Nutlins and Ionizing Radiation in 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 bind 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.

Glucocorticoid Receptor Activation Inhibits p53-induced Apoptosis of MCF10Amyc Cells via Induction of Protein Kinase Cϵ

“…Many cytotoxic drugs (e.g. cisplatin) and irradiation can damage DNA and can activate wild-type p53 (14,15). In several reports, p53 wildtype cancer cells respond better to DNA-damaging therapeutics than p53-mutated or p53-null cancer cells due to activation of wild-type p53 growth-inhibitory pathways (16,17).…”

Signalling Pathways Leading to TRAIL Resistance

“…Many of these combinatorial therapies hold promise for future developments in the treatment of haematological malignancies since they may reduce excessive systemic toxicity toward normal cells and resistance of tumour cells after recurrent treatments. We and other authors have demonstrated that TRAIL-mediated cytotoxicity is increased by ionizing radiation and chemotherapy in both myeloid and erythroid leukaemia cell lines as well as in T lymphoma cell lines (Gong & Almasan, 2000;Di Pietro et al, 2001;Sabatini et al, 2004;Zauli et al, 2005;Caravatta et al, 2008;Impicciatore et al, 2010;Signore et al, 2011). Although an increasing number of drugs warrant further investigation as potential new strategies for the treatment of solid tumours or AML in combination with soluble rTRAIL (Suh et al, 2003), only in few cases the efficacy of the combined treatments has been proved in vivo and a general consensus on how chemotherapy and radiotherapy may synergize with TRAIL therapy is far to be reached (Russo et al, 2010).…”

“…The cytotoxic activity of TRAIL has been evaluated in haematological diseases by different groups of investigators, including our research group (Secchiero & Zauli, 2008;Impicciatore et al, 2010). Overall the activity of TRAIL as a single treatment in acute and chronic leukaemia is poor.…”

“…Another weak point in leukaemia treatment is represented by p53 gene deletions or mutations, that usually occur in less than 15% of AML cases. To augment the poor response of AML to TRAIL cytotoxicity, Secchiero et al (2007) have recently adopted the strategy to combine rTRAIL with Nutlin-3, a potent non-genotoxic activator of the p53 pathway (Impicciatore et al, 2010). In this investigation Nutlin-3 synergized with TRAIL in inducing apoptosis both in AML cell lines and primary M4-type and M5-type AML blasts, but not in mut p53 AML cells, suggesting that the combined treatment of Nutlin-3 plus TRAIL might offer a novel therapeutic strategy for wt p53 AML cells.…”

“…As an alternative strategy to restoring transcriptional activation to mutant p53 proteins in solid tumours, small molecule selective inhibitors of p53/MDM2 interaction (Nutlins) are emerging as an innovative tool in the treatment of malignancies expressing wt p53 including haematological disorders Impicciatore et al, 2010). Nutlins were the first potent and selective small molecules, antagonists of the p53/MDM2 interaction, to be identified 7 years ago (Vassilev et al, 2004).…”