Oncotarget

Research Papers:

The imidazoacridinone C-1311 induces p53-dependent senescence or p53-independent apoptosis and sensitizes cancer cells to radiation

Anna Skwarska, Shaliny Ramachandran, Grzegorz Dobrynin, Katarzyna B. Leszczynska and Ester M. Hammond _

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Oncotarget. 2017; 8:31187-31198. https://doi.org/10.18632/oncotarget.16102

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Abstract

Anna Skwarska1,2, Shaliny Ramachandran1, Grzegorz Dobrynin1, Katarzyna B. Leszczynska1, Ester M. Hammond1

1Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford, UK

2Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdańsk University of Technology, Gdańsk, Poland

Correspondence to:

Anna Skwarska, email: annskwar@pg.gda.pl

Ester M. Hammond, email: ester.hammond@oncology.ox.ac.uk

Keywords: p53, C-1311/Symadex, radiation, senescence, apoptosis

Received: January 27, 2017     Accepted: March 01, 2017     Published: March 10, 2017

ABSTRACT

C-1311 is a small molecule, which has shown promise in a number of pre-clinical and clinical studies. However, the biological response to C-1311 exposure is complicated and has been reported to involve a number of cell fates. Here, we investigated the molecular signaling which determines the response to C-1311 in both cancer and non-cancer cell lines. For the first time we demonstrate that the tumor suppressor, p53 plays a key role in cell fate determination after C-1311 treatment. In the presence of wild-type p53, cells exposed to C-1311 entered senescence. In contrast, cells lines without functional p53 underwent mitotic catastrophe and apoptosis. C-1311 also induced autophagy in a non-p53-dependent manner. Cells in hypoxic conditions also responded to C-1311 in a p53-dependent manner, suggesting that our observations are physiologically relevant. Most importantly, we show that C-1311 can be effectively combined with radiation to improve the radiosensitivity of a panel of cancer cell lines. Together, our data suggest that C-1311 warrants further clinical testing in combination with radiotherapy for the treatment of solid tumors.


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