Enhancement of Soft Tissue Sarcoma Cell Radiosensitivity by Poly(ADP-ribose) Polymerase-1 Inhibitors

被引：25

作者：

Mangoni, Monica ^{[1
,4
]}

Sottili, Mariangela ^{[1
,4
]}

Salvatore, Giulia ^{[1
,4
]}

Meattini, Icro ^{[1
,4
]}

Desideri, Isacco ^{[1
,4
]}

Greto, Daniela ^{[1
,4
]}

Loi, Mauro ^{[1
]}

Becherini, Carlotta ^{[1
]}

Garlatti, Pietro ^{[1
]}

Paoli, Camilla Deli ^{[1
]}

Dominici, Luca ^{[1
]}

Gerini, Chiara ^{[1
]}

Scoccianti, Silvia ^{[1
,4
]}

Bonomo, Pierluigi ^{[1
,4
]}

Silvano, Angela ^{[2
]}

Beltrami, Giovanni ^{[3
,4
]}

Campanacci, Domenico ^{[3
,4
]}

Livi, Lorenzo ^{[1
,4
]}

机构：

[1] Univ Florence, Dept Biomed Expt & Clin Sci Mario Serio, Sect Radiat Oncol, Largo Brambilla 3, I-50134 Florence, Italy

[2] Univ Florence, Dept Expt & Clin Med, Largo Brambilla 3, I-50134 Florence, Italy

[3] Univ Careggi, Azienda Osped, Dept Orthopaed Oncol, Largo Brambilla 3, I-50134 Florence, Italy

[4] Ist Toscano Tumori, Via Taddeo Alderoui 26-N, I-50139 Florence, Italy

来源：

RADIATION RESEARCH | 2018年 / 190卷 / 05期

关键词：

EWING SARCOMA; RADIATION-THERAPY; PARP INHIBITORS; DNA-DAMAGE; OLAPARIB; TUMOR; SENSITIVITY; PATHWAY; GROWTH; OSTEOSARCOMA;

D O I：

10.1667/RR15035.1

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Soft tissue sarcomas (STS) are aggressive tumors with a poor prognosis. Poly(ADP-ribose) polymerase (PARP)-1 inhibitors (PARPi) enhance the cytotoxic effects of radiation. In this study, we evaluated the effect of PARPi on survival and DNA damage of irradiated STS cells. For clonogenic assays, STS cell lines were irradiated with or without olaparib, iniparib or veliparib pretreatment. The effect of PARP inhibition on gamma-H2AX and Rad51 foci formation, on PARP-1, phospho-ERK and cleaved caspase-3 protein expression and on cell cycle progression was evaluated on irradiated rhabdomyosarcoma cells pretreated with olaparib. The results from this work showed that PARPi induced significant radiosensitization in STS cells. Rhabdomyosarcoma cells showed the highest increase in radiosensitivity, with a radiosensitization enhancement ratio at 50% survival (ER50) of 3.41 with veliparib. All PARPi exerted a synergistic effect when combined with radiation. Fibrosarcoma cells showed an ER50 of 2.29 with olaparib. Leiomyosarcoma and liposarcoma cells showed their highest ER50 with veliparib (1.71 and 1.84, respectively). In rhabdomyosarcoma, olaparib enhanced the formation of radiation-induced gamma-H2AX/Rad51 foci and PARP-1 cleavage, induced slightly increased expression of cleaved caspase-3 and reduced phospho-ERK expression. Moreover, the combination of olaparib and radiation resulted in a significantly enhanced cell cycle arrest in the G(2)/M phase compared to the two treatments alone. In conclusion, we have shown that PARPi are potent radiosensitizers of human STS cells. These results support the pursuit of further investigations into the effects of PARPi combined with radiation on STS. (C) 2018 by Radiation Research Society

引用

页码：464 / 472

页数：9

共 39 条

[1] Inhibition of poly (ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models [J].