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Graviola

Family: Annonaceae

Genus: Annona

Species: muricata

Synonyms: Annona macrocarpa, A. bonplandiana, A. cearensis, Guanabanus muricatus

Common Names: Graviola, soursop, guanábana, guanábano, guanavana, guanaba, corossol

épineux, huanaba, toge-banreisi, durian benggala, nangka blanda, cachiman épineux

Parts Used: Leaves, fruit, seeds, bark, roots

Graviola has a long, rich history of use in herbal medicine as well as lengthy recorded indigenous use. In the Peruvian Andes, a leaf tea is used for catarrh (inflammation of mucous membranes) and the crushed seed is used to kill parasites. In the Peruvian Amazon the bark, roots, and leaves are used for diabetes and as a sedative and antispasmodic. Indigenous tribes in Guyana use a leaf and/or bark tea as a sedative and heart tonic. In the Brazilian Amazon a leaf tea is used for liver problems, and the oil of the leaves and unripe fruit is mixed with olive oil and used externally for neuralgia, rheumatism, and arthritis pain. In Jamaica, Haiti, and the West Indies, the fruit and/or fruit juice is used for fevers, parasites and diarrhea, and as a lactagogue; the bark or leaf is used as an antispasmodic, sedative, and nervine for heart conditions, coughs, grippe, difficult childbirth, asthma, asthenia, hypertension, and parasites.

Many bioactive compounds and phytochemicals have been found in graviola, as scientists have been studying its properties since the 1940s. Its many uses in natural medicine have been validated by scientific research. Several studies by different researchers demonstrated that the bark as well as the leaves had hypotensive, antispasmodic, anticonvulsant, vasodilator, smoothmuscle relaxant, and cardiodepressant activities in animals. Researchers verified graviola leaf's hypotensive properties in rats again in 1991. Several studies over the years have demonstrated that leaf, bark, root, stem, and seed extracts of graviola are antibacterial in vitro against numerous pathogens, and that the bark has antifungal properties. Graviola seeds demonstrated active antiparasitic properties in a 1991 study, and a leaf extract showed to be active against malaria in two other studies (in 1990 and 1993). The leaves, root, and seeds of graviola demonstrated insecticidal properties, with the seeds demonstrating strong insecticidal activity in an early 1940 study. In a 1997 clinical study, novel alkaloids found in graviola fruit exhibited antidepressive effects in animals.

In an 1976 plant screening program by the National Cancer Institute, graviola leaves and stem showed active cytotoxicity against cancer cells and researchers have been following up on these findings since. Much of the cancer research on graviola focuses on a novel set of phytochemicals called Annonaceous acetogenins. Graviola produces these natural compounds in its leaf and stem, bark, and fruit seeds. Three separate research groups have isolated these acetogenin compounds in graviola which have demonstrated significant antitumorous and anticancerous properties, and selective toxicity against various types of cancer cells (without harming healthy cells) publishing eight clinical studies on their findings. Many of the acetogenins have demonstrated selective toxicity to tumor cells at very low dosages—as little as 1 part per million. Four studies were published in 1998 which further specify phytochemicals and acetogenins which are demonstrating the strongest anticancerous, antitumorous, and antiviral properties. Thus far, specific acetogenins in graviola have been reported to be selectively toxic to these types of tumor cells: lung carcinoma cell lines; human breast solid tumor lines; prostate adenocarcinoma; pancreatic carcinoma cell lines; colon adenocarcinoma cell lines; liver cancer cell lines; human lymphoma cell lines; and multi-drug resistant human breast adenocarcinoma.

