Natural and glucosyl flavonoids inhibit poly(ADP-ribose) polymerase activity and induce synthetic lethality in BRCA mutant cells

Maeda,Junko; Roybal,Erica J.; Brents,Colleen A.; Uesaka,Mitsuru; Aizawa,Yasushi; Kato,Takamitsu A.

doi:10.3892/or.2013.2902

Natural and glucosyl flavonoids inhibit poly(ADP-ribose) polymerase activity and induce synthetic lethality in BRCA mutant cells

Authors:
- Junko Maeda
- Erica J. Roybal
- Colleen A. Brents
- Mitsuru Uesaka
- Yasushi Aizawa
- Takamitsu A. Kato
View Affiliations

Affiliations: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan, Research and Development Group, Toyo Sugar Refining Co., Ltd., Tokyo 103-0046, Japan
Published online on: December 5, 2013 https://doi.org/10.3892/or.2013.2902
Pages: 551-556
Copyright: © Maeda et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM and Lines TC: A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol. 45:2179–2205. 2007. View Article : Google Scholar : PubMed/NCBI
2	Day AJ and Williamson G: Biomarkers for exposure to dietary flavonoids: a review of the current evidence for identification of quercetin glycosides in plasma. Br J Nutr. 86(Suppl 1): S105–S110. 2001. View Article : Google Scholar : PubMed/NCBI
3	Boots AW, Haenen GR and Bast A: Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol. 585:325–337. 2008. View Article : Google Scholar : PubMed/NCBI
4	Matsukawa N, Matsumoto M, Chiji H and Hara H: Oligo-saccharide promotes bioavailability of a water-soluble flavonoid glycoside, αG-rutin, in rats. J Agric Food Chem. 57:1498–1505. 2009.PubMed/NCBI
5	Chen YW, Chou HC, Lin ST, et al: Cardioprotective effects of quercetin in cardiomyocyte under ischemia/reperfusion injury. Evid Based Complement Alternat Med. 2013:3645192013.PubMed/NCBI
6	Bakhshaeshi M, Khaki A, Fathiazad F, Khaki AA and Ghadamkheir E: Anti-oxidative role of quercetin derived from Allium cepa on aldehyde oxidase (OX-LDL) and hepatocytes apoptosis in streptozotocin-induced diabetic rat. Asian Pac J Trop Biomed. 2:528–531. 2012.PubMed/NCBI
7	Lee KH and Yoo CG: Simultaneous inactivation of GSK-3β suppresses quercetin-induced apoptosis by inhibiting the JNK pathway. Am J Physiol Lung Cell Mol Physiol. 304:L782–L789. 2013.
8	Romano B, Pagano E, Montanaro V, Fortunato AL, Milic N and Borrelli F: Novel insights into the pharmacology of flavonoids. Phytother Res. July.4–2013.(Epub ahead of print).
9	Duraj J, Zazrivcova K, Bodo J, Sulikova M and Sedlak J: Flavonoid quercetin, but not apigenin or luteolin, induced apoptosis in human myeloid leukemia cells and their resistant variants. Neoplasma. 52:273–279. 2005.PubMed/NCBI
10	Nijman SMB: Synthetic lethality: general principles, utility and detection using genetic screens in human cells. FEBS Lett. 585:1–6. 2011. View Article : Google Scholar : PubMed/NCBI
11	Bryant HE, Schultz N, Thomas HD, et al: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 434:913–917. 2005. View Article : Google Scholar : PubMed/NCBI
12	Basu B, Sandhu SK and de Bono JS: PARP inhibitors: mechanism of action and their potential role in the prevention and treatment of cancer. Drugs. 72:1579–1590. 2012. View Article : Google Scholar : PubMed/NCBI
13	Poitras MF, Koh DW, Yu SW, et al: Spatial and functional relationship between poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase in the brain. Neuroscience. 148:198–211. 2007. View Article : Google Scholar : PubMed/NCBI
14	Polyak K and Garber J: Targeting the missing links for cancer therapy. Nat Med. 17:283–284. 2011. View Article : Google Scholar : PubMed/NCBI
