Cancer a standard life expectancy. There are over

Cancer being a catastrophe of the frame ofhigher multicellular organisms consequential from the abnormal growth of thecells attains modifications in the statement of copious amendments, promptingdysregulation of the conventional cell programming concerned with the celldivision and cell separation. This upshot in an unevenness of cell replicationand cell passing that stimulates the development of a tumor cell population.The characters that portray a lopsided growth of a malignant tumor are thecompetence to strike locally, to sweep to neighboring lymph nodes, and tometastasize 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 features as cell antigenicity, invasiveness,metastatic potential, rate of cell proliferation, differentiation state, andresponse to chemotherapeutic agents. At the molecular level, all cancers haveplentiful things in mutual, which implies that the ultimate biochemical lesionssteering to malignant transformation and progression can be fabricated by acommon but not analogous pattern of alterations of gene readout.

In general,malignant cancers cause noteworthy morbidity and will be lethal to the host ifnot treated. Omissions to them give the marks to be concealed, laidback cancersthat may remain clinically undetectable (or in situ), permits the host to havea standard 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. Chronic degenerativediseases like cancer have touched rampant proportions and are regarded as aserious medical condition and therefore, the treatments of these diseases areof clinical importance (WHO, 2005). In consequence, the medicinal plants play apivotal role and are considered as the basis for health preservation and careworldwide. There have been researches done on the anti-cancerousproperties 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.

Variousstudies have concentrated on the anticarcinogenic properties of plants, to namea few, Abrus precatorius, Albizza lebbeckAlstonia scholaries Anacardium occidentale hepatoma, Asparagus racemosa,Boswellia serrata, Ethyrina suberosa, Euphorbia hirta, Gynandropis pentaphylla,Nigella sativa, Peaderia foetida, Picrorrhiza kurroa, Withania somnifera, Annonamuricata. Due to the therapeutic ability of the species Annona muricata of the familyAnnonaceae, wide range of studies has been made over the last decade. Thebioactivity as well as toxicity of this species has diverted the attentiontowards itself.  1.   Annona muricata: Descriptionand ethno-medicinal uses:Annona muricata, commonly called Soursop or Graviola, isa tropical plant species renowned for its edible fruit which has selectedrestorative benefits, in addition to particular toxicological impacts (23). This plant is a species of the genus Annona, of theAnnonaceae family, order Magnoliales and Division Magnoliophyta. The genus Annona comprises over 70 species amongwhich A.

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muricata is the most extensively grown. TheSoursop tree grows up to 5– 10 m tall and 15– 83 cm in breadth with lowbranches. 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 isscattered in the tropical areas. Theflowers of the plant are showy and are yellow-green colored. The fruithere is an ovoid berry, dull green in shading.

Each fruit may comprise 55–170black seeds when fresh and they transform to light brown when dry. The flesh iswhite and creamy with distinctive aroma and flavor.                                    Figure 1: A) Annona muricata, fruit tree    B)Leaves     C) Fruit, an ovoid berry    D) Flower Traditional medicinal benefits of leaves,bark, fruit and seed of A. muricata have beenthe emphasis of myriad medicinal routines(14, 17). The mostsignificantly used preparation in traditional medicine is the decoction ofbark, root, seed or leaf and applications are wide-ranging.

The ingestion ofleaves decoction is used as analgesic and also it is used to cope withdiscomfort accompanying colds, flu and asthma. The use of leaves to treatmalaria is very substantial. The fruit is not only cherished as food, but thejuice is used as galactogogue to treat diarrhea, heart and liver diseases, andagainst intestinal parasites. Customarytherapeutic qualities of A. muricatahave been recognized in tropical locales to ponder different afflictions, forexample, fever, torment, respiratory and skin disease, bacterial infections,hypertension, aggravation, diabetes andcancer. 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 are widely used aslocal and habitual medicines contrary to a large number of human inflammations,infections and disorders. The pulp of the fruit is used as natural medicine forjoint pains, dysentery, neuralgia, diarrhea, rheumatism, fever, malaria, skinrushes and worms. The fruit is also eaten to increase mother’s milk afterparturition. The leaves are used to control cystitis, body aches and diabetes.Additionally, the administration of the leaf’s decoction is thought to displayanti-rheumatic and neuralgic effects.

