Sensitization of chondrosarcoma cells with PARP inhibitor and high-LET radiation

Abstract

Chondrosarcoma is a malignant tumor that arises from cartilaginous tissue and is radioresistant and chemoresistant to conventional treatments. The preferred treatment consists of surgical resection, which might cause severe disabilities for the patient; in addition, this procedure might be impossible for inoperable locations, such as the skull base. Carbon ion irradiation (hadron therapy) has been proposed as an alternative treatment, primarily due to its greater biological effectiveness and improved ballistic properties compared with conventional radiotherapy with X-rays. The goal of this study was to characterize the genetic mutations of a grade III chondrosarcoma cell line (CH2879) and examine the cellular responses to conventional radiotherapy (X-rays) and hadron therapy (proton and carbon ions) in the presence of the PARP inhibitor Olaparib. To better understand PARP inhibition, we first analyzed the formation of poly-ADP ribose chains by western blot; we observed an increase in its signal after irradiation, which disappeared on addition of the PARP inhibitor. PARPi enhanced ratio of approximately 1.3, 1.8, and 1.5 following irradiation of cells with X-rays, protons, and C-ions, respectively, as detected by clonogenic assay. The decrease in cell survival was confirmed by proliferation assay. The radiosensitivity of CH2879 cells was associated with mutations in homologous recombination repair genes, such as RAD50, SMARCA2 and NBN . This study demonstrates the capacity of the PARP inhibitor Olaparib to radiosensitize mutated chondrosarcoma cells to conventional photon irradiation, proton and carbon ion irradiation.

Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status

“…Our results show that combination therapies with temozolomide or radiotherapy and PARP inhibition were synergistic in all chondrosarcoma cell lines and are therefore promising candidate therapeutic strategies for both IDH WT and IDH MUT chondrosarcoma patients. Recently, a similar radio-sensitizing effect was described in a study in which olaparib was combined with different radiotherapeutic strategies in the chondrosarcoma cell line CH2879 [47]. Notably, combination of talazoparib with the DNA alkylating/methylating agent temozolomide seems to be most effective.…”

Molecular Investigation on a Triple Negative Breast Cancer Xenograft Model Exposed to Proton Beams

“…In this regard, even the literature describes the role of remaining tumor cancer stem cells before the RT starting and their ability to repopulate over the course of treatment plan in several conditions including hypoxia, stroma interaction among cells and variations in the intrinsic cells’ sensitivity to radiation, as well as in the modulation of DNA repair or other cell survival pathways [ 23 , 24 , 25 , 26 , 27 ]. Thus, we better explored the stem cell marker modulation in our BC xenograft model during PRT plans, considering our GEP and IHC data ( Table 1 and Table 5 ).…”

Harnessing the targeting potential of differential radiobiological effects of photon versus particle radiation for cancer treatment

“…Several third generation PRPAi's, including olaparib (AZD2281), AG14361, talazoparib (BMN673), niraparib (MK‐4827), and veliparib (ABT‐888), have been developed to sensitise tumour cells to IR (Table 3). Olaparib (AZD2281), the first PARPi to gain US Food and Drug Administration approval, radio‐sensitised tumour cells irradiated with photons, protons and carbon ions, with levels of tumour radio‐sensitivity associated with mutations in HR repair genes (Cesaire et al, 2019). Hence, PARPi's could be applicable to a wide therapeutic range of LET radiation therapies, as a radio‐sensitiser through its DNA repair effects.…”