Cancer is a catastrophe of the frame ofhigher multicellular organisms consequential from the deviant growth of thecells. It is portrayed by modifications in the statement of copious amendments,prompting dysregulation of the conventional cell programming concerned with thecell division and cell separation. This upshot in an unevenness of cellreplication and cell passing that promotes the development of a tumor cellpopulation. The qualities that portray a lopsided growth of a malignant tumorare the competence to strike locally, to sweep to neighboring lymph nodes, andto metastasize far off organs in the body. Clinically, growth seems, by allaccounts, to be an extensive assortment of diseases with various phenotypicattributes. As a cancerous growth ensues, genetic drift in the cell populationforms cell heterogeneity in such physiognomies as cell antigenicity,invasiveness, metastatic potential, rate of cell proliferation, differentiationstate, and response to chemotherapeutic agents.
At the molecular level, allcancers have plentiful things in mutual, which implies that the ultimatebiochemical lesions steering to malignant transformation and progression can befabricated by a common but not analogous pattern of alterations of genereadout. In general, malignant cancers cause noteworthy morbidity and will belethal to the host if not treated. Omissions to them give the marks to beconcealed, laidback cancers that mayremain clinically undetectable (or in situ), permits the host to have astandard life expectancy. There are over 100 diverse categories ofcancer, and each is classified by the type of cell that is initially affected,and these include breast cancer, cervical cancer, skin cancer, leukemia, lungcancer, prostate cancer, and so on. There have been researches done onthe anti-cancerous properties of plants and recognized for centuries. The National Cancer Institute (NCI) has screened approximately35,000 plant species for conceivable anticancer activities. Among them, about3,000 plant species have established reproducible anticancer activity.
Manystudies 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 toname a few. The current review focuses on the efficacy of the plant Annona muricata in inhibiting thevarious cancerous occurrences and growth.Annonamuricata, commonly called Soursop, is a tropical plant speciesvariety renowned for its edible fruit which has selected restorative benefits,yet in addition particular toxicological impacts. This plant is a species of thegenus Annona, of the Annonaceae family, orderMagnoliales and Division Magnoliophyta. The genus Annona comprises over 70 species amongwhich A. muricata is the most extensively grown.
Thesoursop 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, howeverthere are more characterized seasons relying upon the altitude. It is scatteredin the tropical areas.
Soursop organic product is an ovoid berry, dull green inshading. Each fruit may comprise 55–170 black seeds when fresh and they transformto light brown when dry. The flesh is white and creamy with distinctive aromaand flavor. Traditionalmedicinal benefits of leaves, bark, fruit and seed of A.muricata have beenthe emphasis of myriad medicinal routines. The most significantly usedpreparation in traditional medicine is the decoction of bark, root, seed orleaf and applications are wide-ranging. The ingestion of leaves decoction isused as analgesic and also it is used to cope with discomfort accompanyingcolds, flu and asthma; and to treat cutaneous (external) and internalparasites.
The use of leaves to treat malaria is very substantial. The fruit isnot only cherished as food, but the juice is used as galactogogue to treatdiarrhea, heart and liver diseases, and against intestinal parasites. Customary therapeutic qualities of A. muricata have been recognized intropical locales to ponder different afflictions, for example, fever, torment,respiratory and skin disease, bacterial infections, hypertension, aggravation,diabetes and cancer. There havebeen a number of reports on the ethno-medical uses of A.muricata leavesincluding 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 arewidely used as local and habitual medicines contrary to a large number of humaninflamations, infections and disorders. The pulp of the fruit is used asnatural medicine for joint pains, dysentery, neuralgia, diarrhea, rheumatism,fever, malaria, parasites, skin rushes and worms, and also is eaten to increase mother’s milk afterparturition.
