Induction of apoptosis and modulation of homologous recombination DNA repair pathway in prostate cancer cells by the combination of AZD2461 and valproic acid

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dc.contributor.authorSargazi, Saman
dc.contributor.authorSaravani, Ramin
dc.contributor.authorZavar Reza, Javad
dc.contributor.authorJaliani, Hossein Zarei
dc.contributor.authorMirinejad, Shekoufeh
dc.contributor.authorRezaei, Zohreh
dc.contributor.authorZarei, Sadegh
dc.date.accessioned2020-02-17T13:28:40Z
dc.date.available2020-02-17T13:28:40Z
dc.date.issued2019-07-08
dc.description.abstractCancer therapies using defects in homologous recombination (HR) DNA repair pathway of tumor cells are not yet approved to be applicable in patients with malignancies other than BRCA1/2-mutated tumors. This study was designed to determine the efficacy of combination therapy of a histone deacetyl ase inhibitor, valproic acid (VPA) and a novel PARP inhibitor AZD2461 in both PC-3 (PTEN-mutated) and DU145 (PTEN-unmutated) prostate cancer cell lines. The Trypan blue dye exclusion assay an d the tetrazolium-based colorimetric (MTT) assay were performed to measure the cytotoxicity while combination effects were assessed based on Chou-Talalay's princi- ples. Flow-cytometric assay determined the type of cell deat h. The real-time PCR analysis was used to evaluate the alterations in mRNA levels of HR-related genes while their protein levels were measured using the ELISA method. γ -H2AX levels were determined as a marker of DNA damage. We observed a synergistic relationship between VPA and AZD2461 in all affected fractions of PC-3 cells (CI<0.9), but not in DU145 cells (CI>1.1). Annexin-V staining analysis revealed a significant induction of apoptosis when PC-3 cells were treated with VPA+AZD2461 ( p<0.05 ). Both mRNA and protein levels of Rad51 and Mre11 were significantly decreased in PC-3 cells co-treated with VPA+AZD2461 while enhanced H2AX phosphorylation was found in PC-3 cells after 12 and 24 hours of co-treatment ( p<0.05 ). Our findings established a preclinical rationale for selective targeting of HR repair pathways by a combination of VPA and AZD2461 as a mechanism for reducing the HR pathway sufficiency in PTEN -mutated prostate cancer cells.en
dc.identifier.issn1611-2156
dc.identifier.urihttp://hdl.handle.net/2003/38600
dc.identifier.urihttp://dx.doi.org/10.17877/DE290R-20519
dc.language.isoen
dc.relation.ispartofseriesEXCLI Journal;Vol. 18 2019
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAZD2461en
dc.subjectDrug combinationen
dc.subjectProstate canceren
dc.subjectPTENen
dc.subjectValproic aciden
dc.subject.ddc610
dc.titleInduction of apoptosis and modulation of homologous recombination DNA repair pathway in prostate cancer cells by the combination of AZD2461 and valproic aciden
dc.typeText
dc.type.publicationtypearticle
dcterms.accessRightsopen access
eldorado.dnb.zdberstkatid2132560-1
eldorado.secondarypublicationtrue

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