Se sabe que algunas partes de esta planta contienen una neurotoxina asociada a enfermedades neurodegenerativas. Aproximadamente tres millones de euros. Adicionalmente, ha escrito contenidos para varias plataformas, como www. See author's posts. El trabajo citado es: Quispe et al. CIMEL 12 1 :
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Graviola Annona muricata is a small deciduous tropical evergreen fruit tree, belonging to the Annonaceae family, and is widely grown and distributed in tropical and subtropical regions around the world.
The aerial parts of graviola have several functions: the fruits have been widely used as food confectionaries, while several preparations, especially decoctions of the bark, fruits, leaves, pericarp, seeds, and roots, have been extensively used in traditional medicine to treat multiple ailments including cancers by local communities in tropical Africa and South America. The reported therapeutic benefits of graviola against various human tumors and disease agents in in vitro culture and preclinical animal model systems are typically tested for their ability to specifically target the disease, while exerting little or no effect on normal cell viability.
Over phytochemical ingredients have been reported in graviola extracts prepared from different plant parts. The specific bioactive constituents responsible for the major anticancer, antioxidant, anti-inflammatory, antimicrobial, and other health benefits of graviola include different classes of annonaceous acetogenins metabolites and products of the polyketide pathway , alkaloids, flavonoids, sterols, and others.
This review summarize s the current understanding of the anticancer effects of A. It also includes discussion of our current understanding of possible mechanisms of action, with the hope of further stimulating the development of improved and affordable therapies for a variety of ailments.
Cancer is the second leading cause of mortality worldwide. This rapid increase is due to both an aging and growing population, along with carcinogens, infections, genetic mutations, hormones, immune conditions, and the adoption of behavioral and dietary risk factors, such as smoking, unhealthy diet, physical inactivity, and environmental pollutants [ 3 ].
The risk factors may act singly or in concert to cause mutation of normal cells [ 4 ]. Many of these mutations alter the expression or activity of key gene products, causing unregulated cell division leading to cancer. The most commonly used chemotherapy drugs are antimetabolites, DNA-interacting agents, antitubulin agents, hormones, and molecular targeting agents, all of which work to destroy cancerous cells or limit their proliferation [ 5 ].
However, most cytotoxic drugs act on both cancerous and healthy cells and therefore elicit side effects such as hair loss, bone marrow suppression, drug resistance, gastrointestinal lesions, neurologic dysfunction, and cardiac toxicity [ 5 ].
Consequently, development of new anticancer agents with higher efficacy, selectivity, and little or no side effects is an urgent goal. Natural products, especially phytochemicals, have been used to help mankind sustain health since the dawn of medicine [ 4 ].
Phytotherapy also called herbalism or herbal medicine has provided remedies for ailments, including cancer, to the present day [ 6 ]. Dietary phytochemicals have many built-in advantages over synthetic compounds due to their proven safety, low cost, and oral bioavailability [ 7 ]. However, it is only recently that researchers have begun to elucidate the mode of action of plant-derived agents at the molecular, cellular, and tissue level [ 8 — 10 ].
Many natural products have now been extensively researched, and numerous compounds have exhibited anticancer and other beneficial actions in modern controlled studies. Most anticancerous natural products interfere with the initiation, development, and progression of cancer by modulating various mechanisms including cellular proliferation, differentiation, apoptosis, angiogenesis, and metastasis [ 11 ].
Extracts from Annona muricata also known as graviola are among a myriad of botanical products which have shown promising medicinal value [ 12 — 14 ]. Studies have linked A. Moreover, all aerial parts of this plant, including the bark, fruit, leaves, root, and seeds, are used as natural medicines in the tropics [ 39 ].
However, there is a need for more rigorous studies to establish safe and effective care regimes. This review summarizes the recent advances in the application and mechanisms of A. Chemical structure of compounds derived from fungal strain extracts and the cancers sensitive to them. Different solvent extracts of A. Annona muricata is a lowland tropical, fruit-bearing tree of the family Annonaceae found in the rainforests of Africa, South America, and Southeast Asia.
Soft, curved spines cover the leathery skin of the fruits, each of which may contain 55— black seeds distributed in a creamy white flesh with a characteristic aroma and flavor [ 41 , 42 ]. Reports in the literature indicate that seventy-four of these bioactive compounds exhibit a variety of anticancer effects in preclinical cell culture and animal model systems. Several dozen annonaceous acetogenins have been studied 59 of which are listed alphabetically in Table 2 , with key structural features summarized in Figure 2.
