maanantai 21. toukokuuta 2018

Graviola, aka Soursop: What You Need to Know

Graviola: What You Need to Know

Graviola is the ­Portuguese name for a plant that is widely grown and consumed in Latin America. In Spanish-speaking countries, the fruit is called guanábana. Common names for it are soursop, custard apple, cherimoya, and Brazilian paw paw. By whatever name, this tropical evergreen tree produces a fruit with white flesh, many large seeds and an extremely sweet, slightly acidic flavor. Because it is difficult to eat, its pulp is commonly made into juice. In fact, your local grocery store probably sells the popular guanábana nectar.

Not only the fruit but also other parts of this plant -- the leaves, stem, bark, roots, and seeds -- have a long history of medicinal use in the Americas. Graviola is used as a natural remedy for infections, fever, digestive problems and high blood pressure [source: Cassileth]. Researchers have documented many other traditional uses among the indigenous people of the Andes, the Amazon and the Caribbean [source: Taylor].

Recently, scientists have begun to explore the potential of the bioactive chemicals in graviola leaves, stems and seeds, called annonaceous acetogenins. These acetogenins appear to have powerful anti-tumor and anti-cancer qualities. Some test-tube studies have concluded that graviola compounds may be able to target and kill cancer cells, even drug-resistant ones, without interfering with healthy cells. These results, circulated through alternative medicine networks and on the Internet, have created considerable excitement and a measure of hype. Natural health guru Andrew Weil is among those who are skeptical of the claims made for graviola and recommends against its use [source: Weil]. It may take years before clinical trials are conducted to legitimate or disprove the claims made by graviola proponents. In the meantime, the plant has hit the herbal market and many cancer patients are taking it.
This article will attempt to cut through the controversy regarding this form of alternative medicine, its known uses and current research.

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Graviola Benefits
Graviola is a rainforest plant that has been part of the natural and traditional medicine of Central and South America and the Caribbean for centuries. It has an extremely wide range of medicinal properties, which are distributed through the different parts of the plant. The fruit or juice is taken to reduce fever, counteract diarrhea and dysentery, and kill worms and other parasites. The seeds are also a potent antiparasitic and are used traditionally as a remedy for lice. The bark, leaves and roots can be made into a soothing medicinal tea, taken as a sedative or an antispasmodic. Research also bears out the traditional use of graviola tea as a hypotensive -- that is, a remedy for high blood pressure [source: Taylor]. The bark can also be used to treat fever, and the leaves are used topically to speed the healing of wounds. The unripe fruit is especially prized as a digestive aid [source: Weil].

Additional utilization of graviola has been documented within specific native healing traditions. In the Andean mountain ranges of Peru, graviola leaves are brewed to discharge mucus and soothe inflamed mucous membranes.
To the east, in the Amazon region, the bark, leaves and roots are used by diabetics to stabilize blood sugar. The leaf tea is taken as a heart tonic in Guyana, a liver remedy in Brazil, and a treatment for asthma, coughs and flu in the West Indies. It is also used for arthritis and rheumatism, and some mothers eat and drink the graviola fruit to increase lactation [source: Taylor].

New York's Memorial Sloan-Kettering Cancer Center affirms a number of the plant's beneficial properties, including antiviral, antiparasitic, antirheumatic and emetic effects on its Web site [source: Memorial Sloan-Kettering]. In view of this extensive list of benefits, the claims for graviola's cytotoxic effects on tumors and cancer cells have acquired a certain credibility for many people, despite the absence of scientific evidence on human subjects.
Like any potent medicine, albeit natural in origin, graviola has certain contra-indications and side effects. Continue reading to discover what they are.

Results of a neurological study, published in 1998, found that graviola has the capability to stimulate the brain's receptors for serotonin and may have an antidepressant effect [source: Cassileth]. Traditional usage supports this conclusion. To treat anxiety, one herbal manufacturer markets a tincture of graviola combined with the bark of mulungu, another rainforest tree [source:Amazon Botanicals].

Graviola Side Effects
Some side effects follow from graviola's areas of bioactivity. Studies on animal subjects have demonstrated that the plant can dilate blood vessels and lower blood pressure, so those whose blood pressure is already low, or are already on medication to reduce hypertension, should consult their physician before taking graviola [source: Wright]. Also, a large dose taken at one time can cause nausea and vomiting [source: Taylor].
Graviola's purported anti-cancer potency comes largely from its ability to reduce the supply of adenosine triphosphate (ATP) to cancer cells.
ATP often provides metabolic energy to healthy cells as well, and some nutritional supplements, notably Coenzyme Q10, are known for increasing ATP. For this reason, CoQ10 may neutralize the effect of graviola and they should not be taken together [source: 
Some side effects follow from graviola's areas of bioactivity.
Studies on animal subjects have demonstrated that the plant can dilate blood vessels and lower blood pressure, so those whose blood pressure is already low, or are already on medication to reduce hypertension, should consult their physician before taking graviola [source: Wright]. 
Also, a large dose taken at one time can cause nausea and vomiting [source: Taylor].


