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PRIMA-1 and PRIMA-1Met (APR-246): From Mutant/Wild Type p53 Reactivation to Unexpected Mechanisms Underlying Their Potent Anti-Tumor Effect in Combinatorial Therapies
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Cancers 2018, 10(4), 126; https://doi.org/10.3390/cancers10040126

Hypoxia-Induced Cisplatin Resistance in Non-Small Cell Lung Cancer Cells Is Mediated by HIF-1α and Mutant p53 and Can Be Overcome by Induction of Oxidative Stress

1
Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
2
Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium
3
Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium
4
Phase-1 Early Clinical Trials Unit, Antwerp University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium
*
Author to whom correspondence should be addressed.
Received: 8 March 2018 / Revised: 12 April 2018 / Accepted: 14 April 2018 / Published: 21 April 2018
(This article belongs to the Special Issue p53 Signaling in Cancers)
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Abstract

The compound APR-246 (PRIMA-1MET) is a known reactivator of (mutant) p53 and inducer of oxidative stress which can sensitize cancer cells to platinum-based chemotherapeutics. However, the effect of a hypoxic tumor environment has been largely overlooked in this interaction. This study focusses on the role of hypoxia-inducible factor-1α (HIF-1α) and the p53 tumor suppressor protein in hypoxia-induced cisplatin resistance in non-small cell lung cancer (NSCLC) cells and the potential of APR-246 to overcome this resistance. We observed that hypoxia-induced cisplatin resistance only occurred in the p53 mutant NCI-H2228Q331* cell line, and not in the wild type A549 and mutant NCI-H1975R273H cell lines. Cisplatin reduced HIF-1α protein levels in NCI-H2228Q331* cells, leading to a shift in expression from HIF-1α-dependent to p53-dependent transcription targets under hypoxia. APR-246 was able to overcome hypoxia-induced cisplatin resistance in NCI-H2228Q331* cells in a synergistic manner without affecting mutant p53Q331* transcriptional activity, but significantly depleting total glutathione levels more efficiently under hypoxic conditions. Synergism was dependent on the presence of mutant p53Q331* and the induction of reactive oxygen species, with depletion of one or the other leading to loss of synergism. Our data further support the rationale of combining APR-246 with cisplatin in NSCLC, since their synergistic interaction is retained or enforced under hypoxic conditions in the presence of mutant p53. View Full-Text
Keywords: p53; HIF-1α; cisplatin resistance; hypoxia; NSCLC p53; HIF-1α; cisplatin resistance; hypoxia; NSCLC
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Deben, C.; Deschoolmeester, V.; De Waele, J.; Jacobs, J.; Van den Bossche, J.; Wouters, A.; Peeters, M.; Rolfo, C.; Smits, E.; Lardon, F.; Pauwels, P. Hypoxia-Induced Cisplatin Resistance in Non-Small Cell Lung Cancer Cells Is Mediated by HIF-1α and Mutant p53 and Can Be Overcome by Induction of Oxidative Stress. Cancers 2018, 10, 126.

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