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BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

Anti-tumor activity of olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in cultured endometrial carcinoma cells

Authors: Aki Miyasaka, Katsutoshi Oda, Yuji Ikeda, Osamu Wada-Hiraike, Tomoko Kashiyama, Atsushi Enomoto, Noriko Hosoya, Takahiro Koso, Tomohiko Fukuda, Kanako Inaba, Kenbun Sone, Yuriko Uehara, Reiko Kurikawa, Kazunori Nagasaka, Yoko Matsumoto, Takahide Arimoto, Shunsuke Nakagawa, Hiroyuki Kuramoto, Kiyoshi Miyagawa, Tetsu Yano, Kei Kawana, Yutaka Osuga, Tomoyuki Fujii

Published in: BMC Cancer | Issue 1/2014

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Abstract

Background

PTEN inactivation is the most frequent genetic aberration in endometrial cancer. One of the phosphatase-independent roles of PTEN is associated with homologous recombination (HR) in nucleus. Poly (ADP-ribose) polymerase (PARP) plays key roles in the repair of DNA single-strand breaks, and a PARP inhibitor induces synthetic lethality in cancer cells with HR deficiency. We examined the anti-tumor activity of olaparib, a PARP inhibitor, and its correlation between the sensitivity and status of PTEN in endometrial cancer cell lines.

Methods

The response to olaparib was evaluated using a clonogenic assay with SF50 values (concentration to inhibit cell survival to 50%) in 16 endometrial cancer cell lines. The effects of PTEN on the sensitivity to olaparib and ionizing radiation (IR) exposure were compared between parental HEC-6 (PTEN-null) and HEC-6 PTEN + (stably expressing wild-type PTEN) cells by clonogenic assay, foci formation of RAD51 and γH2AX, and induction of cleaved PARP. The effects of siRNA to PTEN were analyzed in cells with wild-type PTEN.

Results

The SF50 values were 100 nM or less in four (25%: sensitive) cell lines; whereas, SF50 values were 1,000 nM or more in four (25%: resistant) cell lines. PTEN mutations were not associated with sensitivity to olaparib (Mutant [n = 12]: 746 ± 838 nM; Wild-type [n = 4]: 215 ± 85 nM, p = 0.26 by Student’s t test). RAD51 expression was observed broadly and was not associated with PTEN status in the 16 cell lines. The number of colonies in the clonogenic assay, the foci formation of RAD51 and γH2AX, and the induction of apoptosis were not affected by PTEN introduction in the HEC-6 PTEN + cells. The expression level of nuclear PTEN was not elevated within 24 h following IR in the HEC-6-PTEN + cells. In addition, knocking down PTEN by siRNA did not alter the sensitivity to olaparib in 2 cell lines with wild-type PTEN.

Conclusions

Our results suggest that olaparib, a PARP inhibitor, is effective on certain endometrial cancer cell lines. Inactivation of PTEN might not affect the DNA repair function. Predictive biomarkers are warranted to utilize olaparib in endometrial cancer.
Appendix
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Metadata
Title
Anti-tumor activity of olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in cultured endometrial carcinoma cells
Authors
Aki Miyasaka
Katsutoshi Oda
Yuji Ikeda
Osamu Wada-Hiraike
Tomoko Kashiyama
Atsushi Enomoto
Noriko Hosoya
Takahiro Koso
Tomohiko Fukuda
Kanako Inaba
Kenbun Sone
Yuriko Uehara
Reiko Kurikawa
Kazunori Nagasaka
Yoko Matsumoto
Takahide Arimoto
Shunsuke Nakagawa
Hiroyuki Kuramoto
Kiyoshi Miyagawa
Tetsu Yano
Kei Kawana
Yutaka Osuga
Tomoyuki Fujii
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-179

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