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

Abstract

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 γ-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 γ-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 G2/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.

• Authors: Monica Mangoni, Mariangela Sottili, Giulia Salvatore, Icro Meattini, Isacco Desideri, Daniela Greto, Mauro Loi, Carlotta Becherini, Pietro Garlatti, Camilla Delli Paoli, Luca Dominici, Chiara Gerini, Silvia Scoccianti, Pierluigi Bonomo, Angela Silvano, Giovanni Beltrami, Domenico Campanacci, Lorenzo Livi
• Journal: Radiation research (Radiat Res) Vol. 190 Issue 5 Pg. 464-472 (11 2018) ISSN: 1938-5404 [Electronic] United States
• PMID: 30067444 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzimidazoles
• Poly(ADP-ribose) Polymerase Inhibitors
• Radiation-Sensitizing Agents
• veliparib
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1

Topics

• Antineoplastic Agents (therapeutic use)
• Benzimidazoles (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Combined Modality Therapy
• DNA Damage (drug effects)
• Humans
• Poly (ADP-Ribose) Polymerase-1 (antagonists & inhibitors)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology, therapeutic use)
• Radiation Tolerance (drug effects)
• Radiation-Sensitizing Agents (pharmacology, therapeutic use)
• Sarcoma (drug therapy, pathology, radiotherapy)
• Xenograft Model Antitumor Assays