Graviola (Annona muricata)
Graviola is a tree prevalent in the rain forests of Africa, South America, and Southeast Asia. Graviola has a long, rich history of use in herbal medicine as well as a lengthy recorded indigenous use.
Uses
All parts of the graviola tree are used in natural medicine in the tropics, including the bark, leaves, roots, fruit, and fruit seeds. Different properties and uses are attributed to the different parts of the tree. Generally, the fruit and fruit juice are taken for worms and parasites, to cool fevers, to increase mother’s milk after childbirth, and as an astringent (drying agent) for diarrhea and dysentery. The crushed seeds are used against internal and external parasites, head lice, and worms. The bark, leaves, and roots are considered antispasmodic, hypotensive, and sedative, and a tea is made for various disorders toward those effects.
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; the bark or leaf is used as an antispasmodic, sedative, and nervine for heart conditions, coughs, flu, difficult childbirth, asthma, hypertension, and parasites.
Today, in the United States and Europe, graviola is sold as a popular adjunctive natural therapy for cancer. This use has stemmed from published research on graviola and its naturally occurring chemicals possessing anticancerous actions, rather than its established traditional uses in South America.
Chemistry/Pharmacology
Many active compounds and chemicals have been found in graviola, as scientists have been studying its properties since the 1940s. Graviola produces these natural compounds in its leaf and stem, bark, and fruit seeds. Most of the research on graviola focuses on a novel set of chemicals called Annonaceous acetogenins. Chemically, they are derivatives of long-chain fatty acids. Annonaceous acetogenins are only found in the Annonaceae family (to which graviola belongs). These chemicals in general have been documented with antitumorous, antiparasitic, insecticidal, and antimicrobial activities.The Annonaceous acetogenins discovered in graviola thus far include: annocatalin, annohexocin, annomonicin, annomontacin, annomuricatin A and B, annomuricin A through E, annomutacin, annonacin, annonacinone, annopentocin A through C, cis-annonacin, ciscorossolone, cohibin A through D, corepoxylone, coronin, corossolin, corossolone, donhexocin, epomuricenin A and B, gigantetrocin, gigantetrocin Aand B, gigantetrocinone, gigantetronenin, goniothalamicin, iso-annonacin, javoricin, montanacin, montecristin, muracin A through G, muricapentocin, muricatalicin, muricatalin, muri-catenol, muricatetrocin A and B muricatin D, muricatocin A through C muricin H, muricin I, muricoreacin, murihexocin 3, murihexocin A through C, murihexol, murisolin, robustocin, rolliniastatin 1 & 2, saba-delin, solamin, uvariamicin I and IV, and xylomaticin.
Clinical Studies
There has been extensive research on graviola over the last three decades. Studies over the years have validated some of graviola’s many uses in herbal medicine. Several early studies demonstrated that the bark as well as the leaves had hypotensive, antispasmodic, anticonvulsant, vasodilator, smooth-muscle 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, which validated its long-standing traditional use, 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.
Research has confirmed that Annonaceous acetogenins have significant antitumorous properties and selective toxicity against various types of cancer cells (without harming healthy cells). 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. Therefore, they are toxic to cancer cells but have no toxicity to healthy 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 Institutes 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 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 anticancer agents, but also seem to have a special affinity for such resistant cells.
An animal study published by Wang L.Q. et. al. found various acetogenins exhibited antitumor activity in mice. First, they inoculated mice with lung cancer cells. Then, one third received nothing (the control group), one third received the chemotherapy 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 percent reduction of tumor mass over the control group, but 50 percent 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 percent—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.”
Biomechanical Mechanism
Annonaceous acetogenins isolated from the leaves, bark, and twigs are among the active constituents. Graviola-induced cell death inhibited by glucose supplementation suggests energy depletion. Graviola has also been shown to stimulate serotonin receptors. Cell-stimulating behaviors may occur either by increased mitochondrial turnover or by preparation to leave the G1 phase, possibly through a promitotic stimulus present within the extract which acts like a growth factor.
In animal models, antidiabetic effects are due to antioxidant, hypolipidemic, and protective effects in pancreatic beta-cells, which improves glucose metabolism. Antiulcer effects may occur via increased nitric oxide and prostaglandin E2 activities. Anti-inflammatory and analgesic actions with a fruit extract occurred via COX-1/2 inhibition and the blocking of opioid receptors.