In addition, the cooked leaves aretopically used to treat abscesses and rheumatism that was reported by de Sousa OV and colleagues (10). The crushed seeds arethought to have anthelmintic activities antagonistic 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). InMalaysia, 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, leavesof A.

muricata are implemented as an ethnomedicine opposed totumors and cancer. Moreover, the smooth muscle relaxant, hypotensivehypoglycemic, anti-inflammatory, sedative, and antispasmodic effects accreditto the leaves, barks and roots of A. muricata. Moreover alongwith the ethnomedicinal uses, the fruits are widely employed for thepreparation of beverages, ice creams,and syrups (3, 22, 24, 27) . 2.    Phytoconstituents: Over 200 chemical compounds have been documented and isolated from thisplant; out of which the most prominent compounds are the alkaloids, phenols,flavonoids and acetogenins. Based on the in vitro studies, extracts andphytochemicals of A. muricata have beensorted out as anti-microbial, anti-inflammatory, anti-protozoan, antioxidant,insecticide, larvicide, and cytotoxic to tumor cells.

Researches onthe extracts and isolated compounds of A.muricata suggested contraceptive, antitumor, anti-ulceric, wound healing,hepato-protective, anxiolytic, anti-stress, anti-inflammatory, anti-icteric andhypoglycemic activities. To amplify the hypoglycemic activity of the ethanolicextracts of A.

muricata leaves,various clinical studies were conducted. Cytotoxic, antioxidant, antimicrobial, anti-nociception and hypotensiveactivities are analyzed and developed by mechanisms of action of a fewpharmacological activities. Although, some phytochemical compounds isolatedfrom A. muricata have shown aneurotoxic effect in vitro and in vivo. Hence, to define the magnitude of theeffects, optimal dosage, long-term safety, and potential side effects,additional studies on these crude extracts and isolated compounds should becarried out (33).

Constant examinations on diverse parts of the A. muricata have shown theoccurrence of varieties of phyto constituents and compounds, includingflavonoltriglycosides (FTGs) alkaloids (ALKs), phenolics (PLs), megastigmanes(MGs), cyclopeptides (CPs) and essential oils. The existence of variousminerals such as Ca, Na, Fe, K, Cu and Mg imply that regular intake of A.

muricata fruit can helpfurnish essential nutrients to the human body. However, Annona species,including A. muricata, have been shown to be a vital source of annonaceousacetogenin compounds (AGEs).

Almost all the parts inclusive of the fruits, leaves, stems and roots ofthis plant are known to be rich in flavonoids, isoquinoline alkaloids andannonaceous acetogenins. (24, 26, 27, 29, 38, 44). Long chain (C-32/C34) fatty acids inthe polyketide pathway give rise to Acetogenins, a unique category of C-35/C37secondary metabolites. It is explained by combining fatty acids with  2-propanol unit at C-2 that gives amethyl-substituted ?, ?-unsaturated ?-lactone. After 1982,a number ofacetogenins have been identified with the discovery of uvaricin from Uvariaaccuminata  . About 500 have been reported from numerous parts of theplants in the Annonaceae family.

In recent times, AGEs have drawn significantscientific interest due to the remarkable structures and broad spectrum ofbiological activities. The active annonaceous acetogenins have shown to besuccessful in inducing death in cancer cells that are resistant to evenchemotherapeutic drugs. It is found that these annonaceous acetogenins aids todebilitating side effects such as neurotoxicity which results in easy traverseof the blood-brain barrier and causes a typical Parkinson’s disease. Thisinhibits the growth of new drug entities.

Various biological activities havebeen reported for AGEs, including antimalarial, anti-parasitic and pesticidalactivities. Yet, the toxicity against cancer cells and inhibitions of themitochondrial complex I are initially influenced by the physiological activitiesof AGEs (11, 12, 25).4.     Anticancer activity:There are plentiful reportsthat signify anti-proliferative effects of various extracts of the plant andisolated AGEs against various cancer cell lines. As mentioned earlier cancer iscategorized based on the primary tissue it occurs in. The antitumor effects of A. muricata against various cancer celllines are described here.

