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.
Torres MP, Rachagani S, Purohit V, Pandey P, Joshi S, Moore ED, Johansson SL, Singh PK, Ganti AK, Batra SK. Source Department of Biochemistry and Molecular Biology, Omaha, NE 68198-5870, USA.
Abstract
Pancreatic tumors are resistant to conventional chemotherapies. The present study was aimed at evaluating the potential of a novel plant-derived product as a therapeutic agent for pancreatic cancer (PC). The effects of an extract from the tropical tree Annona Muricata, commonly known as Graviola, was evaluated for cytotoxicity, cell metabolism, cancer-associated protein/gene expression, tumorigenicity, and metastatic properties of PC cells. Our experiments revealed that Graviola induced necrosis of PC cells by inhibiting cellular metabolism. The expression of molecules related to hypoxia and glycolysis in PC cells (i.e. HIF-1α, NF-κB, GLUT1, GLUT4, HKII, and LDHA) were downregulated in the presence of the extract. In vitro functional assays further confirmed the inhibition of tumorigenic properties of PC cells. Overall, the compounds that are naturally present in a Graviola extract inhibited multiple signaling pathways that regulate metabolism, cell cycle, survival, and metastatic properties in PC cells. Collectively, alterations in these parameters led to a decrease in tumorigenicity and metastasis of orthotopically implanted pancreatic tumors, indicating promising characteristics of the natural product against this lethal disease.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Selective growth inhibition of human breast cancer cells by graviola fruit extract in vitro and in vivo involving downregulation of EGFR expression.
Dai Y, Hogan S, Schmelz EM, Ju YH, Canning C, Zhou K. Source Department of Food Science and Technology, Virginia Tech, Blacksburg, Virginia, USA.
Abstract
The epidermal growth factor receptor (EGFR) is an oncogene frequently overexpressed in breast cancer (BC), and its overexpression has been associated with poor prognosis and drug resistance. EGFR is therefore a rational target for BC therapy development. This study demonstrated that a graviola fruit extract (GFE) significantly downregulated EGFR gene expression and inhibited the growth of BC cells and xenografts. GFE selectively inhibited the growth of EGFR-overexpressing human BC (MDA-MB-468) cells (IC(50) = 4.8 μg/ml) but had no effect on nontumorigenic human breast epithelial cells (MCF-10A). GFE significantly downregulated EGFR mRNA expression, arrested cell cycle in the G0/G1 phase, and induced apoptosis in MDA-MB-468 cells. In the mouse xenograft model, a 5-wk dietary treatment of GFE (200 mg/kg diet) significantly reduced the protein expression of EGFR, p-EGFR, and p-ERK in MDA-MB-468 tumors by 56%, 54%, and 32.5%, respectively. Overall, dietary GFE inhibited tumor growth, as measured by wet weight, by 32% (P < 0.01). These data showed that dietary GFE induced significant growth inhibition of MDA-MB-468 cells in vitro and in vivo through a mechanism involving the EGFR/ERK signaling pathway, suggesting that GFE may have a protective effect for women against EGFR-overexpressing BC. PMID:21767082 [PubMed - indexed for MEDLINE]
Third-Party Published Research on Graviola
Available third-party documentation and research on graviola be found at PubMed. A partial listing of the third-party published research on Graviola is shown below:
Anticancerous & Antitumor Actions
Kojima, N. “Systematic synthesis of antitumor Annonaceous acetogenins” Yakugaku Zasshi. 2004; 124(10): 673-81.
Tormo, J. R., et al. “In vitro antitumor structure-activity relationships of threo/trans/threo mono-tetrahydro-furanic acetogenins: Correlations with their inhibition of mitochondrial complex I.”