Graviola extracts were effective against adriamycin-resistant human mammary adenocarcinoma by blocking ATP access and inhibiting plasma membrane glycoprotein. Inhibition of HIF-1α, NF-κB, glucose transporters, and glycolytic enzymes also decreased glucose uptake and ATP production in pancreatic cancer cells. In breast cancer cells, EGFR expression was downregulated, and free-radical scavenging occurred. In colon and in lung cancer cell lines, G1 cell-cycle arrest occurred by upregulating Bax and downregulating Bcl-2 proteins.
Sources/Articles
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.
Alali, Feras Q., Xiao-Xi Liu, and Jerry L. McLaughlin. "Annonaceous acetogenins: recent progress." Journal of Natural products 62, no. 3 (1999): 504-540. http://m.pawpawresearch.com/acetogenins19991.pdf
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.
Awad, Mai G., Ramadan A. Ali, Abd El-Monem, D. Dalia, and Mohammed A. El-Magd. "Graviola leaves extract enhances the anticancer effect of cisplatin on various cancer cell lines." Molecular & Cellular Toxicology 16, no. 4 (2020): 385-399. https://www.researchgate.net/profile/Dalia-Abd-El-Monem/publication/342531710_Graviola_leaves_extract_enhances_the_anticancer_effect_of_cisplatin_on_various_cancer_cell_lines/links/609ef9fb299bf1476999f676/Graviola-leaves-extract-enhances-the-anticancer-effect-of-cisplatin-on-various-cancer-cell-lines.pdf
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.
Betancur-Galvis, L. A., J. Saez, H. Granados, A. Salazar, and J. E. Ossa. "Antitumor and antiviral activity of Colombian medicinal plant extracts." Memórias do Instituto Oswaldo Cruz 94, no. 4 (1999): 531-535. https://www.scielo.br/j/mioc/a/MVhgrKN6qgsKRHKg5yLTR9L/?format=pdf&lang=en
Bories, Christian, Philippe Loiseau, Diego Cortes, Saw Hla Myint, Reynald Hocquemiller, Philippe Gayral, André Cavé, and Alain Laurens. "Antiparasitic activity of Annona muricata and Annona cherimolia seeds." Planta medica 57, no. 05 (1991): 434-436. https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-2006-960143
Chamcheu, Jean Christopher, Islam Rady, Roxane-Cherille N. Chamcheu, Abu Bakar Siddique, Melissa B. Bloch, Sergette Banang Mbeumi, Abiola S. Babatunde et al. "Graviola (Annona muricata) exerts anti-proliferative, anti-clonogenic and pro-apoptotic effects in human non-melanoma skin cancer UW-BCC1 and A431 cells in vitro: involvement of hedgehog signaling." International journal of molecular sciences 19, no. 6 (2018): 1791. https://www.mdpi.com/1422-0067/19/6/1791
Chan WJ, McLachlan AJ, Hanrahan JR, et al. The safety and tolerability of Annona muricata leaf extract: a systematic review. J Pharm Pharmacol. Jan 2020;72(1):1-16.
Chen Y, Chen JW, Zhai JH, et al. Antitumor activity and toxicity relationship of annonaceous acetogenins. Food Chem Toxicol. Aug 2013;58:394-400.
Daddiouaissa, Djabir, Azura Amid, Muhamad Shirwan Abdullah Sani, and Ahmed AM Elnour. "Evaluation of metabolomics behavior of human colon cancer HT29 cell lines treated with ionic liquid graviola fruit pulp extract." Journal of ethnopharmacology 270 (2021): 113813. http://irep.iium.edu.my/87886/1/Evaluation%20of%20metabolomics%20behavior%20of%20human%20colon%20cancer%20HT29%20cell%20lines%20treated%20with%20ionic%20liquid%20graviola%20fruit%20pulp%20extract.pdf
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.
Deep, Gagan, Rahul Kumar, Anil K. Jain, Deepanshi Dhar, Gati K. Panigrahi, Anowar Hussain, Chapla Agarwal et al. "Graviola inhibits hypoxia-induced NADPH oxidase activity in prostate cancer cells reducing their proliferation and clonogenicity." Scientific reports 6, no. 1 (2016): 1-12. https://www.nature.com/articles/srep23135
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.
El Tawiil, Ghada A., Eman Ali Noaman, Mostafa A. Askar, Neama Mohamed El Fatih, and Hebatallah E. Mohamed. "Anticancer and apoptogenic effect of graviola and low-dose radiation in tumor xenograft in mice." Integrative Cancer Therapies 19 (2020): 1534735419900930. https://journals.sagepub.com/doi/pdf/10.1177/1534735419900930
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.
