Graviola

• How It Works

  Graviola showed anticancer effects in lab studies. Human data are lacking.

  Extracts of graviola have been shown to be effective against a number of viruses, bacteria, and parasites in test tubes. Laboratory studies have also shown graviola to be effective against some types of cancer cells. It contains chemicals called acetogenins, which are thought to be the active ingredient. However, substances derived from graviola damaged nerve cells and caused neurological side effects similar to Parkinson’s disease in laboratory and animal experiments. In addition, some animal studies suggest long-term use may increase the risk of other neurological diseases. Graviola may also affect nuclear imaging because it has been shown to decrease the uptake of radiopharmaceuticals used in such procedures.

• Purported Uses
  • To treat cancer
    Graviola has been shown effective against cancer cells in lab studies. Human studies have not been conducted.
  • To treat herpes
    Graviola is effective against the herpes virus in laboratory experiments. Clinical studies have not been conducted
  • To fight infections
    Lab studies indicate that graviola may prevent certain infections. Human data are lacking.
• Do Not Take If

  You are taking blood pressure medications: Graviola had blood pressure lowering effects in mice, and may have additive effects when taken with drugs for reducing hypertension. Clinical relevance is not known.
  You are taking diabetic medications: Graviola had blood sugar lowering effects in mice, and may have additive effects when taken with hypoglycemic drugs. Clinical significance is  not known.

• Side Effects
  • Laboratory and animal studies showed that compounds in graviola cause movement disorders and myeloneuropathy (neuropathy that affects the myelin sheath), with symptoms similar to those of Parkinson’s disease. Clinical relevance is not known.
• Scientific Name

  Annona muricata

• Clinical Summary

  Graviola is a tree prevalent in the rain forests of Africa, South America, and Southeast Asia. The fruits, also known as soursop, are consumed as food. The leaves and stems are used in traditional medicine for symptoms associated with inflammation and infection. Graviola is also available as a dietary supplement and widely promoted as an alternative treatment for cancer, although clinical evidence is lacking. In some Caribbean countries, it is among the most common herbal remedies used in among prostate, breast and colorectal cancer patients ⁽³³⁾.

  Many of the health benefits from graviola are thought to be derived from its antioxidant properties ^{(1) (2) (3) (4)}. In animal models, graviola extracts showed anti-inflammatory ⁽⁵⁾, analgesic ⁽⁶⁾, antidiabetic ⁽⁷⁾, antiulcer ⁽⁸⁾, and antiviral ⁽⁹⁾ effects. The leaf extracts also have antimicrobial activities ^(10) (11). Graviola extracts from the leaf, fruit, and seed have been tested in laboratories for their anticancer effects. Some studies show these extracts to be active against breast ⁽¹⁶⁾, lung ⁽¹²⁾, colon ⁽¹³⁾, prostate ⁽¹⁴⁾, pancreas ⁽¹⁵⁾, liver ⁽¹⁷⁾, and skin cancer ⁽¹⁸⁾ cell lines. However, graviola products have not been studied in cancer patients.

• Purported Uses
  • Cancer treatment
  • Herpes
  • Infections
  • Parasitic infections
• Mechanism of Action

  Annonaceous acetogenins, phytochemicals isolated from the leaves, bark, and twigs, are among the active ingredients of graviola ⁽³⁵⁾. An ethanolic extract of A. muricata shows in vitro antiviral activity against the Herpes simplex virus ⁽⁹⁾, and antimicrobial activity against Leishmania  ⁽¹¹⁾. Alkaloids from graviola are detrimental to the survival of dopaminergic nerve cells in vitro. This may result in neuronal dysfunction and degeneration. Graviola-induced cell death was inhibited by glucose supplementation suggesting that cell death may have been caused by energy depletion ⁽²⁰⁾. Graviola has also been shown to stimulate serotonin receptors ⁽²⁴⁾. An ethanolic extract produced cell-stimulating behaviors either by increased mitochondrial turnover indicating stimulation in protein production or by preparation to leave the G1 phase, perhaps due to promitotic stimulus present within the extract which acts like a growth factor ⁽²⁸⁾.

