A tryptophanol-derived oxazolopiperidone lactam is cytotoxic against tumors via inhibition of p53 interaction with murine double minute proteins.

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 MDMX-overexpressing 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.

• Authors: Joana Soares, Liliana Raimundo, Nuno A L Pereira, Daniel J V A dos Santos, Maria Pérez, Glória Queiroz, Mariana Leão, Maria M M Santos, Lucília Saraiva
• Journal: Pharmacological research (Pharmacol Res) 2015 May-Jun Vol. 95-96 Pg. 42-52 ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 25814188 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cell Cycle Proteins
• MDM4 protein, human
• Nuclear Proteins
• OXAZ-1 compound
• Oxazoles
• Piperidones
• Proto-Oncogene Proteins
• Reactive Oxygen Species
• Tumor Suppressor Protein p53
• tryptophanol
• Tryptophan
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Cycle Proteins
• Cell Survival (drug effects)
• Drug Synergism
• HCT116 Cells
• Humans
• MCF-7 Cells
• Membrane Potential, Mitochondrial (drug effects)
• Molecular Structure
• Nuclear Proteins (genetics, metabolism)
• Oxazoles (chemical synthesis, chemistry, pharmacology)
• Piperidones (chemical synthesis, chemistry, pharmacology)
• Proto-Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-mdm2 (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Saccharomyces cerevisiae (genetics)
• Tryptophan (analogs & derivatives, chemistry)
• Tumor Suppressor Protein p53 (genetics, metabolism)