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The Targeting of RNA Polymerase I Transcription Using CX-5461 in Combination with Radiation Enhances Tumour Cell Killing Effects in Human Solid Cancers

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Ion Beam Centre, Advanced Technology Institute, University of Surrey, Guildford, Surrey GU2 7XH, UK
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Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK
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Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK
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Author to whom correspondence should be addressed.
Cancers 2019, 11(10), 1429; https://doi.org/10.3390/cancers11101429
Received: 17 June 2019 / Revised: 4 September 2019 / Accepted: 13 September 2019 / Published: 25 September 2019
An increased rate of cellular proliferation is a hallmark of cancer and may be accompanied by an increase in ribosome biogenesis and dysregulation in rRNA synthesis. In this regard, CX-5461 has been developed as a novel RNA polymerase I inhibitor and is currently in Phase I/II clinical trials for solid and hematological malignancies. In the present study, interactions between CX-5461 and single-dose X-ray exposure were assessed using isobologram analysis using MTS assay and drug-induced cell death was assessed using flow cytometric, confocal microscopy and Western blot analysis. Combination treatments involving CX-5461 and single-dose X-ray exposure highlighted increased effectiveness compared to individual treatment alone in the CaSki cervical cancer line, with marked synergistic interaction occurring within the low-drug (50 nM) and low-dose radiation range (2–6 Gy). Cell lines challenged with CX-5461 demonstrated the presence of DNA damage, induction of apoptosis, autophagy and senescence alongside high percentages of G2/M cell cycle arrest. In addition, we report preferential sensitivity of ovarian cancer cells with BRCA2 mutation to this novel agent. Taken together, CX-5461 displayed a broad spectrum of activity in a panel of solid cancer cell lines with IC50 values ranging from 35 nM to >1 µM. The work described herein identifies the synergistic effects of CX-5461 in combination with X-rays in solid cancers and may also aid in the design of clinical trials involving this novel agent. View Full-Text
Keywords: CX-5461; RNA polymerase I targeting; combination studies CX-5461; RNA polymerase I targeting; combination studies
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Ismael, M.; Webb, R.; Ajaz, M.; Kirkby, K.J.; Coley, H.M. The Targeting of RNA Polymerase I Transcription Using CX-5461 in Combination with Radiation Enhances Tumour Cell Killing Effects in Human Solid Cancers. Cancers 2019, 11, 1429.

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