I entsyymi on NADH-dehydrogenaasi, II on sukkinaattidehydrogenaasi, III on sytokromi b-ckompleksi ja IV entsyymi on sytokromi-c-oksidaasi

Elektroninsiirtoketju on mitokondrion sisäkalvolla (eukaryootit) tai solukalvon kalvoproteiineissa (bakteerit) tapahtuva energiaa tuottava reaktiosarja, jossa sitruunahappokierrossa ja sitä edeltäneissä reaktioissa koentsyymeille NADH ja FADHsiirtyneitä elektroneja siirrellään elektroninsiirtoketjun entsyymiltä toiselle, jolloin elektronit menettävät potentiaalienergiaansa vähitellen, vapauttaen samalla energiaa. Vapautuvan energian avulla mitokondrion matriksista pumpataan protoneja mitokondrion kalvojen välitilaan, mikä aiheuttaa elektrokemiallisen gradientin eli potentiaali- ja protonikonsentraatioeron matriksin ja välitilan välille. Muodostunut gradientti purkautuu ATP-syntaasientsyymin kautta, jolloin muodostuu suurenergiaista fosfaattiyhdistettä, ATP:tä.

Electron transport chain
Electron transfer chain in the inner-membrane of mitochondrion. The electron transfer chain contains five complexes designated as complex I, II, III, IV, and V (F 1 F 0 -ATP synthase). The electrochemical H + gradient provided by these membrane-bound complexes serve as energy source for ATP synthesis from ADP and inorganic phosphate by an F 1 F 0 -ATP synthase

The Annonaceous acetogenins are promising new antitumor and pesticidal agents that are found only in the plant family Annonaceae. 
Chemically, they are derivatives of long-chain fatty acids. Biologically, they exhibit their potent bioactivities through depletion of ATP levels via inhibiting complex I of mitochondria and inhibiting the NADH oxidase of plasma membranes of tumor cells. Thus, they thwart ATP-driven resistance mechanisms. This review presents the progress made in the chemistry, biology, and development of these compounds since December 1995

Understanding mitochondrial complex I assembly in health and disease

Complex I (NADH:ubiquinone oxidoreductase) is the largest multimeric enzyme complex of the mitochondrial respiratory chain, which is responsible for electron transport and the generation of a proton gradient across the mitochondrial inner membrane to drive ATP production. Eukaryotic complex I consists of 14 conserved subunits, which are homologous to the bacterial subunits, and more than 26 accessory subunits. In mammals, complex I consists of 45 subunits, which must be assembled correctly to form the properly functioning mature complex. Complex I dysfunction is the most common oxidative phosphorylation (OXPHOS) disorder in humans and defects in the complex I assembly process are often observed.

Researchers exploring the mechanisms that graviola uses claim that the acetogenins in the plant can distinguish cancerous cells from healthy cells because cancer cells have a consistently higher level of cellular activity.
The acetogenins recognize and selectively inhibit the cancer cells. Pregnant women are advised to avoid graviola because the high energy in the cells of the developing fetus may trigger the botanical's toxic activity [source: Wright]. The plant was also found to stimulate the uterus in an animal study [source: Taylor].
The most detrimental effect attributed to graviola is that it "may cause neural dysfunction and degeneration leading to symptoms reminiscent of Parkinson's Disease" [source: Memorial Sloan-Kettering]. The first study to make this assertion was conducted by French researchers in Guadeloupe, who found an abnormally high presence of atypical Parkinson's amongst a poor population that used graviola for both food and medicine. However, the outbreak of neurological disorders was relatively confined, whereas the popularity of graviola is widespread in the region [source: Wright]. In her book "The Healing Power of Rainforest Herbs," botanist Leslie Taylor acknowledges that graviola seeds and roots contain alkaloids that have shown neurotoxic effects in tests. For this reason, she recommends using the leaves instead [source: Taylor].

