviola leaf extract (GLE) pharmacokinetics and absorption kinetics resulting in inhibiting prostate cancer proliferation, viability and clonogenic colonies (43). The caspase 3 activation by the ethanol extract of the leaves also establish an apoptosis-inducing effect in myelogenous leukemic K562 cells, which was verified with a TUNEL assay by Ezirim A. et al.(10)
Anonna muricata also had impacts on Lewis lung carcinoma (LLC) tumor cell lines that were examined both in vivo as well as in vitro which was shown in an another study by Zhao GX1 et,.al. This implies that Graviola had antitumor activity by limiting the natural growth of the lung tumors (45). NADH oxidase inhibition in cancer cell lines, down regulation of the P-glycoprotein pump via ATP depletion and Cell cycle arrest at S-phase progression has shown to be affected by Graviola through its anti-cancerous and cytotoxic mechanisms, which has been shown by additional research.