PARP Inhibitors Talazoparib and Niraparib Sensitize Melanoma Cells to Ionizing Radiation

Abstract

(1) Background: Niraparib and Talazoparib are poly (ADP-ribose) polymerase (PARP) 1/2 inhibitors. It is assumed that combining PARP inhibitors with radiotherapy could be beneficial for cancer treatment. In this study, melanoma cells were treated with Niraparib and Talazoparib in combination with ionizing radiation (IR). (2) Methods: The effects of Talazoparib and Niraparib in combination with IR on cell death, clonogenicity and cell cycle arrest were studied in healthy primary fibroblasts and primary melanoma cells. (3) Results: The melanoma cells had a higher PARP1 and PARP2 content than the healthy fibroblasts, and further increased their PARP2 content after the combination therapy. PARP inhibitors both sensitized fibroblasts and melanoma cells to IR. A clear supra-additive effect of KI+IR treatment was detected in two melanoma cell lines analyzing the surviving fraction. The cell death rate increased in the healthy fibroblasts, but to a larger extent in melanoma cells after combined treatment. Finally, a lower percentage of cells in the radiosensitive G2/M phase is present in the healthy fibroblasts compared to the melanoma cells. (4) Conclusions: Both PARP inhibitors sensitize melanoma cells to IR. Healthy tissue seems to be less affected than melanoma cells. However, the great heterogeneity of the results suggests prior testing of the tumor cells in order to personalize the treatment.

PD-1 Inhibitor Maintenance Therapy Combined Iodine-125 Seed Implantation Successfully Salvage Recurrent Cervical Cancer after CCRT: A Case Report

“…As previously mentioned, PARP is an intracellular protein involved in the repair of single and double-stranded DNA breaks [ 7 , 8 ], and radiotherapy exerts its cytotoxic mitotic effects on tumor cells through DNA damage [ 58 , 59 ], so the combination with a PARP inhibitor would sensitize the effect to DNA-damaging induced by radiation. This sensitizing effect has been demonstrated in in vitro studies for both fraction radiotherapy and continuous LDR radiotherapy [ 60 , 61 , 62 , 63 ]; meanwhile, some clinical studies have investigated it [ 64 , 65 ].…”

Sesquiterpene Lactones Potentiate Olaparib-Induced DNA Damage in p53 Wildtype Cancer Cells

“…1 H NMR (500 MHz, CDCl3) δ 7.64 (dd, J = 8.0, 1.4 Hz, 2H), 7.49-7.40 (m, 1H), 7.35 (t, J = 7.6 Hz, 2H), 6.68 (d, J = 9.9 Hz, 1H), 6.24 (d, J = 9.9 Hz, 1H), 5.26-5.17 (m, 1H), 2.13 (d, J = 1.3 Hz, 3H), 2.01-1.89 (m, 4H), 1.60 (s, 3H), 1.54-1.47 (m, 1H), 1.32 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 186.0, 174.6, 154.6, 150.8, 138.1, 129.9, 129.1, 125.9, 123.8, 79.2, 57.4, 48.7, 41.2, 37.4, 24.9, 22.2, 20.4, 10.9. These data were consistent with those published [21].…”

“…This raises the hypothesis that UBE2D inhibition can hypersensitise cells to PARP inhibitors. Another attractive approach is to amplify S phase PARP-trapping damage by raising the frequency of PARP-DNA complex association, such as via the use of reactive oxygen species (ROS)-inducing small molecules or radiation [13,14]. By eliciting oxidative DNA base damage, ROS generation activates base excision repair (BER), for which PARP1/2 enzymes are early responders, making them amenable for trapping to DNA by suitable inhibitors, such as olaparib and talazoparib [5,14].…”

Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy

“…Talazoparib and Niraparib have also been studied for their sensitizing effects. Primary melanoma cultures treated with combination therapy of Talazoparib, Niraparib and radiation, demonstrate that both PARP inhibitors sensitize melanoma cells to IR ( 162 ). A short-term phase 1 clinical trial looking at the efficacy of combination therapy of radiation and Olaparib has determined the safety of the combination regimen in doses up to 200 mg/day without any side effects ( 163 ).…”