Worldwide Health Concern
Cancer has become a worldwide health concern and a need for a cure exposed us to seek natural alternatives. The Annona muricata is a plant-based remedy which popularity have increase over time due to its anticancer properties. It’s organisms constituents have shown to have promising compounds that can instigate apoptosis and proliferation to cancer cells. Numerous vitro and vivo studies have reveal the A. muricata possess potential anticancer constituents. Indeed, annonaceous acetogenins, ethyl acetate and ionic liquid have shown to be some of the bioactive compound extracted from A. muricata to have a positive effect. This research explores the mechanism action of these active compounds extracted in A. muricta that implies disruption on the mitochondrial complex I and cell arrest in the G0/G1 phase which stimulates apoptosis.
For the past decades cancer death has increase and remained one of the most high risk health concern worldwide. According to the American Cancer Society, in 2019, there will be an estimated of 1,762,450 new cancer cases diagnosed and 606,880 cancer death in the United States. Cancer occurs because of several changes in cell physiology that eventually replicate and produce harm to the body. There are more than 100 types of cancer, found in the human body besides the most commonly diagnosed. Even though, cancer has improved with therapy, several limitations continue to play a crucial role. The most common treatments include surgery, radiation therapy, chemotherapy, immunotherapy target therapy, stem cell transplant and medication. However, for some people the use therapies seemed to create resistance to the treatment. Thus, several studies have begun to focus on the importance of plant-based drugs who significantly have shown to add to anticancer drug discoveries. Ultimately, the use of plant based medicines have been used globally to treat diseases and several body ailments which have revealed to possess an optimistic approach to pharmacological properties. Therefore, this study explores the effect Annona muricata has in stimulating anticancer agents in the body.
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The Annona muricata (A. Muricata) is widely named as the soursop fruit, guanabana, or graviola is native to the Central and South American tropics, Western Africa and Southeast Asia. This fruit flourishes from the Annona muricate tree and gives a taste combination of sour and sweet. A. muricata flavor has been characterized as a strawberry and pineapple. It’s size and shape can be describe oval green covered with spikes on the outside. The inside is white with a sweet flesh containing 55-170 black large seeds. The taxonomic classification of this fruit is a kingdom of plantae and is member of the Annonaceae family. A. muricata is commonly used to prepare candies, syrups, and beverages. Furthermore, A. muricata fruit and leaves are currently used in native cultures as a medicinal fruit. The A. muricata for years have been recognized to help reduce fever, stomach aches, parasites and other health concerns. A. muricata have been receiving great popularity across the nation due to its biochemical pathway of being anticancer fruit. Several Studies have shown certain compounds and chemicals extracted from the leaves, seeds, bark, and fruit itself appear to have a positive correlation to act as an anti-cancer agent. Approximately, 212 phytochemical ingredients have been extracted from A. muricata organism and have shown to induce apoptosis and inhibition of proliferation on the cancer cell’s line of breast, colon and liver cancer.
Annonaceous Acetogenins (ACGS)
One of the constituents extracted in A. muricata is annonaceous acetogenins (ACGs). ACGs are derivatives of a long-chain fatty acid. A unique class of ACGs which has been detected is the C-35/C-37 fatty acids. The ACGs are combined with a 2-propanol unit at C-2 that forms a methyl-substituted ?, ?-unsaturated and ?-lactose ring (Moghadamtousi et al. 2015). The ACGs have gain popularity because they have shown to inhibit the cell growth of cancer cells by slowing down the effects on the mitochondrial complex I in mammals and insects. The complex I is responsible for the mitochondrial electron transport system, also known as the NADH: ubiquinone oxidoreductase. Alali et al.(1998) said, ACGs are potent inhibitors of NADH oxidase of the plasma membranes of cancer cells which action is to decrease oxidative and cytosolic ATP production. The deprivation of ATP causes apoptosis—cell death. Since cancer cells are known to have higher demands of ATP, the A. muricata inhibits the mitochondrial complex I yield a potential cancer therapy. Essentially, the A. muricata have been attributed to contain ACGs in all its organism which have shown to be effective against cancers. For example, Qazi et al. (2018), describe the molecular mechanism’s A. muricata enclosed in several vitro or vivo studies. When the active compound of ACGs of A. muricata was induced in pancreatic, prostate, and breast cancer studies disclose a positive outcome to cancer cells resistant. During the surveillance of pancreatic cancer, capsules containing leaf and steam powder of A.muricata reported antiproliferative antitumor effects and induce downregulation of mucin 4 (MUC4) a protein known to cause cancer. In another, study using vitro studies, lung cancer cell line A549 was extracted and treated with the A.muricata leaf. The treatment revealed A.muricata suppresses nuclear factor-kB (NF-kB) that stimulates inflammation by producing apoptosis. As well hinder the cell cycle at the G0 /G1 phase an important cell cycle mechanism that activates during G1 known as the checkpoint that verifies if everything is ready for DNA synthesis, but if cell gets deprive an alteration in gene expression can occur fluctuating its mechanism into cancerous cells. Also, in a prostate cancer research explained at low concentration (?1 ?g/ml) of A. muricata pulp can influence the antiproliferative activity in pancreatic cell lines. Moreover, in a vivo study using mouse models A.muricata show to slow the growth of MCF-7 breast cancer cells by reducing estrogen receptor, cyclin D1(responsible for the progression of G1 phase) and antiapoptotic gene Bcl2 (the protein regulator of apoptosis). As well, exposed to be antiproliferative and antitumor. The table below provides some anticancer studies on A. muricata and its anticancer effects.
