Radiosensitization Effect of Talazoparib, a Parp Inhibitor, on Glioblastoma Stem Cells Exposed to Low and High Linear Energy Transfer Radiation

Abstract

Despite continuous improvements in treatment of glioblastoma, tumor recurrence and therapy resistance still occur in a high proportion of patients. One underlying reason for this radioresistance might be the presence of glioblastoma cancer stem cells (GSCs), which feature high DNA repair capability. PARP protein plays an important cellular role by detecting the presence of damaged DNA and then activating signaling pathways that promote appropriate cellular responses. Thus, PARP inhibitors (PARPi) have recently emerged as potential radiosensitizing agents. In this study, we investigated the preclinical efficacy of talazoparib, a new PARPi, in association with low and high linear energy transfer (LET) irradiation in two GSC cell lines. Reduction of GSC fraction, impact on cell proliferation, and cell cycle arrest were evaluated for each condition. All combinations were compared with a reference schedule: photonic irradiation combined with temozolomide. The use of PARPi combined with photon beam and even more carbon beam irradiation drastically reduced the GSC frequency of GBM cell lines in vitro. Furthermore, talazoparib combined with irradiation induced a marked and prolonged G2/M block, and decreased proliferation. These results show that talazoparib is a new candidate that effects radiosensitization in radioresistant GSCs, and its combination with high LET irradiation, is promising.

DNA repair genes in astrocytoma tumorigenesis, progression and therapy resistance

“…The CSC population was also affected by the combination of talazoparib, a PARP1 inhibitor, with IR. The combined treatment induced prolonged G2/M arrest and reduced proliferation rates of GBM CSCs (Lesueur et al, 2018). Altogether, these data suggest that the impairment of repair machinery can sensitize CSCs to IR and could improve therapy efficiency.…”

Functionalized mesoporous silica nanoparticles for innovative boron-neutron capture therapy of resistant cancers

“…Large amounts of boron might be loaded into nanoparticle mesopores as o-carborane [30], however there is a risk of carborane leakage and unpredictable boron distribution. Here, we propose to attach 10 [31,32]. In addition, an Acp (aminohexanoic acid) moiety is grafted on the C-terminal portion of the peptide to serve as a spacer between the polycationic domain and the Cys residue for a better efficiency in the thiol-maleimide coupling strategy used.…”

“…The nanoparticles were centrifuged and washed three times with methanol. The nanoparticles were dried under high vacuum for 2 hours.-Incorporation of BSH inside pores(8) NP(7) were dispersed in a mixture of ACN/H2O (50 mL in proportion 4/1) under argon, then10 B-enriched Sodium mercaptoundecahydro-dodecaborate (Na 2 [ 10 B 12 H 11 SH]) (Stella Chemifa, Osaka, Japan) (250 mg) and TCEP were added (300 mg). The reaction was stirred under argon overnight at room temperature.…”

Hadrontherapy Interactions in Molecular and Cellular Biology

“…Particle therapy might be the best irradiation modality to combine with PARPi. Due to the moderate integral dose that is delivered to self-renewing surrounding normal tissues (e.g., skin, digestive tract), with particle irradiation modalities [153][154][155], the toxicity of the combination is expected to be lower. Furthermore, the radiosensitizing effects are higher in extent in the Bragg peak than in the entrance region [156], which allows the therapeutic ratio of PARPi as a radiosensitizer to be increased.…”

“…This damage is essentially repaired by BER, for which PARP is critical. Consequently, the inhibition of PARP delays the repair of oxidative clustered DNA lesions and favors their conversion to highly lethal DSBs [153,154,157].…”