The extreme radiosensitivity of the squamous cell carcinoma SKX is due to a defect in double-strand break repair

Kasten-Pisula, Ulla; Menegakis, Apostolos; Brammer, I.; Borgmann, Kerstin; Mansour, Waël; Degenhardt, Sarah; Krause, Mechthild; Schreiber, Andreas; Dahm-Daphi, Jochen; Petersen, Cordula; Dikomey, Ekkehard; Baumann, Michaël

doi:10.1016/j.radonc.2008.10.019

Cited by 49 publications

(20 citation statements)

References 39 publications

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“…The mechanism behind Olaparib‐mediated cellular radiosensitivity could potentially be explained by induced cell cycle arrest, enhanced apoptosis, or impaired DBS repair efficiency (Kasten‐Pisula et al., 2009). In order to test these possibilities, we first examined the effect of Olaparib treatment on the cell cycle with or without IR in both responders and non‐responders .…”

Section: Resultsmentioning

confidence: 99%

Inhibition of PARP1‐dependent end‐joining contributes to Olaparib‐mediated radiosensitization in tumor cells

et al. 2014

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Olaparib Radiosensitivity PARP1-dependent end-joining A B S T R A C TPoly-ADP-ribose-polymerase inhibitors (PARPi) are considered to be optimal tools for specifically enhancing radiosensitivity. This effect has been shown to be replicationdependent and more profound in HR-deficient tumors. Here, we present a new mode of PARPi-mediated radiosensitization which was observed in four out of six HR-proficient tumor cell lines (responders) investigated, but not in normal cells. This effect is replicationindependent, as the radiosensitization remained unaffected following the inhibition of replication using aphidicolin. We showed that responders are radiosensitized by Olaparib because their DSB-repair is switched to PARP1-dependent end-joining (PARP1-EJ), as evident by (i) the significant increase in the number of residual gH2AX foci following irradiation with 3Gy and treatment with Olaparib, (ii) the enhanced enrichment of PARP1 at the chromatin after 3Gy and (iii) the inhibition of end-joining activity measured by a specific reporter substrate upon Olaparib treatment. This is the first study which directly demonstrates the switch to PARP1-EJ in tumor cells and its contribution to the response to Olaparib as a radiosensitizer, findings which could widen the scope of application of PARPi in tumor therapy.

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Section: Resultsmentioning

confidence: 99%

Inhibition of PARP1‐dependent end‐joining contributes to Olaparib‐mediated radiosensitization in tumor cells

et al. 2014

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“…For the irradiation experiment, the radiosensitive human squamous cell carcinoma cell line SKX was used [31]. Cells were seeded 1 day before irradiation on a thin biofilm as bottom of a chamber slide.…”

Section: Dose Effect Curves and Dose Uncertaintymentioning

confidence: 99%

Dose-controlled irradiation of cancer cells with laser-accelerated proton pulses

et al. 2012

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Proton beams are a promising tool for the improvement of radiotherapy of cancer, and compact laserdriven proton radiation (LDPR) is discussed as an alternative to established large-scale technology facilitating wider clinical use. Yet, clinical use of LDPR requires substantial development in reliable beam generation and transport, but also in dosimetric protocols as well as validation in radiobiological studies. Here, we present the first dose-controlled direct comparison of the radiobiological effectiveness of intense proton pulses from a laser-driven accelerator with conventionally generated continuous proton beams, demonstrating a first milestone in translational research. Controlled dose delivery, precisely online and offline monitored for each out of *4,000 pulses, resulted in an unprecedented relative dose uncertainty of below 10 %, using approaches scalable to the next translational step toward radiotherapy application.

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“…Although studies investigating radiosensitation through tyrosine kinase inhibitors are sparse, enhancement of radiosensitivity by gefitinib, a reversible EGFR inhibitor, has been previously described and the results are in line with our findings(Shintani et al , ). Interestingly, neratinib induces radiosensitation in FaDu cell line, which is known for moderate radiosensitivity(Kasten‐Pisula et al , ), as well as in CAL27 and SCC25 cell lines, known for low radiosensitivity due to p53 mutation/3p loss(Raju et al , ).…”

Section: Discussionmentioning

confidence: 99%

Effects of neratinib and combination with irradiation and chemotherapy in head and neck cancer cells

et al. 2016

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The extreme radiosensitivity of the squamous cell carcinoma SKX is due to a defect in double-strand break repair

Cited by 49 publications

References 39 publications

Inhibition of PARP1‐dependent end‐joining contributes to Olaparib‐mediated radiosensitization in tumor cells

Inhibition of PARP1‐dependent end‐joining contributes to Olaparib‐mediated radiosensitization in tumor cells

Dose-controlled irradiation of cancer cells with laser-accelerated proton pulses

Effects of neratinib and combination with irradiation and chemotherapy in head and neck cancer cells

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