Moreover, at least ten solvent extracts Table 1 in addition to an extract from fungi Periconia sp. Chemical structures of two AGE combinations along with their targeted cancer phenotype. AGEs of A. Structures were drawn using ChemDraw, Arial, point In developing tropical countries including Africa, different parts of A. Furthermore, in both Jamaica [ 59 ] and Trinidad [ 60 ], A.
For example, in Jamaica, a large proportion of cancer patients use medicinal plants in self-medicating practices, with A. In addition, it has been mentioned as an antimicrobial [ 66 ], antidiabetic [ 54 ], anti-inflammatory [ 67 ], antiprotozoan [ 68 ], antioxidant, insecticide [ 69 ], larvicide [ 70 ], and anticancer [ 71 ].
Although these uses of A. The aerial parts of graviola have been extensively studied with several reported in vitro and in vivo pharmacological activities, and have been shown to be effective in the management of several cancer types. The detailed molecular mechanisms of action of various graviola organs against various cancers are summarized in tabular format Table 3 and Figure 3. Overview of the molecular actions of A. Extracts of the different aerial parts of A.
Other reported health benefits include antioxidant, anti-inflammatory, and immunomodulatory activities. Anticancer effects of AGEs and extracts derived from the different aerial organs of A. Simply put, a cytotoxic drug is an agent that has destructive actions on cells, often implying that these cells are targeted for destruction [ 75 ], a concept that certainly applies to many antineoplastic drugs [ 75 ]. The major bioactive components that have been extracted from various A.
These are derivatives of long-chain C32 or C34 fatty acids derived from the polyketide pathway, reviewed in [ 76 ]. Many of these derivatives are reported to be selectively toxic to cancer cells, including multidrug-resistant cancer cell lines [ 77 ].
Annonaceous acetogenins induce cytotoxicity, at least in part, by inhibiting mitochondrial complex I, which is involved in oxidative phosphorylation and ATP synthesis [ 78 ]. As cancer cells have a higher demand for ATP than the normal cells, mitochondrial complex I inhibitors have potential in cancer therapy [ 79 ]. Purified AGEs, such as annocatacin A or B [ 80 ] or annocatalin [ 81 ], have been found to induce significant cytotoxicity in Hep G2 and Hep 2,2,15 hepatic cancer cells in vitro [ 82 , 83 ].
In breast cancer, cytotoxicity can be induced in MCF-7 cells using any of the following purified AGEs: annomuricin A, B [ 17 ], C [ 18 ], or E [ 16 ]; muricatocin A, B, or C [ 47 ]; muricapentocin [ 16 ]; annomutacin [ 43 ]; annohexocin [ 34 ]; annopentocin A, B, or C [ 32 ]; murihexocin A, B [ 15 ], or C [ 47 ]; muricoreacin [ 47 ]; muricatacin [ 48 ]; isoannonacin [ 49 ]; isoannonacinone [ 49 ]; goniothalamicin [ 49 ]; gigantetrocin [ 49 ] A or B [ 50 ], muricatetrocin A or B [ 17 , 84 ], cis -annonacin; cis -annonacinone; cis -goniothalamicin; arianacin; or javoricin [ 85 ].
In addition, synergistic therapeutic effects have been shown with the combination of AGEs. For example, cytotoxicity in breast cancer Figure 2 has been observed using a combination of 2,4- cis R-annonacin-A-one and 2,4- trans R-Annonacin-A-one [ 43 ], or a mixture of cis -annomuricin-D-one and trans -annomuricin-D-one [ 32 ].
Moreover, AGEs induce cytotoxicity in a variety of other cancers such as prostate [ 15 , 16 , 21 , 22 , 34 , 47 ], colorectal [ 16 , 17 , 25 , 32 , 34 , 44 , 86 ], lung [ 15 — 17 , 32 , 34 , 44 , 47 ] 5 , leukemia [ 46 ], renal [ 15 , 16 , 32 , 34 , 47 ], pancreatic [ 87 , 88 ], hepatic [ 35 , 36 ], and oral [ 32 , 43 ] cancers. Organic solvent extracts derived from the different parts of A.
Leaf extracts have also demonstrated reduced cell viability in pancreatic Capan-1 cancer cells [ 92 ]. Extracts derived from seeds are toxic to hepatic Hep G2 [ 31 ] cancer cells, while extracts from leaf, pericarp, seed, and stem have each shown cytotoxicity towards hematological malignant cells such as the leukemia U cell line [ 56 , 69 ].