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.
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.
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.
Gleye, Christophe, Philippe Duret, Alain Laurens, Reynald Hocquemiller, and André Cavé. "cis-Monotetrahydrofuran Acetogenins from the Roots of Annona muricata." Journal of Natural products 61, no. 5 (1998): 576-579. https://pubs.acs.org/doi/abs/10.1021/np970494m
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.
Hansra, Damien Mikael, Orlando Silva, Ashwin Mehta, and Eugene Ahn. "Patient with metastatic breast cancer achieves stable disease for 5 years on graviola and xeloda after progressing on multiple lines of therapy." Advances in Breast Cancer Research 2014 (2014). https://www.scirp.org/html/4-2470063_47526.htm
Hemalatha, G., K. Sivakumari, S. Rajesh, and K. Shyamala Devi. "Phytochemical profiling, anticancer and apoptotic activity of graviola (Annona muricata) fruit extract against human hepatocellular carcinoma (HepG-2) cells." Int. J. Zool. Appl. Biosci 5, no. 1 (2020): 32-47. https://www.researchgate.net/profile/Rajesh-Selvaraj-3/publication/340378055_PHYTOCHEMICAL_PROFILING_ANTICANCER_AND_APOPTOTIC_ACTIVITY_OF_GRAVIOLA_ANNONA_MURICATA_FRUIT_EXTRACT_AGAINST_HUMAN_HEPATOCELLULAR_CARCINOMA_HepG-2_CELLS/links/5e92d6f992851c2f5298977d/PHYTOCHEMICAL-PROFILING-ANTICANCER-AND-APOPTOTIC-ACTIVITY-OF-GRAVIOLA-ANNONA-MURICATA-FRUIT-EXTRACT-AGAINST-HUMAN-HEPATOCELLULAR-CARCINOMA-HepG-2-CELLS.pdf
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.
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.
Jaramillo, M. C., G. J. Arango, M. C. González, S. M. Robledo, and Iván Darío Velez. "Cytotoxicity and antileishmanial activity of Annona muricata pericarp." Fitoterapia 71, no. 2 (2000): 183-186. https://d1wqtxts1xzle7.cloudfront.net/44828361/Cytotoxicity_and_antileishmanial_activit20160417-18885-ludvez-with-cover-page-v2.pdf?Expires=1646082333&Signature=BnXYQIdZMU8AiXkc~f~VvnX8qBjFKBhOe5N5JFx6BlXibi3wRxLIThwWjGuUHrUErOr57AHW8AYsgQVIZaEkTtdNkszh6dk7tIuOoiR6~UXL-DkkDIvVKw3pHnuzvdQ-HJWe6E9OPNo51vaRIntcqIuXvAdjFyroZKbU151Ol7TkyfyZl53wiItHFQqtQHKTP~k5XMl7f8axDUJfVXRzky2SzIlCkTbw0VMEgFD1DnHxApSicza17VaqyqerwOBXizTwLuBpNTIJRrtHtHAxzEhCfjNlW5beV44lu5sflnQ5O3xh-b94gFxHCRGpfI4WWmWC1jjmNCE9JKjiVpyceg__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA
Lannuzel, Annie, Patrick P. Michel, Dominique Caparros‐Lefebvre, Jacqueline Abaul, Reynald Hocquemiller, and Merle Ruberg. "Toxicity of Annonaceae for dopaminergic neurons: potential role in atypical parkinsonism in Guadeloupe." Movement Disorders 17, no. 1 (2002): 84-90. https://movementdisorders.onlinelibrary.wiley.com/doi/abs/10.1002/mds.1246
Li, De-Yu, Jing-Guang Yu, Jiu-Xiang Zhu, Dong-Lei Yu, Xiu-Zhen Luo, Lan Sun, and Shi-Lin Yang. "Annonaceous acetogenins of the seeds from Annona muricata." Journal of Asian natural products research 3, no. 4 (2001): 267-276. https://www.tandfonline.com/doi/abs/10.1080/10286020108040366
Liaw, Chih-Chuang, Fang-Rong Chang, Chih-Yuan Lin, Chi-Jung Chou, Hui-Fen Chiu, Ming-Jung Wu, and Yang-Chang Wu. "New Cytotoxic Monotetrahydrofuran Annonaceous Acetogenins from Annona m uricata." Journal of natural products 65, no. 4 (2002): 470-475. https://pubs.acs.org/doi/abs/10.1021/np0105578
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.