15	Dedes KJ, Wilkerson PM, Wetterskog D, Weigelt B, Ashworth A and Reis-Filho JS: Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations. Cell Cycle. 10:1192–1199. 2011. View Article : Google Scholar : PubMed/NCBI
16	Peralta-Leal A, Rodriguez-Vargas JM, Aguilar-Quesada R, et al: PARP inhibitors: new partners in the therapy of cancer and inflammatory diseases. Free Radic Biol Med. 47:13–26. 2009. View Article : Google Scholar : PubMed/NCBI
17	Brandt A, Lorenzo Bermejo J, Sundquist J and Hemminki K: Breast cancer risk in women who fulfill high-risk criteria: at what age should surveillance start? Breast Cancer Res Treat. 121:133–141. 2010. View Article : Google Scholar : PubMed/NCBI
18	Iqbal J, Ragone A, Lubinski J, et al: The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer. 107:2005–2009. 2012. View Article : Google Scholar : PubMed/NCBI
19	Christopoulou A and Spiliotis J: The role of BRCA1 and BRCA2 in hereditary breast cancer. Gene Ther Mol Biol. 10A:95–99. 2006.
20	Whittemore AS, Gong G, John EM, et al: Prevalence of BRCA1 mutation carriers among U.S. non-Hispanic Whites. Cancer Epidemiol Biomarkers Prev. 13:2078–2083. 2004.PubMed/NCBI
21	Mavaddat N, Barrowdale D, Andrulis IL, et al: Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev. 21:134–147. 2012. View Article : Google Scholar
22	Teng LS, Zheng Y and Wang HH: BRCA1/2 associated hereditary breast cancer. J Zhejiang Univ Sci B. 9:85–89. 2008. View Article : Google Scholar : PubMed/NCBI
23	Verhaegh GW, Jongmans W, Morolli B, et al: A novel type of X-ray-sensitive Chinese hamster cell mutant with radioresistant DNA synthesis and hampered DNA double-strand break repair. Mutat Res. 337:119–129. 1995. View Article : Google Scholar : PubMed/NCBI
24	Geraets L, Moonen HJ, Brauers K, Wouters EF, Bast A and Hageman GJ: Dietary flavones and flavonoles are inhibitors of poly(ADP-ribose)polymerase-1 in pulmonary epithelial cells. J Nutr. 137:2190–2195. 2007.PubMed/NCBI
25	Kanai Y, Tanuma S and Sugimura T: Immunofluorescent staining of poly(ADP-ribose) in situ in HeLa cell chromosomes in the M phase. Proc Natl Acad Sci USA. 78:2801–2804. 1981. View Article : Google Scholar : PubMed/NCBI
26	Kuo LJ and Yang LX: γ-H2AX - a novel biomarker for DNA double-strand breaks. In Vivo. 22:305–309. 2008.
27	Matsuo M, Sasaki N, Saga K and Kaneko T: Cytotoxicity of flavonoids toward cultured normal human cells. Biol Pharm Bull. 28:253–259. 2005. View Article : Google Scholar : PubMed/NCBI
28	Boege F, Straub T, Kehr A, et al: Selected novel flavones inhibit the DNA binding or the DNA religation step of eukaryotic topoisomerase I. J Biol Chem. 271:2262–2270. 1996. View Article : Google Scholar : PubMed/NCBI
29	Spencer JP, Abd-el-Mohsen MM and Rice-Evans C: Cellular uptake and metabolism of flavonoids and their metabolites: implications for their bioactivity. Arch Biochem Biophys. 423:148–161. 2004. View Article : Google Scholar : PubMed/NCBI
30	Ishikawa M, Oikawa T, Hosokawa M, Hamada J, Morikawa K and Kobayashi H: Enhancing effect of quercetin on 3-methylcholanthrene carcinogenesis in C57Bl/6 mice. Neoplasma. 32:435–441. 1985.PubMed/NCBI
31	Venskutonis PR, Dedonyte V, Lazutka J, et al: A preliminary assessment of singlet oxygen scavenging, cytotoxic and genotoxic properties of Geranium macrorrhizum extracts. Acta Biochim Pol. 57:157–163. 2010.PubMed/NCBI
32	Nakayama T, Yamada M, Osawa T and Kawakishi S: Suppression of active oxygen-induced cytotoxicity by flavonoids. Biochem Pharmacol. 45:265–267. 1993. View Article : Google Scholar : PubMed/NCBI
33	Tutt A, Robson M, Garber JE, et al: Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 376:235–244. 2010. View Article : Google Scholar