Breast Adenocarcinoma: Anoncogene, the epidermal growth factor receptor (EGFR) that is quite often overexpressedin breast cancer (BC) and is linked with poor prognosis and drug resistance. Studieshave revealed that there is a selective inhibition of breast cancer cells viaEGFR down regulation by the extract of Graviola. Thus, EGFR is a rationaltarget for BC therapy development.

In addition, xenografts mouse model studies experimentshave showed that the fruit extract reduces the growth of BC cells (9). The Fruit extract specifically suppressed the growth ofEGFR-overexpressing human BC (MDA-MB-468) cells but did not in non-tumorigenichuman breast epithelial cells (MCF-10A). These reports bolster the evidence that Graviolahas selective anti-growth effects between cancer and non-cancer cells (37). In a report by Yu-Min Koa and colleagues it was shownthat Graviola favors apoptosis in ER-related pathways. In addition, it was alsonoted that Graviola had subsided MCF-7 tumor growth while hindering ER-cyclinD1 and Bcl-2 protein expressions in nude mice (46).

A promising antitumor effect was reported in an in vivo study on 7,12-dimethylbenzene anthracene(DMBA)-induced cell proliferation in the breast tissues of mice. Oraladministration of the Graviola leavessupposedly have protective effects towards the development of breastcarcinogenesis was shown by DMBA as it induced a protective effect against DNAdamage. Cervical Cancer:In a study by AN Artanti et,al the results demonstrated that acetogenins from Annona muricata have growth inhibitoryand cytotoxic effect on cervical cancer cell line.

The acetogenins from Annona muricata leaves performed potentcytotoxic effect on HeLa cells. Decreasing cell viability may be because ofeither cell death or cell cycle arrest. The mechanism of cell cycledistribution is also associated with some of celuller protein especially p53 protein.p53 is a tumor suppressor protein. In this study, it was observed that AGEsfrom Annona muricata treatmentincreased p53 level in nucleus. Therefore, AGE may be regarded as a viralinhibitor agent and as competitor of vaccine to prevent the development ofcervical cancer. In conclusion, extracts of Annonamuricata leaves indeed has potential to be developed as aco-chemotherapeutic agent on HeLa cell lines, it can exhibit potential abbilitywith p53 stabilization.

Further molecular target detection to investigate itscellular pathway needs to be conducted (5).Colon Cancer: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 (21).

However, the migration andinvasion of colon cancer cells were profoundly inhibited 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 validated by Moghadamtousi andcolleagues(31). Oral dosage that was administered for 60dayscaused a significant reduction of ACF formation in rats when tested bymethylene blue staining of the colorectal specimens. PCNA and Bcl2 proteinswere down regulated whereas Bax protein was up regulated after theadministration of the extract. This was depicted in the immunohistochemistry analysis where they were compared with cancercontrol group. In addition the levels of enzymatic antioxidants showed an increaseand a suppression was seen in malondialdehyde level of the colon tissuehomogenates.

This suggested the restraint of lipid peroxidation. An AGEannomuricin E was found to inhibit the growth of HT-29 cells. The cytotoxiceffect of annomuricin E was enhanced by the G1 cell cycle arrest. Annomuricinactivated the mitochondrial events comprising the dissipation of themitochondrial membrane potential and caused the leakage of cytochrome c fromthe mitochondria. Followed by this, annomuricin E activated caspase 3/7 andcaspase 9 responsible for the apoptosis (42). Furthermore, Moghadamtousi and colleaguesexamined that ethyl acetate extract of Annona muricata leaves(EEAM) exerted a striking cytotoxic effects on HCT-116 cells as determined byMTT and LDH assays.

