title: Xanthohumol induces apoptosis in human malignant glioblastoma cells by increasing reactive oxygen species and activating MAPK pathways.
abstract: The effect of the biologically active prenylated chalcone and potential anticancer agent xanthohumol (1) has been investigated on apoptosis of the T98G human malignant glioblastoma cell line. Compound 1 decreased the viability of T98G cells by induction of apoptosis in a time- and concentration-dependent manner. Apoptosis induced by 1 was associated with activation of caspase-3, caspase-9, and PARP cleavage and was mediated by the mitochondrial pathway, as exemplified by mitochondrial depolarization, cytochrome c release, and downregulation of the antiapoptotic Bcl-2 protein. Xanthohumol induced intracellular reactive oxygen species (ROS), an effect that was reduced by pretreatment with the antioxidant N-acetyl-L-cysteine (NAC). Intracellular ROS production appeared essential for the activation of the mitochondrial pathway and induction of apoptosis after exposure to 1. Oxidative stress due to treatment with 1 was associated with MAPK activation, as determined by ERK1/2 and p38 phosphorylation. Phosphorylation of ERK1/2 and p38 was attenuated using NAC to inhibit ROS production. After treatment with 1, ROS provided a specific environment that resulted in MAPK-induced cell death, with this effect reduced by the ERK1/2 specific inhibitor PD98059 and partially inhibited by the p38 inhibitor SB203580. These findings suggest that xanthohumol (1) is a potential chemotherapeutic agent for the treatment of glioblastoma multiforme.
authors: Dipartimento di Scienze Farmaceutiche e Biomediche, Università degli Studi di Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy.
authors: Michela
authors: M
authors: Festa
authors: Anna
authors: A
authors: Capasso
authors: Cosimo W
authors: CW
authors: D'Acunto
authors: Milena
authors: M
authors: Masullo
authors: Adriano G
authors: AG
authors: Rossi
authors: Cosimo
authors: C
authors: Pizza
authors: Sonia
authors: S
authors: Piacente
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D053453:Caspase 9 / Q000187:drug effects / Q000378:metabolism; D053138:Cyclohexenes / Q000737:chemistry / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007558:Italy; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015394:Molecular Structure; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D011427:Propiophenones / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D053138:Cyclohexenes; D005419:Flavonoids; D007093:Imidazoles; D011427:Propiophenones; D011725:Pyridines; D017382:Reactive Oxygen Species; D013729:Terpenes; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053453:Caspase 9; C007966:humulon; C093642:SB 203580; C104536:xanthohumol; D000111:Acetylcysteine