The leaves are used to control cystitis, , body aches anddiabetes. Additionally, the administration of the leaf’s decoction is thoughtto display anti-rheumatic and neuralgic effects. In addition, the cooked leavesare topically used to treat abscesses and rheumatism that was reported by de Sousa OV and colleagues.(9) The crushed seeds arethought to have anthelmintic activities antaagonistic to external and internalworms. 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 theroot-bark and leaves are well known to have an anti phlogistic and anthelminticactivities which was worked uponby Adewole SO, Ojewole J.(2)In Malaysia, the crude extract of A.muricata and A. squamosa is used as a syrup on the headto buffer from fainting. In South America and tropical Africa, includingNigeria, leaves of A.muricata are implemented as anethnomedicine opposed to tumors and cancer. Moreover, the smooth muscle relaxant,hypotensive hypoglycemic, anti-inflammatory, sedative, and antispasmodiceffects accredit to the leaves, barks and roots of A.
muricata.Moreover along with the ethnomedicinal uses, the fruits are widely employed forthe preparation of beverages, ice creams,and syrups (3, 21, 23,26)There are more than 200 chemical compoundsthat have been documented and isolated from this plant; the foremost being thealkaloids, 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, andcytotoxic 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 thehypoglycemic activity of the ethanolic extracts of A.
muricata leaves. Mechanisms of action of a few pharmacologicalactivities have been explicated, such as cytotoxic, antioxidant, antimicrobial,anti-nociception and hypotensive activities. Nonetheless, some phytochemicalcompounds isolated from A. muricatahave shown a neurotoxic effect in vitro and in vivo. Thus, these crude extractsand isolated compounds requires further studies to define the magnitude of theeffects, optimal dosage, long-term safety, and potential side effects. (32)Constantexaminations on diverse parts of the A. muricata have shown theoccurrence of varieties of phyto constituents and compounds, including flavonoltriglycosides (FTGs) alkaloids (ALKs), phenolics (PLs), megastigmanes (MGs),cyclopeptides (CPs) and essential oils.
The existence of various minerals suchas Ca, Na, Fe, K, Cu and Mg imply that regular intake of the A.muricata fruit can help furnish essential nutrients to the humanbody. 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 areknown to be rich in flavonoids, isoquinoline alkaloids and annonaceousacetogenins. (23,25,26,28,35,42) Acetogenins are aunique category of C-35/C37 secondary metabolites obtained from long chain(C-32/C34) fatty acids in the polyketide pathway.
They are basicallyillustrated 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 Uvariaaccuminata in 1982,there have been several acetogenins that areidentified. About 500 have been reported from numerous parts of the plants inthe Annonaceae family. Because of the exceptional structures and broad spectrumof biological activities, AGEs have drawn significant scientific interest oflate. The active annonaceous acetogenins have shown to be successful ininducing death in cancer cells that are resistant to even chemotherapeuticdrugs. Besides their remarkable anti proliferative efficacy, these annonaceousacetogenins have been endorsed to debilitating side effects such asneurotoxicity suggesting that these components can easily traverse theblood–brain barrier and are known to cause atypical Parkinson’s disease, thusrestricting their development as new drug entities.
Various biologicalactivities have been reported for AGEs, including antimalarial, anti-parasiticand pesticidal activities. However, the physiological activities of AGEs areinitially characterized by the toxicity against cancer cells and inhibitions ofthe mitochondrial complex I. (11) There are plentiful reportsthat signify anti-proliferative effects of various extracts of the plant andisolated AGEs towards various cancer cell lines. In a study performed by Jaramillo MC et al., the mechanism of action of ethylacetate extract of A.
muricata leaves against colon cancercells (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 cancercells through the mitochondrial-mediated pathway. This anti-proliferativeeffect was alongside with cell cycle arrest in the G1 phase.
(20)However, the migration and invasion of colon cancer cells were profoundlyinhibited by the leaf extract. The in vivo chemo preventive potential of the ethylacetate extract of the A. muricata leaves against azoxymethane-inducedcolonic aberrant crypt foci (ACF) in rats was examined by Moghadamtousi andcolleages.
