title: Natural and glucosyl flavonoids inhibit poly(ADP-ribose) polymerase activity and induce synthetic lethality in BRCA mutant cells.
abstract: Poly(ADP-ribose) polymerase (PARP) inhibitors have been proven to represent superior clinical agents targeting DNA repair mechanisms in cancer therapy. We investigated PARP inhibitory effects of the natural and synthetic flavonoids (quercetin, rutin, monoglucosyl rutin and maltooligosyl rutin) and tested the synthetic lethality in BRCA2 mutated cells. In vitro ELISA assay suggested that the flavonoids have inhibitory effects on PARP activity, but glucosyl modifications reduced the inhibitory effect. Cytotoxicity tests of Chinese hamster cells defective in BRCA2 gene (V-C8) and its parental V79 cells showed BRCA2-dependent synthetic lethality when treated with the flavonoids. BRCA2 mutated cells were three times more sensitive to the flavonoids than the wild-type and gene complemented cells. Reduced toxicity was observed in a glucosyl modification-dependent manner. The present study provides support for the clinical use of new treatment drugs, and is the beginning of the potential application of flavonoids in cancer prevention and the periodic consumption of appropriate flavonoids to reduce cancer risk in individuals carrying a mutant allele of the BRCA2 gene.
authors: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors: Junko
authors: J
authors: Maeda
authors: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors: Erica J
authors: EJ
authors: Roybal
authors: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors: Colleen A
authors: CA
authors: Brents
authors: Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan.
authors: Mitsuru
authors: M
authors: Uesaka
authors: Research and Development Group, Toyo Sugar Refining Co., Ltd., Tokyo 103-0046, Japan.
authors: Yasushi
authors: Y
authors: Aizawa
authors: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors: Takamitsu A
authors: TA
authors: Kato
mesh_terms: D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D016466:CHO Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003412:Cricetulus; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004260:DNA Repair; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011794:Quercetin / Q000494:pharmacology*; D012431:Rutin / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D024682:BRCA2 Protein; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012431:Rutin; D011794:Quercetin