Flow cytometric analysis illucidated the cell cycle arrestat G1 phase and also the externalization of phosphatidylserineacting as an indicator of the induction of apoptosis. EEAM treatment activatedexcessive accumulation of ROS followed by disruption of MMP, cytochrome c leakageand activation of the initiator and executioner caspases in both colon cancercells. These processes subsequently steer to attenuationof mitochondrial membrane potential (MMP) and cytochrome c release. Release ofcytochrome c activates apotosome and the intrinsic caspase cascade thattriggers execution of apoptosis through DNA fragmentation. Immunofluorescence analysis portrayed theup-regulation of Bax and down-regulation of Bcl-2 proteins while treated withEEAM.

Furthermore, EEAM conspicuously blocked the migration and invasion ofHT-29 and HCT-116 cells. (32, 33, 34).  Thus, these findings verifythe usage of A. muricata leaves in ethnomedicine against cancer and emphasizeannomuricin E as one of the contributing compounds in the anticancer activityof A. muricata leaves.Leukemia: Investigationshave also been done to check the ability of ethanolic extracts of Annona muricata leaves for itscytotoxicity potential and capacity of inducing apoptosis in K562 cancer cells,a chronic myelogenous cell line.The activity of Caspase-3 was remarkably enhanced during the apoptosisstimulated by the extract at a low quantity.

Terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling (TUNEL) assay results verified theprocess of apoptosis. The Caspase-3 activity and TUNEL assay reports endorsedthat the ethanolic extract of A. muricataleaves induced apoptosis in K562 cell lines.

Ezirim, A U and colleaguesthus concluded in their paper that Annonamuricata could be considered as a natural source for the preparation of proapoptotic drugs(16). Also in the reportsby, Constant Anatole Pieme and others, A. muricata had exhibited anti proliferative effects on HL-60cells (Human promyelocytic leukemia cell line) by promoting the loss ofcell viability, morphological differences, loss in membrane mitochondrialpotential and G0/G1 phase cell arrest. Their conclusions confirmed the efficacyof A.

muricata as an agent of chemotherapeutic and cytostaticactivity in HL-60 cells (8).  Liver Carcinoma:The aqueous extracts of Annona muricata was tested for theactivation of caspases in Huh-7 (human liver cancer cells). Huh-7 cells whentreated with the extracts, both caspase-9 and caspase-3 activities in the cellswere uplifted.

This suggested that the extract had induced apoptosis byactivating the mitochondrial mediated intrinsic pathway. The protein analysis(western blot) of caspases demonstrated that the expressions of the cleavedcaspases was dose dependent. Considering these results, it was concluded thatthe extract of A.

muricata leaves havea good potential to play a vital role as cancer chemotherapeutic agents.Furthermore, the reports by Banerjee A. et,al.

indicate the reduction in theviability of hepatocellular carcinoma cell lines possibly through G0/G1 or S phase arrest or via induction ofsub-G0/G1 DNA fragmentation thus supporting the anti-cancerous property of A.muricata.(6).Lung Cancer: The A549 cells(adenocarcinomic human alveolar basal epithelial cells) when treated withaqueous extracts of A. muricatashowed elevated levels of ROS, reduction of MMP (matrix metalloproteinases)through the upheaval of expression of Bax and decreased expression of Bcl-2.These events led to the release of cytochrome c release to the cytosol. Thereleased cyt-c activated caspase-9and caspase-3, thus causing apoptosis. Concomitantly, there was a cell cyclearrest at G0G1 phase.

The incubation of A549 cells with superoxide dismutaseand catalase predominantly suppressed the cytotoxicity that was induced by theextract. This highlighted that the intracellular ROS plays an important role incell death. Anonna muricata also has had impacts on Lewis lung carcinoma (LLC)tumor cell lines that were examined both invivo as well as in vitro wasshown in a study by Zhao GX1 et,. al. Thisvalidated that Graviola had antitumor activity by limiting the natural growthof the lung tumors (47)NADH oxidase inhibitionin cancer cell lines, down regulation of the P-glycoprotein pump via ATPdepletion and Cell cycle arrest at S-phase progression has shown to be affectedby Graviola through its anti-cancerous and cytotoxic mechanisms, which has beenshown by additional research (45).  Ovarian Cancer: Other than its various medicinal properties,the acetogenins of Annona muricatahave showed potent anti-ovarian cancer activity which specifically attackcancerous cells without affecting the healthy cells and prevent metastasis. Theplant has been proven to be an effective anti-tumor and anti-cancer medicinalplant, and thus represents a source for new antiovarian cancer drug discovery.

