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Gynecol Oncol. 2014 Jun;133(3):599-606. doi: 10.1016/j.ygyno.2014.03.007. Epub 2014 Mar 11.

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

Author information

1
Department of Medical Oncology, Medical Gynecologic Oncology Program, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
2
Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.
3
Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. Electronic address: dineo.khabele@vanderbilt.edu.

Abstract

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.

KEYWORDS:

Histone deacetylase inhibitors (HDACi); Olaparib (Ola); Ovarian cancer; Phosphorylated gamma histone H2AX (pH2AX); Poly(ADP-ribose) polymerase inhibitors (PARPi); Vorinostat (SAHA)

PMID:
24631446
PMCID:
PMC4347923
DOI:
10.1016/j.ygyno.2014.03.007
[Indexed for MEDLINE]
Free PMC Article

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