Active Compound (SF-1603)
Moreover, a research by Tejasari et al. (2018) investigated the active compound (SF-1603) extracted from the A.muricata leaves instigated apoptosis induction of liver cancer cell. Let’s recall apoptosis means cells death; its purpose is to remove cells that are unnecessary, unhealthy or that can damage. As well, apoptosis helps to keep processes balanced in the body, as cell’s ages and make room for new cells. Consequently, apoptosis play an important process in suppressing the progression of liver diseases too much or too little can degenerative disease and cancer. The apoptosis process occurs because extrinsic pathway (death receptors) activates the caspases 8 and 10 and the intrinsic pathway (mitochondrial pathway) activate the caspase 9. Thus, the activation of these caspases leads to apoptosis. In this research, a vitro study was used in which HepG2 cell lines were derived from a tumor tissue of hepatocellular carcinoma (most common type of liver cancer) suffers and were treated with active compound (SF-1603) extracted from the A. muricata leaves. The study showed that when administering SF-1603 compound at higher doses than the control group the apoptosis process increased. Results can be observed at the graph below. The active compound (SF-1603) found in the leaves of A. muricata enclose a powerful anticancer ability to induce apoptosis in liver cancer cell (HepG2) line cultures.
On the other hand, Moghadamatousi et al. (2014) investigated the anticancer properties of ethyl acetate extract of Annona muricata leave (EEAM) on HT-29 and HCT-116 colon cancer cells. EEAM uncover to arrest the cell cycle of colon cancer cells at the G1 phase which stimulate apoptosis in colon cancer cells. As well, reveal that the disruption in the mitochondrial membrane potential (MMP) was caused by excessive accumulation of reactive oxygen species (ROS) in cancer cells inducing mitochondrial mediated, apoptosis in colon cancer cells which were associated with the G1 cell cycle. This mechanism can be observed in the figure below.
Figure 1.Possible anticancer mechanisms of graviola. Graviola induced apoptosis by loss of MMP and activation of caspases. Suppression of EGFR and JAK signaling leads to blockade of the PI3K, RAS and STAT pathways, respectively, culminating in decreasing cell viability and metabolic catastrophe by down-regulating HIF-1?, GLUT1, GLUT4, expression, associated with decreased glucose uptake and cell cycle arrest in human cancer cells. Graviola inhibits NF-?B mediated TNF-? and IL-1 expression to control inflammation. Graviola increases ROS generation by effecting the expression of catalase (CAT), SOD and heme-oxygenase (HO-1) expression. Graviola also kills the drug-resistant cells possible by modulating multidrug-resistant export proteins. (Qazi et al., 2018)
As mention earlier induction of apoptosis plays a crucial role in prevention and suppression of cancer cells, as well with breast cancer cells. Daddiouaissa et al. (2019) investigate the vitro effect’s breast cancer cell had when ionic liquid extract of Graviola fruit (IL-GFE) was placed on MCF-7 breast cancer cells. Results reveal IL-GFE can stimulate anti-proliferative effects against MCF-7 breast cancer cell lines by inducing loss of cell viability via apoptosis, morphology changes, and cell cycle arrest at the G0 / G1 phase (.., 2019). Thus, the image below represents how the IL-GFE treatment inhibits MCF-7 breast cancer at several time intervals. The longer they are expose the more the cell growth is reduced. Furthermore, it identified one clinical case in which consumption of boiled leaves of A. muricata with the chemotherapeutic drug has shown to stabilize cancer in a 66-year-old woman with breast cancer. According to the research, this woman self-medicated by boiling 10-12 dry leaves of A. muricata for 5-7 minutes and consumed 8 oz daily. Consequently, her cancer remained stable for five years.
Anticancer mechanism of A. Muricata
The A. muricata has shown to demonstrate to be an efficient candidate herbal remedy that possesses anticancer properties. For example, Qazi et al.( 2018) explained ACGs have shown to be an effect metabolism through a down-regulation of mitochondrial NADH oxidase function, inhibiting the mitochondrial complex I of the electron transport chain. As well, A. muricata has demonstrated to have a positive effect on the NF-kB pathway which is associated to have a helpful benefit in the management of cancer by inhibiting the site of inflammation. The depletion of ATP also shows to be another optimistic mechanism A. muricata has on anticancer properties. The detailed molecular mechanisms of A. muricata against cancer can be summarized on the figure below.
Overall, it may be said A. muricata possess a range of biological activities most promising activities are anticancer. For example, the A. muricata has shown to have several compounds such as annonaceous acetogenins which is an anticancer beneficial. As well, when the ethyl acetate extracted from the Annona muricate leaves treatment help with the excessive accumulation of reactive oxygen species disrupting the mitochondrial mediated potential known to cause cancers. However, continuation of research must be investigates the use of A. muricata as most recent research involve vitro studies and a urge of vivo study is still needed.