Cytotoxicity tests were performed in vitro using MTT assay as described CletusA. et,al. In vivo pilot experiment experiment was performed with thirty Swissalbino mice consisting of all females (average weights 18-25g). The mice wereinjected with 1 x 104 OV7-96020764-CDNA-(20uL) cell line intraperitoneally intothe abdominal cavity to form ascites which mimicked ovarian cancer. Once theascites were formed, 5 groups of mice were examined of which 4 were control, 12were treated with the leaf extract of A.muricata and 4 were treated with doxorubicin. It was remarkably noted thatthe Annona muricataextract had inhibited tumor growth in a mouse model with intraperitonealmetastasis ascites formation.

Above 90% of the tumor inhibition has been succefully achieved using Annona muricata (7).. Pancreatic Cancer (PC): Pancreatic tumor aggressiveness is alliedwith a heightened metabolic activity and glucose concentration of malignanttumors(43). Also a hypoxic environment has been proven to be necessaryfor the oncogenic and metabolic transformation and the survival of the pancreaticcancer cells. In particular, it is believed that resistance to drugs isinduced by hypoxia by the activation of PI3K, Akt, NF-?B and MAPK pathways(15).  The cells after being treated with the Graviolaextract, showed low viability as the phosphorylation of the molecules washindered by the extract. Accordingly, the major transcription factor that isactivated under hypoxic conditions, HIF-1a expression was investigated.

Thereports stated that a product of the extract had blocked glucose transporters(GLUT1 and GLUT4), NF-?B,HIF-1a and other glycolytic enzymes like LDHA, which reduced the uptake ofglucose molecules and the production of ATP by the PC cells. This overallreduction caused the cell death. In accord with the ATP reduction, the extractalso increased the ROS levels within the cells that eventually led to necrosis(41, 30). Necroticagents by itself being less significant in the treatment of cancer as theyinduce a local inflammation. But the inflammation thus caused leads to theactivation of the innate immune system to initiate anti-tumor activities (41). This effectalong with the progression of PC cells was evaluated in the KrasG12DPdx1- Cremice(36,40). The micewith a developing pancreatic intraepithelial neoplastic (PanIN) lesions was fedwith the plant extract.

The cells were analyzed and it was concluded that thecytotoxic effects were particular to the tumor cells. Thus the administrationof Graviola caused glycolytic inhibition was seen in the PC cells that led tothe depletion of the tumor.Prostate CancerThe anti-proliferative effects of the waterextract of leaves of A. muricata was examined in vivo against the benignprostatic hyperplasia (BPH-1) cell line and the rat prostates were observed.Normal histology of all the other testes was observed. There was a significantreduction in the size of the seminal vesicles of the test groups and displayeda remarkable atrophy with a raised cellularity and zero secretion in theacinii.

The apoptotic characteristics of the glandular epithelium was typicallyseen (pycknotic nuclei and nuclear material towards the periphery). Also, theBax protein was up regulated, while Bcl-2 was suppressed. Thus it was concludedthat Annona muricatahas anti-proliferative effects on BPH-1 cells and deduces the prostate size,possibly through apoptosis (4).

The effect of Graviola extract against theprostate cancer cell lines has also been expounded in vitro. Experiments havebeen performed to show that Graviola initiates necrosis in PC-3 cells throughthe inhibition of cellular metabolism and tumor mobility. Further evaluationdepicted the downregulation of the expression of the hypoxia-related factorsand glycolytic factors following treatment in PC cells with Graviola (41). Theinhibition of prostate cancer proliferation, viability and clonogenic colonieshave been proved as an outcome of the Graviola leaf extract (GLE)pharmacokinetics and absorption kinetics (43).