title: In vivo inhibition of tumor progression by 5 hydroxy-1,4-naphthoquinone (juglone) and 2-(4-hydroxyanilino)-1,4-naphthoquinone (Q7) in combination with ascorbate.
abstract: The purpose of the study was to obtain further in vivo data of antitumor effects and mechanisms triggered by juglone and Q7 in combination with ascorbate. The study was done using Ehrlich ascites tumor-bearing mice. Treatments were intraperitoneal every 24 h for 9 days. Control group was treated with excipient. Previous tests selected the doses of juglone and Q7 plus ascorbate (1 and 100 mg/kg, respectively). Samples of ascitic fluid were collected to evaluate carbonyl proteins, GSH and activity of antioxidant enzymes such as catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase. Hypoxia inducible factor HIF-1α, GLUT1, proteins driving cell cycle (p53, p16 and cyclin A) and apoptosis (poly-ADP-polymerase PARP, Bax and Bcl-xL) were assessed by western blot. Tumor cells were categorized by the phase of cell cycle using flow cytometry and type of cell death using acridine orange/ethidium bromide. A glucose uptake assessment was performed by liquid scintillation using Ehrlich tumor cells cultured with (14)C-deoxyglucose. Treatments caused increased protein carbonylation and activity of antioxidant enzymes and decreased levels of GSH, HIF-1α, GLUT1 and glucose uptake in tumor cells. They also caused increased number of tumor cells in G1, p53 and p16 activation and decreased cyclin A, but only when combined with ascorbate. Apoptosis was induced mostly when treatments were done with ascorbate, causing PARP and Bax cleavage, and increased Bax/Bcl-xL ratio. Juglone and Q7 in combination with ascorbate caused inhibition of tumor progress in vivo by triggering apoptosis and cell cycle arrest associated with oxidative stress, suppression of HIF-1 and uncoupling of glycolytic metabolism.
authors.affiliation: Department of Biochemistry, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Ourique
authors.affiliation: Postgraduate Programe of Health Science, Universidade do Sul de Santa Catarina (UNISUL), Palhoça, SC, Brazil.
authors.forename: Maicon R
authors.initials: MR
authors.lastname: Kviecinski
authors.affiliation: Department of Biochemistry, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil.
authors.forename: Guilherme
authors.initials: G
authors.lastname: Zirbel
authors.affiliation: Department of Biochemistry, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil.
authors.forename: Luiza S E P W
authors.initials: LSEPW
authors.lastname: Castro
authors.affiliation: Department of Biochemistry, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil.
authors.forename: Allisson Jhonatan
authors.initials: AJ
authors.lastname: Gomes Castro
authors.affiliation: Department of Biochemistry, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil.
authors.forename: Fátima Regina
authors.initials: FR
authors.lastname: Mena Barreto Silva
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, Universidad Arturo Prat, Iquique, Chile.
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Valderrama
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, Universidad Arturo Prat, Iquique, Chile.
authors.forename: David
authors.initials: D
authors.lastname: Rios
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, Universidad Arturo Prat, Iquique, Chile.
authors.forename: Julio
authors.initials: J
authors.lastname: Benites
authors.affiliation: Toxicology and Cancer Biology Research Group (GTOX), Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Pedro Buc
authors.initials: PB
authors.lastname: Calderon
authors.affiliation: Department of Biochemistry, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil. Electronic address: rozangelapedrosa@gmail.com.
authors.forename: Rozangela Curi
authors.initials: RC
authors.lastname: Pedrosa
mesh_terms: D000627:Aminophenols / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000008:administration & dosage; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009285:Naphthoquinones / Q000008:administration & dosage
chemical_list: C581644:2-(4-hydroxyanilino)-1,4-naphthoquinone; D000627:Aminophenols; D009285:Naphthoquinones; D001205:Ascorbic Acid; C005134:juglone
keywords: Antitumor; Apoptosis; Ascorbate; Juglone; Oxidative stress; Q7 (2-(4-hydroxyanilino)-1,4-naphthoquinone)