Annonaceous acetogenins, phytochemicals isolated from the leaves, bark, and twigs, are thought to be the active ingredients of graviola. 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).
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). In rodent models of hepatic cancer, although constituents of graviola led to reduced tumor growth, the acetogenin bullatacin caused liver and kidney toxicity via increasing calcium concentration, ROS production, and Bax expression and Bax/Bcl-2 ratio with repeated treatment (25).