  In animal models, antidiabetic effects are due to antioxidant, hypolipidemic, and protective effects in pancreatic beta-cells, which improves glucose metabolism ⁽⁷⁾. Graviola extract demonstrated antiulcer effects by increasing nitric oxide and prostaglandin E2 activities ⁽⁸⁾. Graviola fruit extract has anti-inflammatory and analgesic actions by inhibiting cyclooxygenase (COX)-1 and COX-2 and by blocking opioid receptors ⁽⁵⁾. However, other animal studies suggest that long-term ingestion of graviola juice promotes generation of reactive nitrogen species that may accelerate development of neurodegenerative diseases involving the microtubule-associated protein tau ⁽³⁴⁾.

  Graviola extracts were effective against adriamycin-resistant human mammary adenocarcinoma (MCF-7/Adr) by blocking access of cancer cells to ATP and by inhibiting the actions of plasma membrane glycoprotein ⁽²⁹⁾. They also inhibited expression of HIF-1α, NF-κB, glucose transporters, and glycolytic enzymes resulting in decreased glucose uptake and ATP production in pancreatic cancer cells ⁽¹⁵⁾, and downregulated EGFR expression in breast cancer cells ⁽¹⁶⁾. Phenolic compounds in graviola demonstrate free-radical scavenging potential against human breast carcinoma cells ⁽³⁰⁾ and in promyelocytic leukemia cells ⁽¹⁹⁾. Extracts of acetogenin muricins J, K, and L have antiproliferative effects against human prostate cancer cells, with the effect of muricin K being strongest ⁽²⁷⁾. In colon and in lung cancer cell lines, the ethanolic extract of graviola caused G1 cell-cycle arrest by upregulating Bax and downregulating Bcl-2 proteins ^(12) (13).

• Adverse Reactions

  Alkaloids present in graviola caused movement disorders and myeloneuropathy with symptoms mimicking Parkinson’s disease in vitro. Clinical significance is not known ^(20) (21).

• Herb-Drug Interactions

  Antidiabetics: Graviola showed hypoglycemic effects in a murine model ⁽³¹⁾, and can have additive effects with antidiabetic drugs. Clinical relevance is not known.
  Antihypertensives: Graviola showed hypotensive effects in a murine model ⁽³²⁾, and can have additive effects with antihypertensive medications. Clinical relevance has yet to be determined.

• Herb Lab Interactions

  Nuclear imaging (radiopharmaceutical biodistribution): Graviola significantly decreased uptake of radioactivity per gram of tissue in bladder, kidney, and blood in animal models ⁽²²⁾.
  Blood glucose test: Graviola reduced blood glucose levels in a murine model ⁽³¹⁾.
  Blood pressure readings: Graviola reduced blood pressure readings in a murine model ⁽³²⁾.

• References

  1. George VC, Kumar DR, Suresh PK, et al. Antioxidant, DNA protective efficacy and HPLC analysis of Annona muricata (soursop) extracts. J Food Sci Technol. Apr 2015;52(4):2328-2335. doi: 10.1007/s13197-014-1289-7

  2. Zamudio-Cuevas Y, Diaz-Sobac R, Vazquez-Luna A, et al. The antioxidant activity of soursop decreases the expression of a member of the NADPH oxidase family. Food Funct. Feb 2014;5(2):303-309. doi: 10.1039/c3fo60135h

  3. Gavamukulya Y, Abou-Elella F, Wamunyokoli F, et al. Phytochemical screening, anti-oxidant activity and in vitro anticancer potential of ethanolic and water leaves extracts of Annona muricata (Graviola). Asian Pac J Trop Med. Sep 2014;7s1:S355-363. doi: 10.1016/s1995-7645(14)60258-3

  4. Lee YH, Choo C, Watawana MI, et al. An appraisal of eighteen commonly consumed edible plants as functional food based on their antioxidant and starch hydrolase inhibitory activities. J Sci Food Agric. Dec 9 2014. doi: 10.1002/jsfa.7039