Annonaceous acetogenins are only found in the Annonaceae family (to which graviola belongs). In general, various Annonaceous acetogenins in the plant family have been documented with antitumorous, antiparasitic, pesticidal, antiprotozoal, antifeedant, anthelmintic, and antimicrobial activities.31 Mode of action studies in three separate laboratories have recently determined that these acetogenins are superb inhibitors of enzyme processes that are only found in the membranes of cancerous tumor cells. Purdue University, in West Lafayette, Indiana, has conducted a great deal of the research on the acetogenins, much of which has been funded by The National Cancer Institute and/or the National Institute of Health (NIH). Thus far, Purdue University and/or its staff have filed at least nine U.S. and/or international patents on their work around the antitumorous and insecticidal properties and uses of these acetogenins. In one of their reviews, titled “Recent Advances in Annonaceous Acetogenins,” they state, “Recently, we reported that the Annonaceous acetogenins can selectively inhibit the growth of cancerous cells and also inhibit the growth of adriamycin resistant tumor cells. As more acetogenins have been isolated and additional cytotoxicity assays have been conducted, we have noticed that, although most of acetogenins have high potencies among several solid human tumor cell lines, some of the derivatives within the different structural types and some positional isomers showed remarkable selectivities among certain cell lines; e.g., against prostate cancer (PC-3). We now understand the primary modes of action for the acetogenins. They are potent inhibitors of NADH: ubiquinone oxidoreductase, which is in an essential enzyme in complex I leading to oxidative phosphorylation in mitochondria. A recent report showed that they act directly at the ubiquinone-catalytic site(s) within complex I and in microbial glucose dehydrogenase. They also inhibit the ubiquinone-linked NADH oxidase that is peculiar to the plasma membranes of cancerous cells."

In 1997, Purdue University published information with promising news that several of the Annonaceous acetogenins " . . . not only are effective in killing tumors that have proven resistant to anti-cancer agents, but also seem to have a special affinity for such resistant cells." In several interviews after this information was publicized, the head pharmacologist in Purdue's research explained how this worked. As he explains it, cancer cells that survive chemotherapy can develop resistance to the agent originally used as well as to other, even unrelated, drugs. This phenomenon is called multi-drug resistance (MDR). One of the ways that cancer cells develop resistance to chemotherapy drugs is by creating an intercellular efflux pump called a P-glycoprotein mediated pump. These types of pumps are capable of pushing anticancer agents out of the cell before they can kill it. On average, only about two percent of the cancer cells in any given person might develop this pump—but they are the two percent that can eventually grow and expand to create multi-drug resistant tumors. Some of the latest research on acetogenins reported that they were capable of shutting down these intercellular pumps, thereby killing MDR tumors. Purdue researchers reported that the acetogenins preferentially killed multi-drug-resistant cancer cells by blocking the transfer of ATP—the chief source of cellular energy—into them. A tumor cell needs energy to grow and reproduce, and a great deal more to run its pump and expel attacking agents. By inhibiting energy to the cell , it can no longer run its pump. When acetogenins block ATP to the tumor cell over time, the cell no longer has enough energy to operate sustaining processes—and it dies. Normal cells seldom develop such a pump; therefore, they don't require large amounts of energy to run a pump and, generally, are not adversely affected by ATP inhibitors. Purdue researchers reported that different acetogenins tested thus far demonstrate potent ATP blocking properties (including several found only in graviola). They also reported that 13 of these 14 acetogenins tested were more potent against MDR breast cancer cells than all three of the standard drugs (adriamycin, vincristine, and vinblastine) they used as controls.

An interesting in vivo study was published in March of 2002 by researchers in Japan, who were studying various acetogenins found in several species of plants. They inoculated mice with Lewis lung carcinoma cancer cells. One third received nothing, one third received the chemo-therapy drug adriamycin, and one third received the main graviola acetogenin, annonacin (at a dosage of 10 mg/kg). At the end of two weeks, five of the six in the untreated control group were still alive and lung tumor sizes were then measured. The adriamycin group showed a 54.6% reduction of tumor mass over the control group—but 50% of the animals had died from toxicity (three of six). The mice receiving annonacin were all still alive, and the tumors were inhibited by 57.9%—slightly better than adriamycin—and without toxicity. This led the researchers to summarize; “This suggested that annonacin was less toxic in mice. On considering the antitumor activity and toxicity, annonacin might be used as a lead to develop a potential anticancer agent.” Its important to note, however, that annonacin only inhibited the normal growth of the lung tumors during this two-week period; it did not eradicate the tumors nor stop their growth altogether.

Cancer research is ongoing on these important plants and plant chemicals, as several pharmaceutical companies and universities continue to research, test, patent, and attempt to synthesize these chemicals into new chemotherapeutic drugs. In addition, researchers have reported that NADH dehydrogenase inhibitors can suppress HIV infection. As this is a familiar property of Annonaceous acetogenins, several acetogenins found in graviola and other Annona plants have been submitted to the NIH anti-AIDS screening program by Purdue University; research work is continuing in this area as well.

