title: Alterations in the extracellular catabolism of nucleotides are involved in the antiproliferative effect of quercetin in human bladder cancer T24 cells.
abstract: Bladder cancer is the most prevalent tumor in the genitourinary tract and the current treatments are not efficient to prevent recurrence and progression of tumor cases. Studies have revealed evidence of the involvement of the purinergic system in bladder tumorigenesis, particularly ecto-5'-NT/CD73, the enzyme responsible for AMP hydrolysis. Quercetin (3,3',4',5,7-pentahydroxyflavone) is a plant-derived flavonoid that has been shown to exert a broad range of pharmacologic properties, including potential anticancer activity. Here, we investigated the quercetin effect on the E-NTPDases and ecto-5'-nucleotidase/CD73, which catalyzes the introversion of the extracellular purine nucleotides in T24 human bladder cancer cells. The results showed that this flavonoid was able to increase ADP hydrolysis and inhibit the ecto-5'-nucleotidase/CD73 activity, with no effect on protein expression. The treatment with APCP (α,β-methyleneadenosine-5'-diphosphate), another ecto-5'-NT/CD73 inhibitor, led to a significant reduction in cell proliferation. In addition, we showed that AMP, which can be accumulating by enzyme inhibition, had an antiproliferative effect on T24 cells, which was enhanced when its hydrolysis was inhibited by APCP treatment. Otherwise, adenosine did not cause any significant effect on cell proliferation and the quercetin effects were not altered by the simultaneous presence of adenosine. Taken together, the results suggest that the antiproliferative effect of quercetin on tumor cells may occur, at least in part, via alterations in the extracellular catabolism of nucleotides, that could be by AMP accumulation, or could be due to blocked adenosine receptors by this flavonoid, supporting the potential use of quercetin in bladder cancer treatment.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
authors.forename: Liliana
authors.initials: L
authors.lastname: Rockenbach
authors.forename: Luci
authors.initials: L
authors.lastname: Bavaresco
authors.forename: Patrícia
authors.initials: P
authors.lastname: Fernandes Farias
authors.forename: Angélica Regina
authors.initials: AR
authors.lastname: Cappellari
authors.forename: Carlos Henrique
authors.initials: CH
authors.lastname: Barrios
authors.forename: Fernanda
authors.initials: F
authors.lastname: Bueno Morrone
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Oliveira Battastini
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000241:Adenosine / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005110:Extracellular Space / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D009711:Nucleotides / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology*; D013997:Time Factors; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D058851:GPI-Linked Proteins; D009711:Nucleotides; C523965:alpha,beta-methyleneadenosine 5'-diphosphate; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D011794:Quercetin; D015720:5'-Nucleotidase; C548241:NT5E protein, human; D000241:Adenosine