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Title
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APR-246 (PRIMA-1(MET)) strongly synergizes with AZD2281 (olaparib) induced PARP inhibition to induce apoptosis in non-small cell lung cancer cell lines
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Author
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Abstract
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| APR-246 (PRIMA-1(Met)) is able to bind mutant p53 and restore its normal conformation and function. The compound has also been shown to increase intracellular ROS levels. Importantly, the poly-[ADP-ribose] polymerase-1 (PARP-1) enzyme plays an important role in the repair of ROS-induced DNA damage. We hypothesize that by blocking this repair with the PARP-inhibitor AZD2281 (olaparib), DNA damage would accumulate in the cell leading to massive apoptosis. We observed that APR-246 synergistically enhanced the cytotoxic response of olaparib in TP53 mutant non-small cell lung cancer cell lines, resulting in a strong apoptotic response. In the presence of wild type p53 a G2/M cell cycle block was predominantly observed. NOXA expression levels were significantly increased in a TP53 mutant background, and remained unchanged in the wild type cell line. The combined treatment of APR-246 and olaparib induced cell death that was associated with increased ROS production, accumulation of DNA damage and translocation of p53 to the mitochondria. Out data suggest a promising targeted combination strategy in which the response to olaparib is synergistically enhanced by the addition of APR-246, especially in a TP53 mutant background. (C) 2016 Elsevier Ireland Ltd. All rights reserved. |
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Language
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English
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Source (journal)
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Cancer letters. - Amsterdam
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Publication
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Amsterdam
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2016
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ISSN
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0304-3835
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DOI
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10.1016/J.CANLET.2016.03.017
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Volume/pages
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375
:2
(2016)
, p. 313-322
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ISI
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000375630800013
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Pubmed ID
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26975633
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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