Abstract
Radioresistance stands as a fundamental barrier that limits the effectiveness of radiotherapy in cancer treatment. Recent evidences suggest that radioresistance is due to tumour repopulation and involves several signalling pathways, including p53/MDM2 interaction. Ionizing radiation induces p53-dependent MDM2 gene transcription that, in turn, inhibits p53 transcriptional activity, favouring its nuclear export and stimulating its degradation. In light of the observation that in many human tumours the inadequate function of p53 is the result of MDM2 over-expression, several authors have considered as an attractive therapeutic strategy to activate p53 signalling in tumours by inhibiting MDM2 activities or p53/MDM2 interaction. We retain that, by preventing the interaction p53/MDM2 with Nutlin, a small molecule that binds at the interface between these two proteins, the effectiveness of ionizing radiation treatment could be improved. Promising results have recently emerged from in vitro studies performed on laryngeal, prostate and lung cancer cell lines treated with Nutlin in combination with ionizing radiation. Based on these findings, we believe that the combined approach Nutlin/ionizing radiation should be further investigated for efficacy on both solid tumours and lymphoproliferative disorders as well as for side effects on normal cells and tissues. Therefore, the purpose of this review is to report the first results obtained by using Nutlins alone or in combination with other therapeutic agents on primary tumour cells, in vitro cell lines or tumour xenografts and to present the most recent advances in the understanding of the molecular mechanisms underlining ionizing radiation cytotoxicity and resistance.
Keywords: p53, MDM2, Nutlins, Ionizing Radiation (IR), Cancer Therapy
Current Pharmaceutical Design
Title: Nutlins and Ionizing Radiation in Cancer Therapy
Volume: 16 Issue: 12
Author(s): Gianna Impicciatore, Silvia Sancilio, Sebastiano Miscia and Roberta Di Pietro
Affiliation:
Keywords: p53, MDM2, Nutlins, Ionizing Radiation (IR), Cancer Therapy
Abstract: Radioresistance stands as a fundamental barrier that limits the effectiveness of radiotherapy in cancer treatment. Recent evidences suggest that radioresistance is due to tumour repopulation and involves several signalling pathways, including p53/MDM2 interaction. Ionizing radiation induces p53-dependent MDM2 gene transcription that, in turn, inhibits p53 transcriptional activity, favouring its nuclear export and stimulating its degradation. In light of the observation that in many human tumours the inadequate function of p53 is the result of MDM2 over-expression, several authors have considered as an attractive therapeutic strategy to activate p53 signalling in tumours by inhibiting MDM2 activities or p53/MDM2 interaction. We retain that, by preventing the interaction p53/MDM2 with Nutlin, a small molecule that binds at the interface between these two proteins, the effectiveness of ionizing radiation treatment could be improved. Promising results have recently emerged from in vitro studies performed on laryngeal, prostate and lung cancer cell lines treated with Nutlin in combination with ionizing radiation. Based on these findings, we believe that the combined approach Nutlin/ionizing radiation should be further investigated for efficacy on both solid tumours and lymphoproliferative disorders as well as for side effects on normal cells and tissues. Therefore, the purpose of this review is to report the first results obtained by using Nutlins alone or in combination with other therapeutic agents on primary tumour cells, in vitro cell lines or tumour xenografts and to present the most recent advances in the understanding of the molecular mechanisms underlining ionizing radiation cytotoxicity and resistance.
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Cite this article as:
Impicciatore Gianna, Sancilio Silvia, Miscia Sebastiano and Di Pietro Roberta, Nutlins and Ionizing Radiation in Cancer Therapy, Current Pharmaceutical Design 2010; 16 (12) . https://dx.doi.org/10.2174/138161210791033932
DOI https://dx.doi.org/10.2174/138161210791033932 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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