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 G/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.

PARP inhibitors affect growth, survival and radiation susceptibility of human alveolar and embryonal rhabdomyosarcoma cell lines

“…2a). These observations are in agreement with data very recently reported by Mangoni et al (2018). In the present study we examined in detail the molecular mechanisms of PARPi effects on cell cycle progression and survival.…”

“…Only very recently, Mangoni et al have shown that pretreatment with Olaparib, Iniparib or Veliparib, three PARP1 inhibitors, is able to induce a significant radiosensitization in different soft tissue sarcoma cell lines (Mangoni et al 2018). …”

“…A limited amount of information is available about the effects and the molecular mechanisms of PARP inhibition, as monotherapy or in combination with conventional therapies, in RMS. Only very recently, Mangoni et al have shown that pretreatment with Olaparib, Iniparib or Veliparib, three PARP1 inhibitors, is able to induce a significant radiosensitization in different soft tissue sarcoma cell lines (Mangoni et al 2018 ).…”

PARP1 Inhibition Radiosensitizes Models of Inflammatory Breast Cancer to Ionizing Radiation

“…More recent trials are testing whether PARPi is effective in combination with radiation in squamous cell carcinoma (48) (NCT02229656), locally advanced rectal cancer (NCT02921256 and NCT01589419), high grade gliomas (NCT03212742), non-small cell lung cancer (NCT01386385 and NCT02412371), and soft tissue sarcoma (NCT02787642; ref. 49). Thus, although this study is the first to report that PARP inhibition may be an effective strategy in patients with IBC, the concept of PARP inhibitor-mediated radiosensitization is being explored in many other cancer contexts.…”

Prioritization of Novel Agents for Patients with Rhabdomyosarcoma: A Report from the Children’s Oncology Group (COG) New Agents for Rhabdomyosarcoma Task Force

“…Olaparib (inhibitor of PARP 1/2) and AZD2461 (inhibitor of PARP 1/2/3) resulted in a reduction in growth at clinically achievable concentrations (1-5 µM olaparib and 5-10 µM AZD2461); however, talazoparib (inhibitor of PARP 1/2) was not effective against FP-RMS or FN-RMS [26,29,30]. Preclinical combination studies in RMS have shown that PARP inhibitors can enhance the efficacy of topoisomerase II inhibitors, ionizing radiation, and alkylating agents such as temozolomide [26,29,31,32]. The combination of olaparib with temozolomide was particularly effective when tested in mouse and zebrafish xenografts [33].…”