Oncol. Res. 2003; 14(3): 147-54. Yuan, S. S., et al. “Annonacin, a mono-tetrahydrofuran acetogenin, arrests cancer cells at the G1 phase and causes cytotoxicity in a Bax- and caspase-3-related pathway.” Life Sci. 2003 May: 72(25): 2853-61. Liaw, C. C., et al. “New cytotoxic monotetrahydrofuran Annonaceous acetogenins from Annona muricata.” J. Nat.
Prod. 2002; 65(4): 470-75 Gonzalez-Coloma, A., et al. “Selective action of acetogenin mitochondrial complex I inhibitors.” Z. Naturforsch. 2002; 57(11-12): 1028-34. Chang, F. R., et al.
“Novel cytotoxic Annonaceous acetogenins from Annona muricata.” J. Nat. Prod. 2001; 64(7): 925-31.
Jaramillo, M. C., et al. “Cytotoxicity and antileishmanial activity of Annona muricata pericarp.” Fitoterapia. 2000; 71 (2): 183-6. Betancur-Galvis, L., et al. “Antitumor and antiviral activity of Colombian medicinal plant extracts.” Mem. Inst. Oswaldo Cruz. 1999; 94(4): 531-35.
Kim, G. S., et al. “Muricoreacin and murihexocin C, mono-tetrahydrofuran acetogenins, from the leaves of Annona muricata.” Phytochemistry. 1998; 49(2): 565-71.
Kim, G. S., et al. “Two new mono-tetrahydrofuran ring acetogenins, annomuricin E and muricapentocin, from the leaves of Annona muricata.” J. Nat. Prod. 1998; 61(4): 432-36.
Nicolas, H., et al. “Structure-activity relationships of diverse Annonaceous acetogenins against multidrug resistant human mammary adenocarcinoma (MCF-7/Adr) cells.” J. Med. Chem. 1997; 40(13): 2102-6.
Zeng, L., et al. “Five new monotetrahydrofuran ring acetogenins from the leaves of Annona muricata.” J. Nat. Prod. 1996; 59(11): 1035-42. Wu, F. E., et al.
“Two new cytotoxic monotetrahydrofuran Annonaceous acetogenins, annomuricins A and B, from the leaves of Annona muricata.” J. Nat. Prod. 1995; 58(6): 830-36.
Oberlies, N. H., et al. “Tumor cell growth inhibition by several Annonaceous acetogenins in an in vitro disk diffusion assay.” Cancer Lett. 1995; 96(1): 55-62.
Wu, F. E., et al. “Additional bioactive acetogenins, annomutacin and (2,4-trans and cis)-10R-annonacin-A-ones, from the leaves of Annona muricata.” J. Nat. Prod. 1995; 58(9): 1430-37.
Wu, F. E., et al. “New bioactive monotetrahydrofuran Annonaceous acetogenins, annomuricin C and muricatocin C, from the leaves of Annona muricata.” J. Nat. Prod. 1995; 58(6): 909-5.
Wu, F. E., et al. “Muricatocins A and B, two new bioactive monotetrahydrofuran Annonaceous acetogenins from the leaves of Annona muricata.” J. Nat. Prod. 1995; 58(6): 902-8.
Sundarrao, K., et al. “Preliminary screening of antibacterial and antitumor activities of Papua New Guinean native medicinal plants.” Int. J. Pharmacog. 1993; 31(1): 3-6.
Antimicrobial Actions
Takahashi, J.A., et al. “Antibacterial activity of eight Brazilian Annonaceae plants.” Nat. Prod. Res. 2006; 20(1): 21-6.
Betancur-Galvis, L., et al. “Antitumor and antiviral activity of Colombian medicinal plant extracts.” Mem. Inst. Oswaldo Cruz 1999; 94(4): 531-35.
Antoun, M. D., et al. "Evaluation of the flora of Puerto Rico for in vitro cytotoxic and anti-HIV activities." Pharmaceutical Biol. 1999; 37(4): 277-280.
Padma, P., et al. “Effect of the extract of Annona muricata and Petunia nyctaginiflora on Herpes simplex virus.” J. Ethnopharmacol. 1998; 61(1): 81–3.