There was a significant reduction in ACF formation in rats becauseof the oral administration of the extract at two doses (250 and 500 mg/kg) for60 days, as gaged by methylene blue staining of colorectal specimens. The down-regulation of PCNA and Bcl-2 proteins andthe up-regulation of Bax protein after the administration of EEAML comparedwith the cancer control group was depicted in the Immunohistochemistryanalysis. In addition, an increasein the levels of enzymatic antioxidants and a reduction in the malondialdehydelevel of the colon tissue homogenates were found, suggesting the suppression oflipid 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 ofannomuricin E was supplementarily substantiated by G1 cell cycle arrest andearly apoptosis induction in HT-29 cells.
Annomuricin E activatedmitochondria-initiated events, comprising the dissipation of the mitochondrialmembrane potential and caused the leakage of cytochrome c from themitochondria. Preceding these events, annomuricin E activated caspase 3/7 andcaspase 9. Further annomuricin E, induced a time-dependent upregulation of Baxand downregulation of Bcl-2 at the mRNA and protein levels.Thus, these findingsverify the usage of A.
muricata leaves in ethnomedicine againstcancer and emphasize annomuricin E as one of the contributing compounds in theanticancer activity of A. muricataleaves. Furthermore, Moghadamtousi and colleagues examined that ethylacetate extract of Annona muricata leaves (EEAM) exerted astriking cytotoxic effects on HCT-116 and HT-29 cells as determined by MTT andLDH assays.
After 24 h of treatment, EEAM showed the IC50 valueagainst HT-29 and HCT-116 cells. Flow cytometric analysis illucidated the cellcycle arrest at G1 phase and also the externalization ofphosphatidylserine acting as an indicator of the induction of apoptosis. EEAMtreatment activated excessive accumulation of ROS followed by disruption ofMMP, cytochrome c leakage and activation of the initiatorand executioner caspases in both colon cancer cells. Immunofluorescenceanalysis portrayed the up-regulation of Bax and down-regulation of Bcl-2proteins while treated with EEAM. Furthermore, EEAM conspicuously blocked themigration and invasion of HT-29 and HCT-116 cells (29,31).In colon cancer cells, Graviola leaves alsohave significant effects on cell survival potential via mitochondrial-mediatedapoptosis associated with the G1 cell cycle arrest.
Graviola elicits apoptosisby generating reactive oxygen species ROS and down-regulating theanti-apoptotic Bcl-2 protein, while up-regulating pro-apoptotic Bax protein.These processes subsequently steer to attenuation of mitochondrial membranepotential (MMP) and cytochrome c release. Release of cytochrome c activatesapotosome and the intrinsic caspase cascade that triggers execution ofapoptosis through DNA fragmentation. (30).The effect ofGraviola extract against the prostate cancer cell lines has also been expoundedin vitro. The experiments performed to show that Graviola initiates necrosis inPC-3 cells through inhibition of cellular metabolism and tumor mobility.Further evaluation depicted the downregulation of the expression of thehypoxia-related factors and glycolytic factors following treatment in PC cellswith Graviola (41).
The activity of the water extract of leavesof A. muricataagainst the benign prostatic hyperplasia (BPH-1) cell line and rats prostateswas examined where the the anti-proliferative effects with an IC50 of 1.36mg/mL was indicated. Bax gene was up regulated, while Bcl-2 was suppressed.Normal histology of all the other testes was observed. Seminal vesicle wassignificantly reduced in test groups (P < .05) and showed marked atrophywith increased cellularity and the acinii, empty of secretion.
Prostate of testgroups were abridged with epithelial lining showing condensation, pyknoticnucleus and marginalization of the nuclear material as the characteristic ofapoptosis of the glandular epithelium. Furthermore, inadequate prostaticsecretion with flattening of acinar epithelial lining was observed. Thus wasconcluded that Annonamuricata has anti-proliferative effects on BPH-1 cells anddeduces the prostate size, possibly through apoptosis (5). This promising antitumor effect was also reported inan in vivo studyon 7,12-dimethylbenzene anthracene (DMBA)-induced cell proliferation in thebreast tissues of mice.