Ioannis, Patrikios, Stephanou Anastasis, and Yiallouris Andreas. "Graviola: A systematic review on its anticancer properties." Am J Cancer Prev 3, no. 6 (2015): 128-131. https://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.1090.8590&rep=rep1&type=pdf
Magadi, Visveswaraiah Paranjyothi, Venkatadasappa Ravi, Litha Anantharaju Arpitha, Kikkerilakshminarayana Kumaraswamy, and Krishnappa Manjunath. "Evaluation of cytotoxicity of aqueous extract of Graviola leaves on squamous cell carcinoma cell-25 cell lines by 3-(4, 5-dimethylthiazol-2-Yl)-2, 5-diphenyltetrazolium bromide assay and determination of percentage of cell inhibition at G2M phase of cell cycle by flow cytometry: An in vitro study." Contemporary Clinical Dentistry 6, no. 4 (2015): 529. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678553/
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.
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.
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.
N'gouemo, P., B. Koudogbo, H. Pambou Tchivounda, C. Akono‐Nguema, and Minko M. Etoua. "Effects of ethanol extract of Annona muricata on pentylenetetrazol‐induced convulsive seizures in mice." Phytotherapy Research: An International Journal Devoted to Medical and Scientific Research on Plants and Plant Products 11, no. 3 (1997): 243-245. https://d1wqtxts1xzle7.cloudfront.net/47908541/_28sici_291099-1573_28199705_2911_3A3_3C243_3A_3Aaid-ptr66_3E3.0.co_3B2-a20160809-16102-596pi9-with-cover-page-v2.pdf?Expires=1646082870&Signature=K74J3iogxo2wtlnexpFrR1O457PPrfxDNwuw49EST-~x-SJra~oPjwjw3cM0b-YehRgDU-yEdhIroYyiWdK-bc179vAVzkMqM8wuGSCKZ8bQtdewp8tosDwBXisBzbViVZyRBClEczNewl9WKUzEqlcZN2wATxuLABZwz40FIGzJmYGCmOQymkZOankY~uEticVHvx0TIz0WiPF9K8xz8PBNVVpYczXSrI~wwaPXOSSxne8DFU0beLtM-CGix4mHMDa2So8Uz8w~7v3fI1o~4~HoUwPZWHfem41iFVMOb90wcWH4JqDVwxYfBrADOdwrJrZu-cyXzIfpZIttVWn9eA__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA
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.
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.
Oberlies, Nicholas H., Ching-jer Chang, and Jerry L. McLaughlin. "Structure− Activity relationships of diverse annonaceous acetogenins against multidrug resistant human mammary adenocarcinoma (MCF-7/Adr) Cells." Journal of Medicinal Chemistry 40, no. 13 (1997): 2102-2106. https://pubs.acs.org/doi/abs/10.1021/jm9700169
Padma, P., J. P. N. Chansauria, R. L. Khosa, and A. K. Ray. "Effect of Annooa muricata and Polyalthia cerasoides on brain neurotransimitters and enzyme monoamine oxidase following cold immobilization stress." Journal of Natural Remedies 1, no. 2 (2001): 144-146. http://ischolar.info/index.php/jnr/article/view/27739
Padma, P., N. P. Pramod, S. P. Thyagarajan, and R. L. Khosa. "Effect of the extract of Annona muricata and Petunia nyctaginiflora on Herpes simplex virus." Journal of ethnopharmacology 61, no. 1 (1998): 81-83. https://www.sciencedirect.com/science/article/abs/pii/S0378874198000130
Paul, Jeno, R. Gnanam, R. M Jayadeepa, and L. Arul. "Anti cancer activity on Graviola, an exciting medicinal plant extract vs various cancer cell lines and a detailed computational study on its potent anti-cancerous leads." Current topics in medicinal chemistry 13, no. 14 (2013): 1666-1673. https://www.ingentaconnect.com/content/ben/ctmc/2013/00000013/00000014/art00006
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.
Prabhakaran, Keerthana, Gnanam Ramasamy, Uma Doraisamy, Jayakanthan Mannu, and Jayadeepa Rajamani Murugesan. "Polyketide natural products, acetogenins from graviola (Annona muricata L), its biochemical, cytotoxic activity and various analyses through computational and bio-programming methods." Current pharmaceutical design 22, no. 34 (2016): 5204-5210. https://www.ingentaconnect.com/content/ben/cpd/2016/00000022/00000034/art00004
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.