Sundarrao, K., et al. “Preliminary screening of antibacterial and antitumor activities of Papua New Guinean native medicinal plants.” Int. J. Pharmacog. 1993; 31(1): 3–6.
Misas, C. A. J., et al. “Contribution to the biological evaluation of Cuban plants. IV.” Rev. Cubana Med. Trop. 1979; 31(1): 29–35.
Antidepressant & Antistress Actions
Padma, P., et al. “Effect of Annona muricata and Polyalthia cerasoides on brain neurotransmitters and enzyme monoamine oxidase following cold immobilization stress.” J. Natural Remedies 2001; 1(2): 144–46.
Hasrat, J. A., et al. “Screening of medicinal plants from Suriname for 5-HT 1A ligands: Bioactive isoquinoline alkaloids from the fruit of Annona muricata.” Phytomedicine. 1997; 4(20: 133-140.
Padma, P., et al. “Effect of alcohol extract of Annona muricata on cold immobilization stress induced tissue lipid peroxidation.” Phytother. Res. 1997; 11(4): 326-327.
Hasrat, J. A., et al. “Isoquinoline derivatives isolated from the fruit of Annona muricata as 5-HTergic 5-HT1A receptor agonists in rats: unexploited antidepressive (lead) products.” J. Pharm. Pharmacol. 1997; 49(11): 1145–49.
Antiparasitic, Antimalarial, & Insecticidal Actions
Luna, J. S., et al. “Acetogenins in Annona muricata L. (Annonaceae) leaves are potent molluscicides.” Nat. Prod. Res. 2006; 20(3): 253-7.
Jaramillo, M. C., et al. “Cytotoxicity and antileishmanial activity of Annona muricata pericarp.” Fitoterapia. 2000; 71(2): 183–6.
Alali, F. Q., et al. “Annonaceous acetogenins as natural pesticides; potent toxicity against insecticide-susceptible and resistant German cockroaches (Dictyoptera: Blattellidae).” J. Econ. Entomol. 1998; 91(3): 641-9.
Antoun, M. D., et al. "Screening of the flora of Puerto Rico for potential antimalarial bioactives.” Int. J. Pharmacog. 1993; 31(4): 255–58.
Heinrich, M., et al. “Parasitological and microbiological evaluation of Mixe Indian medicinal plants (Mexico).” J. Ethnopharmacol. 1992; 36(1): 81–5.
Bories, C., et al. “Antiparasitic activity of Annona muricata and Annona cherimolia seeds.” Planta Med. 1991; 57(5): 434–36.
Gbeassor, M., et al. “In vitro antimalarial activity of six medicinal plants.” Phytother. Res. 1990; 4(3): 115–17.
Tattersfield, F., et al. “The insecticidal properties of certain species of Annona and an Indian strain of Mundulea sericea (Supli).” Ann. Appl. Biol. 1940; 27: 262–73.
Anticonvulsant, Antispasmodic, & Smooth Muscle Relaxant Actions
N’gouemo, P., et al. “Effects of ethanol extract of Annona muricata on pentylenetetrazol-induced convulsive seizures in mice.” Phytother. Res. 1997; 11(3): 243–45.
Feng, P. C., et al. “Pharmacological screening of some West Indian medicinal plants.” J. Pharm. Pharmacol. 1962; 14: 556–61.
Hypotensive & Cardiodepressant Actions
Carbajal, D., et al. “Pharmacological screening of plant decoctions commonly used in Cuban folk medicine.” J. Ethnopharmacol. 1991; 33(1/2): 21–4.
Feng, P. C., et al. “Pharmacological screening of some West Indian medicinal plants.” J. Pharm. Pharmacol. 1962; 14: 556–61. Meyer, T. M. “The alkaloids of Annona muricata.” Ing. Ned. Indie. 1941; 8(6): 64.