  5. Ishola IO, Awodele O, Olusayero AM, et al. Mechanisms of analgesic and anti-inflammatory properties of Annona muricata Linn. (Annonaceae) fruit extract in rodents. J Med Food. Dec 2014;17(12):1375-1382. doi: 10.1089/jmf.2013.0088

  6. de Sousa OV, Vieira GD, de Jesus RGdPJ, et al. Antinociceptive and anti-inflammatory activities of the ethanol extract of Annona muricata L. leaves in animal models. Int J Mol Sci. 2010;11(5):2067-2078. doi: 10.3390/ijms11052067

  7. Florence NT, Benoit MZ, Jonas K, et al. Antidiabetic and antioxidant effects of Annona muricata (Annonaceae), aqueous extract on streptozotocin-induced diabetic rats. J Ethnopharmacol. Feb 3 2014;151(2):784-790. doi: 10.1016/j.jep.2013.09.021

  8. Moghadamtousi SZ, Rouhollahi E, Karimian H, et al. Gastroprotective activity of Annona muricata leaves against ethanol-induced gastric injury in rats via Hsp70/Bax involvement. Drug Des Devel Ther. 2014;8:2099-2110. doi: 10.2147/dddt.s70096

  9. Padma P, Pramod NP, Thyagarajan SP, et al. Effect of the extract of Annona muricata and Petunia nyctaginiflora on Herpes simplex virus. J Ethnopharmacol. May 1998;61(1):81-83.

  10. Mohd Abd Razak MR, Afzan A, Ali R, et al. Effect of selected local medicinal plants on the asexual blood stage of chloroquine resistant Plasmodium falciparum. BMC Complement Altern Med. 2014;14(1):492. doi: 10.1186/1472-6882-14-492

  11. Jaramillo MC, Arango GJ, Gonzalez MC, et al. Cytotoxicity and antileishmanial activity of Annona muricata pericarp. Fitoterapia. Apr 2000;71(2):183-186.

  12. Moghadamtousi SZ, Kadir HA, Paydar M, et al. Annona muricata leaves induced apoptosis in A549 cells through mitochondrial-mediated pathway and involvement of NF-kappaB. BMC Complement Altern Med. 2014;14:299. doi: 10.1186/1472-6882-14-299

  13. Zorofchian Moghadamtousi S, Karimian H, Rouhollahi E, et al. Annona muricata leaves induce G(1) cell cycle arrest and apoptosis through mitochondria-mediated pathway in human HCT-116 and HT-29 colon cancer cells. J Ethnopharmacol. Oct 28 2014;156:277-289. doi: 10.1016/j.jep.2014.08.011

  14. Asare GA, Afriyie D, Ngala RA, et al. Antiproliferative activity of aqueous leaf extract of Annona muricata L. on the prostate, BPH-1 cells, and some target genes. Integr Cancer Ther. Jan 2015;14(1):65-74. doi: 10.1177/1534735414550198

  15. Torres MP, Rachagani S, Purohit V, et al. Graviola: a novel promising natural-derived drug that inhibits tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering cell metabolism. Cancer Lett. Oct 1 2012;323(1):29-40. doi: 10.1016/j.canlet.2012.03.031

  16. Dai Y, Hogan S, Schmelz EM, et al. Selective growth inhibition of human breast cancer cells by graviola fruit extract in vitro and in vivo involving downregulation of EGFR expression. Nutr Cancer. 2011;63(5):795-801. doi: 10.1080/01635581.2011.563027

  17. Liaw CC, Chang FR, Lin CY, et al. New cytotoxic monotetrahydrofuran annonaceous acetogenins from Annona muricata. J Nat Prod. Apr 2002;65(4):470-475.

  18. Hamizah S, Roslida AH, Fezah O, et al. Chemopreventive potential of Annona muricata L leaves on chemically-induced skin papillomagenesis in mice. Asian Pac J Cancer Prev. 2012;13(6):2533-2539.

  19. Pieme CA, Kumar SG, Dongmo MS, et al. Antiproliferative activity and induction of apoptosis by Annona muricata (Annonaceae) extract on human cancer cells. BMC Complement Altern Med. 2014;14(1):516. doi: 10.1186/1472-6882-14-516

  20. Lannuzel A, Michel PP, Caparros-Lefebvre D, et al. Toxicity of Annonaceae for dopaminergic neurons: potential role in atypical parkinsonism in Guadeloupe. Mov Disord. Jan 2002;17(1):84-90.

