Suberoylanilide hydroxamic acid (SAHA) enhances olaparib activity by targeting homologous recombination DNA repair in ovarian cancer.

Konstantinopoulos PA, Wilson AJ, Saskowski J, Wass E, Khabele D
Gynecol Oncol. 2014 133 (3): 599-606

PMID: 24631446 · PMCID: PMC4347923 · DOI:10.1016/j.ygyno.2014.03.007

OBJECTIVES - Approximately 50% of serous epithelial ovarian cancers (EOC) contain molecular defects in homologous recombination (HR) DNA repair pathways. Poly(ADP-ribose) polymerase inhibitors (PARPi) have efficacy in HR-deficient, but not in HR-proficient, EOC tumors as a single agent. Our goal was to determine whether the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), can sensitize HR-proficient ovarian cancer cells to the PARPi AZD-2281 (olaparib).

METHODS - Ovarian cancer cell lines (SKOV-3, OVCAR-8, NCI/ADR-Res, UWB1.289 BRCA1null and UWB1.289+BRCA1 wild-type) were treated with saline vehicle, olaparib, SAHA or olaparib/SAHA. Sulforhodamine B (SRB) assessed cytotoxicity and immunofluorescence and Western blot assays assessed markers of apoptosis (cleaved PARP) and DNA damage (pH2AX and RAD51). Drug effects were also tested in SKOV-3 xenografts in Nude mice. Affymetrix microarray experiments were performed in vehicle and SAHA-treated SKOV-3 cells.

RESULTS - In a microarray analysis, SAHA induced coordinated down-regulation of HR pathway genes, including RAD51 and BRCA1. Nuclear co-expression of RAD51 and pH2AX, a marker of efficient HR repair, was reduced approximately 40% by SAHA treatment alone and combined with olaparib. SAHA combined with olaparib induced apoptosis and pH2AX expression to a greater extent than either drug alone. Olaparib reduced cell viability at increasing concentrations and SAHA enhanced these effects in 4 of 5 cell lines, including BRCA1 null and wild-type cells, in vitro and in SKOV-3 xenografts in vivo.

CONCLUSIONS - These results provide preclinical rationale for targeting DNA damage response pathways by combining small molecule PARPi with HDACi as a mechanism for reducing HR efficiency in ovarian cancer.

Copyright © 2014. Published by Elsevier Inc.

MeSH Terms (25)

Animals Antineoplastic Agents Carcinoma, Ovarian Epithelial Cell Line, Tumor Cell Proliferation Cell Survival DNA, Neoplasm DNA Damage Down-Regulation Drug Resistance, Neoplasm Drug Synergism Female Histone Deacetylase Inhibitors Humans Hydroxamic Acids Mice Mice, Nude Neoplasms, Glandular and Epithelial Ovarian Neoplasms Phthalazines Piperazines Recombinational DNA Repair Tissue Array Analysis Vorinostat Xenograft Model Antitumor Assays

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