Oxazoloisoindolinones with in vitro antitumor activity selectively activate a p53-pathway through potential inhibition of the p53–MDM2 interaction

Soares, Joana; Pereira, Nuno; Monteiro, Ângelo; Leão, Miguel; Bessa, Cláudia; Santos, Daniel J. V. A. dos; Raimundo, Liliana; Queiróz, Glória; Bisio, Alessandra; Inga, Alberto; Pereira, Clara; Santos, Maria M. M.; Saraiva, Lucı́lia

doi:10.1016/j.ejps.2014.10.006

Cited by 41 publications

(48 citation statements)

References 19 publications

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“…The endogenous negative regulators such as Mdm2 could inactivate the p53 protein in half of human cancers. The expression levels of p53 target genes (Mdm2, p21, and Bax) were increased with the increasing of p53 in tumor cells expressing wild-type p53, which induced cell cycle arrest and apoptosis [25].…”

Section: Discussionmentioning

confidence: 99%

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Adenovirus type 12 E1B 55-kilodalton oncoprotein promotes p53-mediated apoptotic response of ovarian cancer to cisplatin

Wang

Gao

2015

Tumor Biol.

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The tumor suppressor p53-mediated apoptotic response plays an important role in cisplatin resistant in ovarian cancer. The adenovirus (Ad) type 12 E1B 55-kDa protein binds to p53 and inactivates its transcriptional transactivation function. In this study, we test the hypothesis that Ad12 E1B 55-kDa oncoprotein promotes p53-mediated apoptotic response of ovarian cancer to cisplatin. First, we observed the upregulation protein level of p53 target genes in cisplatin-resistant or cisplatin-sensitive ovarian cancer by Western blotting. Second, after transfection of Ad12 E1b 55-kDa expression plasmid, the expressions of p53 target genes in A2780 cells were further enhanced. Co-IP experiment demonstrated Ad12 E1b 55 kDa associated with p53. MTT assay confirmed that the cell proliferation was enhanced after transfection, as well as the enhanced cell inhibitory rate in the presence of cisplatin. Using flow cytometry, transfection of Ad12 E1B 55-kDa protein induced apoptosis and promoted S-phase transition in proliferation. Finally, results showed that all these changes promoted by Ad12 E1b 55 kDa were attenuated by the exposure of specific inhibitor of p53 signaling, pifithrin-α. Taken together, we concluded that Ad E1B 55-kDa oncoprotein promotes p53-mediated apoptotic response of ovarian cancer to cisplatin.

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Section: Discussionmentioning

confidence: 99%

“…The p53 tumor suppressor protein is involved in regulating key cellular processes, such as cell cycle, DNA repair, cell apoptosis, and angiogenesis [25]. In human cancers, the inactivation of p53 function is an almost universal feature.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus type 12 E1B 55-kilodalton oncoprotein promotes p53-mediated apoptotic response of ovarian cancer to cisplatin

Wang

Gao

2015

Tumor Biol.

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“…1) were tested for their ability to inhibit the p53 interaction with MDM2 and MDMX, using previously developed yeast-based screening assays [6][7][8]. These compounds contain an oxazolo ring fused with a piperidinone ring, two scaffolds that are described to act as p53-MDM2 interaction inhibitors [8,13].…”

Section: 1mentioning

confidence: 99%

“…Whole protein extracts from yeast and human cell lines were obtained as described [7,8]. For mitochondrial and cytosolic fractions of human tumor cell lines, the Mitochondrial Fractionation Kit from Active Motif (Frilabo, Porto, Portugal) was used according to the manufacturer's instructions.…”

Section: Western Blot Analysismentioning

confidence: 99%

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

Soares

Raimundo

Pereira

et al. 2015

Pharmacological Research

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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.

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DIMP53-1: a novel small-molecule dual inhibitor of p53-MDM2/X interactions with multifunctional p53-dependent anticancer properties

et al. 2017

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The transcription factor p53 plays a crucial role in cancer development and dissemination, and thus, p53‐targeted therapies are among the most encouraging anticancer strategies. In human cancers with wild‐type (wt) p53, its inactivation by interaction with murine double minute (MDM)2 and MDMX is a common event. Simultaneous inhibition of the p53 interaction with both MDMs is crucial to restore the tumor suppressor activity of p53. Here, we describe the synthesis of the new tryptophanol‐derived oxazoloisoindolinone DIMP53‐1 and identify its activity as a dual inhibitor of the p53–MDM2/X interactions using a yeast‐based assay. DIMP53‐1 caused growth inhibition, mediated by p53 stabilization and upregulation of p53 transcriptional targets involved in cell cycle arrest and apoptosis, in wt p53‐expressing tumor cells, including MDM2‐ or MDMX‐overexpressing cells. Importantly, DIMP53‐1 inhibits the p53–MDM2/X interactions by potentially binding to p53, in human colon adenocarcinoma HCT116 cells. DIMP53‐1 also inhibited the migration and invasion of HCT116 cells, and the migration and tube formation of HMVEC‐D endothelial cells. Notably, in human tumor xenograft mice models, DIMP53‐1 showed a p53‐dependent antitumor activity through induction of apoptosis and inhibition of proliferation and angiogenesis. Finally, no genotoxicity or undesirable toxic effects were observed with DIMP53‐1. In conclusion, DIMP53‐1 is a novel p53 activator, which potentially binds to p53 inhibiting its interaction with MDM2 and MDMX. Although target‐directed, DIMP53‐1 has a multifunctional activity, targeting major hallmarks of cancer through its antiproliferative, proapoptotic, antiangiogenic, anti‐invasive, and antimigratory properties. DIMP53‐1 is a promising anticancer drug candidate and an encouraging starting point to develop improved derivatives for clinical application.

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Oxazoloisoindolinones with in vitro antitumor activity selectively activate a p53-pathway through potential inhibition of the p53–MDM2 interaction

Cited by 41 publications

References 19 publications

Adenovirus type 12 E1B 55-kilodalton oncoprotein promotes p53-mediated apoptotic response of ovarian cancer to cisplatin

Adenovirus type 12 E1B 55-kilodalton oncoprotein promotes p53-mediated apoptotic response of ovarian cancer to cisplatin

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

DIMP53-1: a novel small-molecule dual inhibitor of p53-MDM2/X interactions with multifunctional p53-dependent anticancer properties

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