  21. Lannuzel A, Hoglinger GU, Champy P, et al. Is atypical parkinsonism in the Caribbean caused by the consumption of Annonacae? J Neural Transm Suppl. 2006(70):153-157.

  22. Holanda CM, Barbosa DA, Demeda VF, et al. Influence of Annona muricata (soursop) on biodistribution of radiopharmaceuticals in rats. Acta Cir Bras. Mar 2014;29(3):145-150. doi: 10.1590/s0102-86502014000300001

  23. Awodele O, Ishola IO, Ikumawoyi VO, et al. Toxicological evaluation of the lyophilized fruit juice extract of Annona muricata Linn. (Annonaceae) in rodents. J Basic Clin Physiol Pharmacol. Dec 18 2013:1-11. doi: 10.1515/jbcpp-2013-0085

  24. Roman G. Tropical myeloneuropathies revisited. Curr Opin Neurol. Oct 1998;11(5):539-544.

  25. Chen Y, Chen JW, Zhai JH, et al. Antitumor activity and toxicity relationship of annonaceous acetogenins. Food Chem Toxicol. Aug 2013;58:394-400. doi: 10.1016/j.fct.2013.05.028

  26. Thang TD, Dai DN, Hoi TM, et al. Study on the volatile oil contents of Annona glabra L., Annona squamosa L., Annona muricata L. and Annona reticulata L., from Vietnam. Nat Prod Res. 2013;27(13):1232-1236. doi: 10.1080/14786419.2012.724413

  27. Sun S, Liu J, Kadouh H, et al. Three new anti-proliferative Annonaceous acetogenins with mono-tetrahydrofuran ring from graviola fruit (Annona muricata). Bioorg Med Chem Lett. Jun 15 2014;24(12):2773-2776. doi: 10.1016/j.bmcl.2014.03.099

  28. Nawwar M, Ayoub N, Hussein S, et al. A flavonol triglycoside and investigation of the antioxidant and cell stimulating activities of Annona muricata Linn. Arch Pharm Res. May 2012;35(5):761-767. doi: 10.1007/s12272-012-0501-4

  29. Oberlies NH, Chang CJ, McLaughlin JL. Structure-activity relationships of diverse Annonaceous acetogenins against multidrug resistant human mammary adenocarcinoma (MCF-7/Adr) cells. J Med Chem. Jun 20 1997;40(13):2102-2106. doi: 10.1021/jm9700169

  30. George VC, Kumar DR, Rajkumar V, et al. Quantitative assessment of the relative antineoplastic potential of the n-butanolic leaf extract of Annona muricata Linn. in normal and immortalized human cell lines. Asian Pac J Cancer Prev. 2012;13(2):699-704.

  31. Adeyemi DO, Komolafe OA, Adewole OS, et al. Anti hyperglycemic activities of Annona muricata (Linn). Afr J Tradit Complement Altern Med. 2008;6(1):62-69.

  32. Nwokocha CR, Owu DU, Gordon A, et al. Possible mechanisms of action of the hypotensive effect of Annona muricata (soursop) in normotensive Sprague-Dawley rats. Pharm Biol. Nov 2012;50(11):1436-1441. doi: 10.3109/13880209.2012.684690

  33. Clement YN, Mahase V, Jagroop A, et al. Herbal remedies and functional foods used by cancer patients attending specialty oncology clinics in Trinidad. BMC Complement Altern Med. Oct 21 2016;16(1):399.

  34. Rottscholl R, Haegele M, Jainsch B, et al. Chronic consumption of Annona muricata juice triggers and aggravates cerebral tau phosphorylation in wild-type and MAPT transgenic mice. J Neurochem. Nov 2016;139(4):624-639.

  35. Qazi AK, Siddiqui JA, Jahan R, et al. Emerging therapeutic potential of graviola and its constituents in cancers. Carcinogenesis. Apr 5 2018;39(4):522-533.