Graviola -hedelmän ja -lehtien aineosat, annonaceus acetogenins, etsivät
nopeasti kasvavat, paljon energiaa tuhlaavat syöpäsolut ja estävät niiden ravinnon
ja hapen saannin.
- Graviolan aineosat pysäyttävät syöpäsolujen kasvun jo niiden energian-
tuotannossa, mitokondrioissa, Complex 1: n elektronisiirto -ketjussa.
Electron transport chain COMPLEX 1 (NADH ubiquinone oxidoreductase)

The Warburg hypothesis, sometimes known as the Warburg theory of cancer,
postulates that the driver of tumorigenesis is an insufficient cellular respiration caused by insult to mitochondria.[1] The term Warburg effect describes the observation that

cancer cells, and many cells grown in-vitro, exhibit glucose fermentation even when
enough oxygen is present to properly respire. In other words, instead of fully respiring
in the presence of adequate oxygen, cancer cells ferment.

He hypothesized that cancer, malignant growth, and tumor growth are caused by the
fact that tumor cells mainly generate energy (as e.g., adenosine triphosphate / ATP)
by non-oxidative breakdown of glucose (a process called glycolysis).
This is in contrast to "healthy" cells which mainly generate energy from oxidative
breakdown of pyruvate.
Pyruvate is an end-product of glycolysis, and is oxidized within the mitochondria.

4.2. Annonaceous Acetogenins
AGEs are a unique class of C-35/C37 secondary metabolites derived from long chain
(C-32/C34) fatty acids in the polyketide pathway. They are usually characterized by a combination of fatty acids with a 2-propanol unit at C-2 that forms a methyl-substituted α,β-unsaturated γ-lactone [72]. Since the discovery of uvaricin from Uvaria accuminata
in 1982, more than 500 AGEs have been identified from different parts of the plants in the Annonaceae family [73,74]. Due to the special structures and extensive biological activities, AGEs have attracted significant scientific interest in recent years.
Various biological activities have been reported for AGEs, including antimalarial, antiparasitic and pesticidal activities [72,75].

However, the biological activities of AGEs are primarily characterized with toxicity against cancer cells and inhibitory effects against the mitochondrial complex I (mitochondrial NADH: ubiquinone oxidoreductase) [76,77].

Phytochemical investigations and biological studies on different parts of the A. muricata plant resulted in the identification of a wide array of AGE compounds, as summarized in Table 1.
The chemical structures of the major acetogenins are shown in Figure 2.
To the best of our knowledge, at the time of preparation (January 2015) of the present review over 100 AGEs have been identified in A. muricata.

Electron Transport Chain | 8.12.2016
The Electron Transport Chain & complexes I-IV that pump protons out of the Mitochondria by the transfer of the electrons carried on NADH & FADH2 to maintain the concentration gradient of the protons "high in the intermembrane space & low in the matrix of the Mitochondria"

Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1

(Scientific Reports volume 6, Article number: 36462 (2016) doi:10.1038/srep36462)

In this study, we evaluated a novel PAI-1 inhibitor, annonacinone, a natural product from the Annonaceous acetogenins group
- High plasma levels of PAI-1 are related to the development of thrombosis as well as several other pathologies such as cardiovascular diseases and metabolic disturbances 1,2,3.
- Moreover PAI-1 is able to promote tumor angiogenesis and high PAI-1 level in solid tumors are associated with a poor prognosis 4,5.


 In conclusion, our work showed that, as well as their other biological properties, natural Annonaceous acetogenins, and particularly annonacinone, have an effect on fibrinolysis.
Indeed, annonacinone is a potent inhibitor of PAI-1 in vitro, ex vivo and in vivo.
Annonacinone mechanism of action and binding site on PAI-1 were also enlightened.
Altogether, annonacinone appears to be a very promising antithrombotic agent and should be further studied.

Fibrinolysis is a process that prevents blood clots from growing and becoming problematic.[1] The fibrinolytic system is closely linked to control of inflammation, and plays a role in disease states associated with inflammation.Plasmin is produced in an inactive form, plasminogen, in the liver.
PAI-1 is present in increased levels in various disease states, such as a number of forms of cancer, as well as in obesity and the metabolic syndrome. It has been linked to the increased occurrence of thrombosis in patients with these conditions.