The most commonly used solvents for the A. However, according to available data, ethanolic fruit extracts induce toxicity only against both breast T47D [ 22 ] and lung H [ 95 ] cancer cells. In addition, while ethanolic twig extract shows cytotoxic activity against ECV cancer cells in vitro [ 96 ], methanolic extracts of the leaves, pericarp, or seeds of A. Moreover, stem methanolic extract induces cytotoxicity towards leukemia U cells [ 33 ]. Apoptosis, or programmed cell death, is integral for normal development and tissue homeostasis in most multicellular organisms [ 99 ].
In many cancers, however, the gene s regulating apoptosis are faulty which leads to uncontrolled proliferation [ ]. The ability to induce cellular apoptosis in tumor tissue is the key to finding a successful natural product as an anticancer agent [ 27 , ]. Apoptosis displays characteristic morphological and biochemical changes which may include cell shrinkage, nuclear fragmentation, chromatin condensation, and membrane blebbing [ 99 , , ]. The major apoptotic pathways are intrinsic and extrinsic [ ].
The intrinsic or mitochondrial pathway can be induced through intracellular stresses such as DNA damage or oxidative stress leading to the release of mitochondrial cytochrome c forming the apoptosome complex [ ]. This complex is composed of cytochrome c, apoptotic protease activating factor, and procaspase [ ], which activates different caspases [ ].
These ligands bind to their cell surface receptors tumor necrosis factors , death receptors, and Fas causing sequential activation of caspase-8, caspase-3, and caspase-7 [ ]. Several studies examining the anticancerous properties in A. According to the available data, there are about six extract types with regard to solvent extraction of A.
Leaf extracts of A. Similarly, A. An ethanolic extract of A. Similarly, in HT colorectal cancer cells, annomuricin E derived from leaves of A. In K leukemia cancer cells, an ethanolic leaf extract significantly enhanced caspase-3 activity to induce apoptosis, which was confirmed by a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling TUNEL assay [ 19 ].
In addition, ethanolic extracts of roots, fruits, or leaves of A. An aqueous leaf extract was shown to reduce prostate size which was suggested to have been due to apoptosis [ 21 ]. Leaf extracts prepared using various solvents were also able to induce apoptosis on HeLa cervical cancer cells [ 37 ].
Treatment of colorectal HT and HCT cancer cells with an ethyl acetate extract of leaves caused apoptosis through excessive accumulation of ROS followed by disruption of MMP, cytochrome c leakage, activation of the initiator and executioner caspases, upregulation of Bax, and downregulation of Bcl-2 protein [ 25 ].
An ethyl acetate leaf extract also elicited a This effect was associated with a downregulation of PCNA and Bcl-2 proteins and an upregulation of Bax protein as well as an increase in the levels of enzymatic antioxidants and a decrease in the malondialdehyde level of the colon tissue homogenates suggesting the suppression of lipid peroxidation [ 25 ].
Similarly, an ethyl acetate extract derived from leaves of A. These effects were accompanied by the release of cytochrome c into the cytosol, which triggered the activation of caspase-9 followed by caspase-3 activation. Apoptosis also has been shown in HeLa cervical cancer cells after treatment with an ethyl acetate leaf extract [ 37 ].
Furthermore, leaf extracts using ethyl acetate and ethanol-distillate water, as well as n -hexane and chloroform leaf extracts, have also been shown to induce apoptosis in HeLa cervical cancer cells [ 37 ]. In cancer, the normal cell cycle process is impaired, resulting in uncontrolled cell proliferation, growth, and tumor progression A.
According to the available data, there are about seven AGEs and five extracts which have demonstrated antiproliferative activity. Extracts with antiproliferative properties include those using solvents such as hexane [ 30 ], ethyl acetate [ 77 ], methanol [ ], ethanol [ 27 ], and water [ 91 ] as discussed below.
Annomuricin E derived from leaves of A. A hexane leaf extract significantly reduced cell proliferation in PC-3 colorectal cancer cells [ 30 ]. Hexane and methanol extracts of A. Antiproliferative and cytotoxic activities were seen in NCI-H cancer lung cells after treatment with methanol pericarp extract [ ]. An aqueous leaf extract showed promising antiproliferative activity by arresting the cell cycle in the G2M phase in SCC squamous cell carcinoma [ 91 ].
Finally, A. Necrotic cell death is distinguished from its counterpart, apoptosis, in that caspase activation is not required for cell death.
La graviola no cura el cáncer