Rady, Islam, Melissa B. Bloch, Roxane-Cherille N. Chamcheu, Sergette Banang Mbeumi, Md Rafi Anwar, Hadir Mohamed, Abiola S. Babatunde et al. "Anticancer properties of Graviola (Annona muricata): a comprehensive mechanistic review." Oxidative medicine and cellular longevity 2018 (2018).
Rieser, Matthew J., Zhe-Ming Gu, Xin-Ping Fang, Lu Zeng, Karl V. Wood, and Jerry L. McLaughlin. "Five novel mono-tetrahydrofuran ring acetogenins from the seeds of Annona muricata." Journal of Natural Products 59, no. 2 (1996): 100-108. https://pubs.acs.org/doi/abs/10.1021/np960037q
Rieser, Matthew J., Xing-Ping Fang, J. Kent Rupprecht, Yu-Hua Hui, David L. Smith, and Jerry L. McLaughlin. "Bioactive single-ring acetogenins from seed extracts of Annona muricata." Planta medica 59, no. 01 (1993): 91-92. https://www.hindawi.com/journals/omcl/2018/1826170/
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.
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.
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.
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.
Wang, Li-Quan, Byung-Sun Min, Yan Li, Norio Nakamura, Guo-Wei Qin, Can-Jun Li, and Masao Hattori. "Annonaceous acetogenins from the leaves of Annona montana." Bioorganic & medicinal chemistry 10, no. 3 (2002): 561-565. https://www.sciencedirect.com/science/article/abs/pii/S0968089601003030
Wu, Feng-E., Lu Zeng, Zhe-Ming Gu, Geng-Xian Zhao, Yan Zhang, Jon T. Schwedler, Jerry L. McLaughlin, and Soelaksono Sastrodihardjo. "New bioactive monotetrahydrofuran Annonaceous acetogenins, annomuricin C and muricatocin C, from the leaves of Annona muricata." Journal of Natural Products 58, no. 6 (1995): 909-915. https://pubs.acs.org/doi/pdf/10.1021/np50120a014
Wu, Feng-E., Lu Zeng, Zhe-Ming Gu, Geng-Xian Zhao, Yan Zhang, Jon T. Schwedler, Jerry L. McLaughlin, and Soelaksono Sastrodihardjo. "Muricatocins A and B, two new bioactive monotetrahydrofuran Annonaceous acetogenins from the leaves of Annona muricata." Journal of Natural Products 58, no. 6 (1995): 902-908. https://pubs.acs.org/doi/pdf/10.1021/np50120a013
Xelha, Araujo-Padilla, Ramón-Gallegos Eva, Díaz-Cedillo Francisco, and Silva-Torres Rafael. "Astragalin identification in graviola pericarp indicates a possible participation in the anticancer activity of pericarp crude extracts: In vitro and in silico approaches." Arabian Journal of Chemistry (2022): 103720. https://www.sciencedirect.com/science/article/pii/S1878535222000363
Yuan, Shyng-Shiou F., Hsueh-Ling Chang, Hsiao-Wen Chen, Yao-Tsung Yeh, Ying-Hsien Kao, Kuei-Hsiang Lin, Yang-Chang Wu, and Jinu-Huang Su. "Annonacin, a mono-tetrahydrofuran acetogenin, arrests cancer cells at the G1 phase and causes cytotoxicity in a Bax-and caspase-3-related pathway." Life Sciences 72, no. 25 (2003): 2853-2861. https://www.researchgate.net/profile/Shyng-Shiou-Yuan/publication/10803606_Annonacin_a_mono-tetrahydrofuran_acetogenin_arrests_cancer_cells_at_the_G1_phase_and_causes_cytotoxicity_in_a_Bax-_and_caspase-3-related_pathway/links/5ab9fec845851515f5a130e0/Annonacin-a-mono-tetrahydrofuran-acetogenin-arrests-cancer-cells-at-the-G1-phase-and-causes-cytotoxicity-in-a-Bax-and-caspase-3-related-pathway.pdf
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.
Zeng, Lu, Feng-E. Wu, Nicholas H. Oberlies, Jerry L. McLaughlin, and Soelaksono Sastrodihadjo. "Five new monotetrahydrofuran ring acetogenins from the leaves of Annona muricata." Journal of Natural Products 59, no. 11 (1996): 1035-1042. https://pubs.acs.org/doi/abs/10.1021/np960447e
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.