One researcher summarized his work eloquently: “At the time of preparation (August 1998) of this current review, over 350 Annonaceous acetogenins have been isolated from 37 species. Our preliminary efforts show that about 50%, of over 80 Annonaceous species screened, are significantly bioactive and are worthy of fractionation; thus, this class of compounds can be expected to continue to grow at an exponential rate in the future, provided that financial support for such research efforts can be found. With the demise of the world’s tropical rain forests, such work is compelling before the great chemical diversity, contained within these endangered species, is lost.” Perhaps—if enough people believe that the possible cure for cancer or AIDS truly is locked away in a rainforest plant—we will take the steps needed to protect our remaining rainforests from destruction.

Documented Properties and Actions: Antibacterial, anthelmintic, anticancerous, anticonvulsant, antidepressant, antifungal, antimicrobial, antineoplastic, antiparasitic, antispasmodic, antitumorous, antiviral, astringent, cardiodepressant, cytotoxic, febrifuge, hypotensive, insecticide, nervine, pectoral, piscicide, sedative, stomachic, vasodilator, vermifuge

Main Phytochemicals: Annonaceous acetogenins: annocatalin, annohexocin, annomonicin, annomontacin, annomuricatin A & B, annomuricin A thru E, annomutacin,  annonacin, (multiple iso, cis, one, etc.), annonacinone, annopentocin A thru C, cis-annonacin, cis-corossolone, cohibin A thru D, corepoxylone, coronin, corossolin, corossolone, donhexocin, epomuricenin A & B, gigantetrocin, gigantetrocin A & B, gigantetrocinone, gigantetronenin, goniothalamicin, isoannonacin, javoricin, montanacin, montecristin, muracin A thru G, muricapentocin, muricatalicin, muricatalin, muri-catenol, muricatetrocin A & B muricatin D, muricatocin A thru C muricin H, muricin I, muricoreacin, murihexocin 3, murihexocin A thru C, murihexol, murisolin, robustocin, rolliniastatin 1 & 2, saba-delin, solamin, uvariamicin I & IV, xylomaticin.

Traditional Remedy: The therapeutic dosage is reported to be 5–7 grams daily in capsules or tablets (in 3–4 divided dosages). A standard infusion (one cup 2–3 times daily) or a 4:1 standard tincture (2–4 ml three times daily) can be substituted if desired.

Contraindications: Graviola has demonstrated uterine stimulant activity in an animal study (rats) and should therefore not be used during pregnancy. Graviola has demonstrated hypotensive, vasodilator, and cardiodepressant activities in animal studies and is contraindicated for people with low blood pressure. People taking antihypertensive drugs should check with their doctors before taking graviola and monitor their blood pressure accordingly (as medications may need adjusting).

Graviola has demonstrated significant in vitro antimicrobial properties. Chronic, long-term use of this plant may lead to die-off of friendly bacteria in the digestive tract due to its antimicrobial properties. Supplementing the diet with probiotics and digestive enzymes is advisable if this plant is used for longer than 30 days.

Graviola has demonstrated emetic properties in one animal study with pigs. Large single dosages may cause nausea or vomiting. Reduce the usage accordingly if this occurs. One study with rats given a stem-bark extract intragastrically (at 100 mg/kg) reported an increase in dopamine, norepinephrine, and monomine oxidase activity, as well as a inhibition of serotonin release in stress-induced rats.36 As such, the use of this plant is probably contraindicated in combination with MAO inhibitors and some prescription antidepressants. Check with your doctor first if you are taking prescription antidepressants or MAO inhibitor drugs prior to taking graviola. Alcohol extracts of graviola leaf showed no toxicity or side effects in mice at 100 mg/kg; however, at a dosage of 300 mg/kg, a reduction in explorative behavior and mild abdominal constrictions was observed.37 If sedation or sleepiness occurs, reduce the amount used.

Drug Interactions: None have been reported; however, graviola may potentiate antihypertensive and cardiac depressant drugs. It may potentiate antidepressant drugs and interfere with MAOinhibitor drugs. See contraindications above.