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.

Puerarin protects against CCl4-induced liver fibrosis in mice: possible role of PARP-1 inhibition

“…There seems to be a positive correlation between PARP activity and cytochrome C release. Interestingly, puerarin could mimic these inhibitory effects on PARP-1 because the ligand molecules of puerarin are well compatible with the active pocket of PARP-1 which is exhibited in a tight binding mode and the common molecular substructure of well known PARP-1 inhibitors, such as olaparib, can also be detected in puerarin [50][51][52]. And also, we identified that puerarin could partly inhibit the expression of PARP-1 and further disrupt the activation of NF-κB signaling pathway, reduce the generation of ROS and stabilize the function of mitochondria.…”

Luteolinidin Protects the Postischemic Heart through CD38 Inhibition with Preservation of NAD(P)(H)

“…Luteolinidin may provide a greater preservation of the NAD(H) pool than a-NAD because the liposomal formulations used provide a much more potent inhibition of CD38 with good uptake throughout the heart. Alternatively, luteolinidin could exert some additional effects on inhibition of other pathways such as poly(ADP-ribose) polymerase, which has been shown to cause severe depletion of the myocardial NAD 1 pool in I/R (Pieper et al, 2000;Liaudet et al, 2001;Szabó et al, 2004;Geraets et al, 2007;Maeda et al, 2014;Boesten et al, 2015).…”

Polyphenols and DNA Damage: A Mixed Blessing

“…At low concentrations, SBs induced by aflatoxin B1 (AFB1), methyl methanesulphonate (MMS), Dox, HgCl 2 or methyl mercury in HepG2 cells were decreased [100,101]. At high concentrations, quercetin and also rutin (glycoside of quercetin with rutinose) caused massive γ-H2AX foci, probably reflecting lethality [94], and yet they decreased DNA damage (SBs) induced by food mutagens PhIP and IQ [96]. …”