Figure 5: Depiction of a putative binding mode of annonacinone against the active form of PAI-1


Chemical structures of the major compounds isolated from Annona muricata.
Published online 2015 Jul 10. doi:  10.3390/ijms160715625

Graviola and Cancer
The National Cancer Institute first noted the anticancer activity of graviola leaves in 1976, in an internal study not publicly released. Much of the subsequent research has been conducted at Purdue University in Indiana [source: Bluestein].
The studies concentrate on the antitumor properties and selective toxicity of annonaceous acetogenins. In 1997, the Purdue team announced that these phytochemicals, in studies, appeared especially effective at destroying cells that had survived chemotherapy. Such cells can develop resistance to several anti-cancer agents, earning the name multi-drug resistant (MDR). Typically, less than two percent of cancer cells have MDR properties, but this small set can quickly multiply after initial chemotherapy, rendering subsequent rounds of chemo useless. Expelling the anti-cancer agents requires large amounts of cellular energy, which MDR cells acquire from the chemical ATP. 
Acetogenins inhibit ATP transfer (complex I of mitochondria) into these cells, retarding their function in a process that eventually leads to cell death.
This process bypasses the healthy cells, which do not require infusions of ATP [source: Taylor].



Clinical Summary

Graviola, a tree prevalent in the rain forests of Africa, South America, and Southeast Asia, has been used in traditional medicine in many countries.

Extracts of graviola show antiviral (1), antiparasitic, antirheumatic, astringent, emetic (2), antileishmanial and cytotoxic (3) (4), antinociceptive, anti-inflammatory (9), antihyperglycemic (10) and anticancer effects (5)(12) (13) in vitro and in vivo.

Purported Uses

Cancer treatment, Herpes, Infections, Parasitic infections

These research findings have generated tremendous excitement, as well as an effort to market graviola supplements. Skeptical analysts point out that test-tube experiments are only a preliminary stage in cancer research, and it is therefore premature to ascribe a potent anticancer effect to graviola. Nevertheless, one study claimed that graviola was 10,000 times more effective against cancer than the well-known chemotherapy drug Adriamycin, and this dubious assertion has found its way to numerous promotional sites [source:]. Ralph Moss, a respected cancer writer who has been critical of mainstream oncology, comments that "astounding claims concerning cancer cures spread like a virus from Web site to Web site." However, Moss admits that graviola is "of potential importance to the future of medicine" [source: Moss]. Its increasing popularity indicates that some individuals are not content to wait for the blessing of the scientific establishment.
To learn more about graviola, visit the sites on the following page.

Pharmaceutical companies have succeeded in reproducing several annonaceous acetogenins in the laboratory. They are presently tinkering with chemical structures, with the goal of creating a synthetic acetogenin unique enough to patent and effective enough to market. They cannot patent the natural phytochemical, and therefore cannot assure a profit from it. This may explain the conundrum of why no clinical studies have been done on such a promising medicinal plant [source: Taylor].


  • Amazon Botanicals. "Anti-Anxiety Herbs." (Accessed March 8, 2009)
  • Bluestein, Chuck. "Cancer Cure: The Story About Graviola and Cancer." (Accessed March 7, 2009)
  • Cassileth, Barrie. "Integrative Oncology: Complementary Therapies, Herbs, and Other OTC Agents." Oncology, September 2008. (Accessed March 8, 2009)
  • "The Graviola Information Site." (Accessed March 8, 2009)
  • Memorial Sloan-Kettering Cancer Center. "About Herbs: Graviola." (Accessed March 7, 2009)
  • Moss, Ralph W. "The War on Cancer: A Friendly Skeptic Looks at Graviola." (Accessed March 7, 2009)
  • Taylor, Leslie. "Graviola." From The Healing Power of Rainforest Herbs (Square One Publishers, 2005). (Accessed March 7, 2009)
  • Weil, Andrew. "Graviola: A Worthwhile Botanical Against Cancer?" (Accessed March 7, 2009)
  • Wright, Kathryn Mays. "Groundbreaking Plant From the Amazon Takes on Cancer, Skeptics, and Controversy." Health Sciences Institute newsletter, October 2005. (Accessed March 8, 2009)
Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1
High plasma levels of PAI-1 are related to the development of thrombosis as well as several other pathologies such as cardiovascular diseases and metabolic disturbances1,2,3. Moreover PAI-1 is able to promote tumor angiogenesis and high PAI-1 level in solid tumors are associated with a poor prognosis4,5. Therefore, development of small molecule PAI-1 inhibitors should prove useful not only in the treatment of thrombotic disorders but also in diverse disease states.

Database File for: GRAVIOLA (Annona muricata)

Family: Annonaceae 
Genus: Annona 
Species: muricata 
Synonyms: Annona macrocarpa, A. bonplandiana, A. cearensis, Guanabanus muricatus 
Common names: Graviola, soursop, Brazilian paw paw, guanábana, guanábano, guanavana, guanaba, corossol épineux, huanaba, toge-banreisi, durian benggala, nangka blanda, cachiman épineux 
Part Used: Leaves, fruit, seeds, bark, roots

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