Oral administration of the A.muricata leavesprobably have protective effects towards the development of breastcarcinogenesis was shown by DMBA as it induced a protective effect against DNA damage. Theleaves, even at a low dosage of 30 mg/kg suppressed the initiation andpromotion stage of skin papillomagenesis in mice that was induced by DMBA andcroton oil, respectively (27).
Inxenografts studies, the oral administration of 100mg/kg bw GLE show tumorgrowth-inhibition in human prostate tumor. This study alsovalidates 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 andothers A. muricata exhibitedanti proliferative effects on HL-60 cells by promoting loss of cell viability,morphology changes, loss of membrane mitochondrial potential and G0/G1 phasecell arrest. Their reports confirmed the efficacy of A.
muricata asan agent of chemotherapeutic and cytostatic activity in HL-60 cells (7). Studies have revealedthat the extracts have selective inhibition of breast cancer cells via EGFRdownregulation. An oncogene, the epidermal growth factor receptor (EGFR) isthat is often overexpressed in breast cancer (BC), along with itsoverexpression 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 BCcells utilizing xenografts mouse model studies. Moreover, GFE selectivelyrestrained the growth of EGFR-overexpressing human BC (MDA-MB-468) cells butnot in non-tumorigenic human breast epithelial cells (MCF-10A). These studies strengthen the evidencethat Graviola has selective anti-growth effects between cancer and non-cancercells (8).Another reporton breast cancer cells by Yu-Min Koa andcolleagues supported that Graviola endorses apoptosis in ER-relatedpathways.
Moreover, Graviola subsided MCF-7 tumor growth while hinderingER-cyclin D1 and Bcl-2 protein expressions in nude mice (44). It has been analyzed that Graviola also seemedto 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. Itwas authenticated and confirmed that Graviola does indeed haveanti-proliferative and cytostatic activity in HL-60 cells by these findings(7). Overexpression ofanti-apoptotic proteins is archetypal in many forms of cancer. In the studyperformed by Priya Antony and Ranjit Vijayan, there wereconclusions on the insights on how a potential Bcl-Xl-selective inhibitors of cancer where molecular docking and simulations may beused to identify potential lead compounds from A.
muricata thatcould be inhibitors of these anti-apoptotic proteins can be designed fromacetogenins of A. muricata . The results depicted that theacetogenins namely annomuricin-D-one, annomuricin A, annohexocin, muricatocinA, , and muricatetrocin A/B showed higher docking score in Bcl-Xl but not inBcl-2 and Mcl-1. Structural and interaction analysis presented that thesemolecules through large lipophilic interactions bound stably in the active siteof Bcl-Xl.
In comprehensive docking studies, using natural and syntheticinhibitors of Bcl-Xl, acetogenins indicated better binding scores andintermolecular interactions. When the protein–ligand complexes were rescoredusing frames from MD simulations, docking scores were also significantly upgradedsuggesting that the water molecules play a crucial role in the binding siteinteraction (39).Further studies by Yang C et, .al have shown that the Graviola leafextract (GLE) pharmacokinetics and absorption kinetics resulting in inhibitingprostate cancer proliferation, viability and clonogenic colonies (43). The caspase 3 activation by the ethanol extract of the leaves also establishan apoptosis-inducing effect in myelogenous leukemic K562 cells, which wasverified with a TUNEL assay by Ezirim A. et al.(10)Anonnamuricata also had impacts onLewis 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 hadantitumor activity by limiting the natural growth of the lung tumors (45). NADHoxidase inhibition in cancer cell lines, down regulation of the P-glycoproteinpump via ATP depletion and Cell cycle arrest at S-phase progression has shownto be affected by Graviola through its anti-cancerous and cytotoxic mechanisms,which has been shown by additional research.