Targeting Poly(ADP-Ribose) Polymerase: A Two-Armed Strategy for Cancer Therapy

Plummer, Elizabeth Ruth; Calvert, Hilary

doi:10.1158/aacr.edb-ccr-07-0617

Cited by 19 publications

(22 citation statements)

References 41 publications

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“…The six genes correspond to 4.1% of significantly altered genes, with a known function, in group DON5. The protein is involved in DNA repair and has a critical role in signalling DNA single-strand breaks (Plummer and Calvert, 2007). Shifrin and Anderson (1999) showed that the addition of DON to the Jurkat human lymphoid cell line led to the activation of pro-caspase-3, leading to a higher cleavage of PARP1, a substrate of caspase-3.…”

Section: Dna Repairmentioning

confidence: 99%

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

Dietrich

Neuenschwander

Bucher

et al. 2012

Animal

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The effects of mycotoxins in the production of animal feed were investigated using broiler chickens. For the feeding trial, naturally Fusarium mycotoxin-contaminated wheat was used, which mainly contained deoxynivalenol (DON). The main effects of DON are reduction of the feed intake and reduced weight gain of broilers. At the molecular level, DON binds to the 60 S ribosomal subunit and subsequently inhibits protein synthesis at the translational level. However, little is known about other effects of DON, for example, at the transcriptional level. Therefore, a microarray analysis was performed, which allows the investigation of thousands of transcripts in one experiment. In the experiment, 20 broilers were separated into four groups of five broilers each at day 1 after hatching. The diets consisted of a control diet and three diets with calculated, moderate concentrations of 1.0, 2.5 and 5.0 mg DON/kg feed, which was attained by exchanging uncontaminated wheat with naturally mycotoxin-contaminated wheat up to the intended DON concentration. The broilers were held at standard conditions for 23 days. Three microarrays were used per group to determine the significant alterations of the gene expression in the liver (P , 0.05), and qPCR was performed on the liver and the jejunum to verify the results. No significant difference in BW, feed intake or feed conversion rate was observed. The nutrient uptake into the hepatic and jejunal cells seemed to be influenced by genes: SLC2A5 (fc: 21.54, DON2.5), which facilitates glucose and fructose transport and SLC7A10 (fc: 11.49, DON5), a transporter of D-serine and other neutral amino acids. In the jejunum, the palmitate transport might be altered by SLC27A4 (fc: 21.87, DON5) and monocarboxylates uptake by SLC16A1 (fc: 21.47, DON5). The alterations of the SLC gene expression may explain the reduced weight gain of broilers chronically exposed to DON-contaminated wheat. The decreased expressions of EIF2AK3 (fc: 21.29, DON2.5/5) and DNAJC3 (fc: 21.44, DON2.5) seem to be related to the translation inhibition. The binding of DON to the 60 S ribosomal subunit and the subsequent translation inhibition might be counterbalanced by the downregulation of EIF2AK3 and DNAJC3. The genes PARP1, MPG, EME1, XPAC, RIF1 and CHAF1B are mainly related to single-strand DNA modifications and showed an increased expression in the group with 5 mg DON/kg feed. The results indicate that significantly altered gene expression was already occurring at 2.5 mg DON/kg feed.

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Section: Dna Repairmentioning

confidence: 99%

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

Dietrich

Neuenschwander

Bucher

et al. 2012

Animal

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“…The branching ADP-ribose polymers provide a scaffold for the assembly of repair proteins and the initiation of the complex repair reaction (Haince et al, 2005). Chemo-and radiosensitization by PARP inhibition has been the subject of many reviews (Haince et al, 2005;Plummer, 2006;Plummer and Calvert, 2007;Ratnam and Low, 2007;Lord and Ashworth, 2008). A review of the original research reports indicates that although chemo-and radiotherapy can synergize with PARP inhibitors (PARPi), the assessment of the resulting cellular responses may be limited if clonogenic survival or growth inhibition are chosen as end points (Calabrese et al, 2003(Calabrese et al, , 2004Curtin et al, 2004).…”

Section: Arrest/senescencementioning

confidence: 99%

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

et al. 2010

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“…PARP inhibitors block the repair of DNA single-strand breaks (SSB); unrepaired SSBs lead to the formation of DNA double-strand breaks (DSB). If DSBs cannot be repaired because of homologous recombination dysfunction, genomic instability or cell death can result (6). Therefore, PARP inhibitors may be effective against various human cancer cells with defective DNA repair genes.…”

Section: Introductionmentioning

confidence: 99%

RAD51C-Deficient Cancer Cells Are Highly Sensitive to the PARP Inhibitor Olaparib

Min

Yoon

et al. 2013

Molecular Cancer Therapeutics

123

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A PARP inhibitor is a rationally designed targeted therapy for cancers with impaired DNA repair abilities. RAD51C is a paralog of RAD51 that has an important role in the DNA damage response. We found that cell lines sensitive to a novel oral PARP inhibitor, olaparib, had low levels of RAD51C expression using microarray analysis, and we therefore hypothesized that low expression of RAD51C may hamper the DNA repair process, resulting in increased sensitivity to olaparib. Compared with the cells with normal RAD51C expression levels, RAD51C-deficient cancer cells were more sensitive to olaparib, and a higher proportion underwent cell death by inducing G 2 -M cell-cycle arrest and apoptosis. The restoration of RAD51C in a sensitive cell line caused attenuation of olaparib sensitivity. In contrast, silencing of RAD51C in a resistant cell line enhanced the sensitivity to olaparib, and the number of RAD51 foci decreased with ablated RAD51C expression. We also found the expression of RAD51C was downregulated in cancer cells due to epigenetic changes and RAD51C expression was low in some gastric cancer tissues. Furthermore, olaparib significantly suppressed RAD51C-deficient tumor growth in a xenograft model. In summary, RAD51C-deficient cancer cells are highly sensitive to olaparib and offer preclinical proof-of-principle that RAD51C deficiency may be considered a biomarker for predicting the antitumor effects of olaparib. Mol Cancer Ther; 12(6); 865-77. Ó2013 AACR.

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Targeting Poly(ADP-Ribose) Polymerase: A Two-Armed Strategy for Cancer Therapy

Cited by 19 publications

References 41 publications

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

RAD51C-Deficient Cancer Cells Are Highly Sensitive to the PARP Inhibitor Olaparib

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