title: Anthocyans as tertiary chemopreventive agents in bladder cancer: anti-oxidant mechanisms and interaction with mitomycin C.
abstract: Bladder cancer is associated with high rates of recurrence making tertiary chemoprevention an attractive intervention strategy. Anthocyanins have been shown to possess chemopreventive properties and are detectable in urine after oral ingestion, with higher concentrations achievable via intravesical administration alongside current chemotherapeutic regimens. Yet their apparent ability to protect against certain DNA damage may in turn interfere with cancer treatments. Our aim was therefore to determine the potential of anthocyanins as chemopreventive agents in bladder cancer, their mode of action and effects, both alone and in combination with mitomycin C (MMC). In this study we showed that mirtoselect, a standardised mixture of anthocyanins, possesses significant anti-proliferative activity, causing growth inhibition and apoptosis in bladder cancer cell lines. The anti-oxidative potential of mirtoselect was examined and revealed significantly fewer H2O2-induced DNA strand breaks, as well as oxidised DNA bases in pre-treated cells. In contrast, endogenous levels of oxidised DNA bases were unaltered. Investigations into the possible protective mechanisms associated with these anti-oxidant properties revealed that mirtoselect chelates metal ions. In mirtoselect/MMC combination studies, no adverse effects on measures of DNA damage were observed compared to treatment with MMC alone and there was evidence of enhanced cell death. Consistent with this, significantly more DNA crosslinks were formed in cells treated with the combination. These results show that mirtoselect exerts effects consistent with chemopreventive properties in bladder cancer cell lines and most importantly does so without adversely affecting the effects of drugs used in current treatment regimens. We also provide evidence that mirtoselect's anti-oxidative mechanism of action is via metal ion chelation. Overall these results suggest that mirtoselect could be an effective chemopreventive agent in bladder cancer and provides the necessary pre-clinical data for future in vivo animal studies and clinical trials.
authors.affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, University Road, Leicester LE1 7RH, UK.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Higgins
authors.affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, University Road, Leicester LE1 7RH, UK.
authors.forename: Murizal
authors.initials: M
authors.lastname: Zainol
authors.affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, University Road, Leicester LE1 7RH, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Brown
authors.affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, University Road, Leicester LE1 7RH, UK gdj2@le.ac.uk.
authors.forename: George D D
authors.initials: GD
authors.lastname: Jones
mesh_terms: D000872:Anthocyanins / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D018890:Chemoprevention; D003432:Cross-Linking Reagents / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects; D004249:DNA Damage; D004347:Drug Interactions; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D014965:X-Rays
chemical_list: D000872:Anthocyanins; D000970:Antineoplastic Agents; D000975:Antioxidants; D002614:Chelating Agents; D003432:Cross-Linking Reagents; D016685:Mitomycin