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Title: A tryptophanol-derived oxazolopiperidone lactam is cytotoxic against tumors via inhibition of p53 interaction with murine double minute proteins
Author: Soaresa, Joana
Raimundo, Liliana
Pereira, Nuno A. L.
dos Santos, Daniel J. V. A.
Pérez Bosch, Maria
Queiroz, Glória
Leão, Mariana
Santos, Maria M. M.
Saraiva, Lucília
Keywords: Medicaments antineoplàstics
Compostos orgànics
Antineoplastic agents
Organic compounds
Issue Date: May-2015
Publisher: Elsevier B.V.
Abstract: Inactivation of the p53 tumor suppressor protein by interaction with murine double minute (MDM) proteins, MDM2 and MDMX, is a common event in human tumors expressing wild-type p53. In these tumors, the simultaneous inhibition of these interactions with MDMs, for a full p53 reactivation, represents a promising anticancer strategy. Herein, we report the identification of a dual inhibitor of the p53 interaction with MDM2 and MDMX, the (S)-tryptophanol derivative OXAZ-1, from the screening of a small library of enantiopure tryptophanol-derived oxazolopiperidone lactams, using a yeast-based assay. With human colon adenocarcinoma HCT116 cell lines expressing wild-type p53 (HCT116 p53+/+) and its p53-null isogenic derivative (HCT116 p53−/−), it was shown that OXAZ-1 induced a p53-dependent tumor growth-inhibitory effect. In fact, OXAZ-1 induced p53 stabilization, up-regulated p53 transcription targets, such as MDM2, MDMX, p21, Puma and Bax, and led to PARP cleavage, in p53+/+, but not in p53−/−, HCT116 cells. In addition, similar tumor cytotoxic effects were observed for OXAZ-1 against MDMXoverexpressing breast adenocarcinoma MCF-7 tumor cells, commonly described as highly resistant to MDM2-only inhibitors. In HCT116 p53+/+ cells, the disruption of the p53 interaction with MDMs by OXAZ- 1 was further confirmed by co-immunoprecipitation. It was also shown that OXAZ-1 potently triggered a p53-dependent mitochondria-mediated apoptosis, characterized by reactive oxygen species generation, mitochondrial membrane potential dissipation, Bax translocation to mitochondria, and cytochrome c release, and exhibited a p53-dependent synergistic effect with conventional chemotherapeutic drugs. Collectively, in this work, a novel selective activator of the p53 pathway is reported with promising antitumor properties to be explored either alone or combined with conventional chemotherapeutic drugs. Moreover, OXAZ-1 may represent a promising starting scaffold to search for new dual inhibitors of the p53 MDMs interaction.
Note: Versió postprint del document publicat a:
It is part of: Pharmacological Research, 2015, vol. 95-96, p. 42-52
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ISSN: 1043-6618
Appears in Collections:Articles publicats en revistes (Nutrició, Ciències de l'Alimentació i Gastronomia)

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