The Targeting of RNA Polymerase I Transcription Using CX-5461 in Combination with Radiation Enhances Tumour Cell Killing Effects in Human Solid Cancers
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 so...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-09-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/11/10/1429 |
| _version_ | 1797711037565239296 |
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| author | Mohammed Ismael Roger Webb Mazhar Ajaz Karen J. Kirkby Helen M. Coley |
| author_facet | Mohammed Ismael Roger Webb Mazhar Ajaz Karen J. Kirkby Helen M. Coley |
| author_sort | Mohammed Ismael |
| collection | DOAJ |
| description | 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 IC<sub>50</sub> 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. |
| first_indexed | 2024-03-12T07:01:09Z |
| format | Article |
| id | doaj.art-6eff904355e44f35acc4473daab02e4d |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T07:01:09Z |
| publishDate | 2019-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6eff904355e44f35acc4473daab02e4d2023-09-02T23:43:34ZengMDPI AGCancers2072-66942019-09-011110142910.3390/cancers11101429cancers11101429The Targeting of RNA Polymerase I Transcription Using CX-5461 in Combination with Radiation Enhances Tumour Cell Killing Effects in Human Solid CancersMohammed Ismael0Roger Webb1Mazhar Ajaz2Karen J. Kirkby3Helen M. Coley4Ion Beam Centre, Advanced Technology Institute, University of Surrey, Guildford, Surrey GU2 7XH, UKIon Beam Centre, Advanced Technology Institute, University of Surrey, Guildford, Surrey GU2 7XH, UKFaculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UKIon Beam Centre, Advanced Technology Institute, University of Surrey, Guildford, Surrey GU2 7XH, UKFaculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UKAn 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 IC<sub>50</sub> 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.https://www.mdpi.com/2072-6694/11/10/1429cx-5461rna polymerase i targetingcombination studies |
| spellingShingle | Mohammed Ismael Roger Webb Mazhar Ajaz Karen J. Kirkby Helen M. Coley The Targeting of RNA Polymerase I Transcription Using CX-5461 in Combination with Radiation Enhances Tumour Cell Killing Effects in Human Solid Cancers Cancers cx-5461 rna polymerase i targeting combination studies |
| title | The Targeting of RNA Polymerase I Transcription Using CX-5461 in Combination with Radiation Enhances Tumour Cell Killing Effects in Human Solid Cancers |
| title_full | The Targeting of RNA Polymerase I Transcription Using CX-5461 in Combination with Radiation Enhances Tumour Cell Killing Effects in Human Solid Cancers |
| title_fullStr | The Targeting of RNA Polymerase I Transcription Using CX-5461 in Combination with Radiation Enhances Tumour Cell Killing Effects in Human Solid Cancers |
| title_full_unstemmed | The Targeting of RNA Polymerase I Transcription Using CX-5461 in Combination with Radiation Enhances Tumour Cell Killing Effects in Human Solid Cancers |
| title_short | The Targeting of RNA Polymerase I Transcription Using CX-5461 in Combination with Radiation Enhances Tumour Cell Killing Effects in Human Solid Cancers |
| title_sort | targeting of rna polymerase i transcription using cx 5461 in combination with radiation enhances tumour cell killing effects in human solid cancers |
| topic | cx-5461 rna polymerase i targeting combination studies |
| url | https://www.mdpi.com/2072-6694/11/10/1429 |
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