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

被引:57
|
作者
Miyasaka, Aki [1 ]
Oda, Katsutoshi [1 ]
Ikeda, Yuji [1 ]
Wada-Hiraike, Osamu [1 ]
Kashiyama, Tomoko [1 ]
Enomoto, Atsushi [2 ]
Hosoya, Noriko [2 ]
Koso, Takahiro [1 ]
Fukuda, Tomohiko [1 ]
Inaba, Kanako [1 ]
Sone, Kenbun [1 ]
Uehara, Yuriko [1 ]
Kurikawa, Reiko [1 ]
Nagasaka, Kazunori [1 ]
Matsumoto, Yoko [1 ]
Arimoto, Takahide [1 ]
Nakagawa, Shunsuke [3 ]
Kuramoto, Hiroyuki [4 ]
Miyagawa, Kiyoshi [2 ]
Yano, Tetsu [5 ]
Kawana, Kei [1 ]
Osuga, Yutaka [1 ]
Fujii, Tomoyuki [1 ]
机构
[1] Univ Tokyo, Dept Obstet & Gynecol, Fac Med, Bunkyo Ku, Tokyo 1138655, Japan
[2] Univ Tokyo, Grad Sch Med, Ctr Dis Biol & Integrat Med, Lab Mol Radiol, Tokyo 1138655, Japan
[3] Teikyo Univ, Fac Med, Dept Obstet & Gynecol, Tokyo 173, Japan
[4] Kanagawa Hlth Serv Assoc, Kanagawa, Japan
[5] Natl Ctr Global Hlth & Med, Dept Obstet & Gynecol, Tokyo, Japan
关键词
PARP inhibitor; Homologous recombination; Endometrial cancer; PTEN; RAD51; DOUBLE-STRAND BREAKS; DNA-REPAIR DEFECT; BRCA MUTANT-CELLS; POLY(ADP-RIBOSE) POLYMERASE; MICROSATELLITE INSTABILITY; HOMOLOGOUS RECOMBINATION; CANCER-CELLS; PTEN; COMPROMISES; DEFICIENCY;
D O I
10.1186/1471-2407-14-179
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 gamma H2AX, 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 gamma H2AX, 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.
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页数:10
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