Potentiation of genomic instability with combined exposure of olaparib and cisplatin.
Shuhei Ito
Conleth G. Murphy
Ekaterina Doubrovina
Maria Jasin
Mary Ellen Moynahan
10.1371/journal.pone.0159341.g005
https://plos.figshare.com/articles/figure/Potentiation_of_genomic_instability_with_combined_exposure_of_olaparib_and_cisplatin_/3893373
<p><b>A.</b> Dose-response curve of survival with cisplatin alone and cisplatin with 1μM olaparib of MCF-10A and primary T cell 1. In MCF-10A, cells were grown with indicated concentration of cisplatin for the first 30 hr with or without continuous exposure at 1 μM olaparib. Clonogenic survival was assessed by colony counting at 9 days. In primary T cell 1, cells were grown with indicated concentration of cisplatin with or without 1 μM olaparib for the first 24 hr. Viable cells were scored and enumerated by trypan blue exclusion at 7 days. Means with SD are shown (MCF-10A: n = 3, primary T cell 1: n = 2). <b>B.</b> Induction of SCEs by cisplatin and/or olaparib in MCF-10A and primary T cell 1. In MCF-10A, cells were exposed at 0.5 μM cisplatin with or without 1 μM olaparib for 30 hr. In primary T cell 1, cells were exposed at 0.5 μM cisplatin for the first 24hr with or without 1 μM olaparib for 70 hr. Fold increases of SCE per chromosome compared with no treatment or 0.5 μM cisplatin are shown for each cell type. Approximately 50 metaphases were counted for each cell. Error bars depict the mean with SD. Asterisks designate statistical significance for unpaired <i>t</i>-test at <i>P</i> < 0.0001. <b>C.</b> Chromatid-type aberrations following cisplatin with or without olaparib in primary T cell 1. Cells were exposed at 0.5 μM cisplatin with or without 1 μM olaparib for 24 hr. One hundred metaphases were counted for each exposure. Fold increases of chromatid-type aberrations per chromosome compared with no treatment or 0.5 μM cisplatin are shown for each cell type. The y-axis is the number of total chromatid-type aberrations per chromosome for each metaphase counted. Error bars indicate mean with SEM. The <i>P</i>-values were calculated using unpaired t-test.</p>
2016-07-18 14:46:06
stage cancers
PARPi warrants consideration
non-tumorigenic cells
sister chromatid exchange
Induce Genomic Instability
DNA repair pathways
HR-deficient cells
prevention strategies
cytogenetic alterations
DSB
Significant dose-dependent increases
tumorigenic epithelial cell lines
BRCA 2-associated breast
PARP inhibitors
lymphoid cells
prostate cancer
repair processes
DNA double-strand
Genomic instability
PARP Inhibitors
FDA-approved olaparib
non-oncologic indications
DNA damage response
repair pathway
olaparib potentiated SCE induction
HR-proficient cells
PAR activity
BRCA 1
BRCA-deficient ovary cancer
genotoxic effects
HR-defective cells