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Nanoparticle encapsulation of non-genotoxic p53 activator Inauhzin-C for improved therapeutic efficacy.

ABSTRACT: The tumor suppressor protein p53 remains in a wild type but inactive form in ~50% of all human cancers. Thus, activating it becomes an attractive approach for targeted cancer therapies. In this regard, our lab has previously discovered a small molecule, Inauhzin (INZ), as a potent p53 activator with no genotoxicity. Method: To improve its efficacy and bioavailability, here we employed nanoparticle encapsulation, making INZ-C, an analog of INZ, to nanoparticle-encapsulated INZ-C (n-INZ-C). Results: This approach significantly improved p53 activation and inhibition of lung and colorectal cancer cell growth by n-INZ-C in vitro and in vivo while it displayed a minimal effect on normal human Wi38 and mouse MEF cells. The improved activity was further corroborated with the enhanced cellular uptake observed in cancer cells and minimal cellular uptake observed in normal cells. In vivo pharmacokinetic evaluation of these nanoparticles showed that the nanoparticle encapsulation prolongates the half-life of INZ-C from 2.5 h to 5 h in mice. Conclusions: These results demonstrate that we have established a nanoparticle system that could enhance the bioavailability and efficacy of INZ-C as a potential anti-cancer therapeutic.

SUBMITTER: Bhattarai N

PROVIDER: S-EPMC8171090 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Nanoparticle encapsulation of non-genotoxic p53 activator Inauhzin-C for improved therapeutic efficacy.

Bhattarai Nimisha N Wang Jieqiong J Nguyen Daniel D Yang Xiaoxiao X Helmers Linh L Paruch Jennifer J Li Li L Zhang Yiwei Y Meng Kun K Wang Alun A Jayawickramarajah Janarthanan J Wang Binghe B Zeng Shelya S Lu Hua H

Theranostics 20210512 14

The tumor suppressor protein p53 remains in a wild type but inactive form in ~50% of all human cancers. Thus, activating it becomes an attractive approach for targeted cancer therapies. In this regard, our lab has previously discovered a small molecule, Inauhzin (INZ), as a potent p53 activator with no genotoxicity. <b>Method:</b> To improve its efficacy and bioavailability, here we employed nanoparticle encapsulation, making INZ-C, an analog of INZ, to nanoparticle-encapsulated INZ-C (n-INZ-C). ...[more]

PMID: 34093867

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Project description:BackgroundPreviously, we reported that Inauhzin (INZ) induces p53 activity and suppresses tumor growth by inhibiting Sirt1. However, it remains unknown whether INZ may globally affect p53-dependent gene expression or not. Herein, we have conducted microarray and real-time PCR analyses of gene expression to determine the global effect of INZ on human p53-responsive transcriptome.Methodology/principal findingsIn this study, we conducted microarray analysis followed by PCR validation of general gene expression in HCT116(p53+/+) and HCT116(p53-/-) cells treated with or without INZ. Microarray data showed that 324 genes were up-regulated by ≥ 2.3-fold and 266 genes were down-regulated by ≥ 2-fold in response to INZ treatment in a p53-dependent manner. GO analysis for these genes further revealed that INZ affects several biological processes, including apoptosis (GO:0006915), cell cycle (GO:0007049), immune system process (GO:0002376), and cell adhesion (GO:0007155), which are in line with p53 functions in cells. Also, pathway and STRING analyses of these genes indicated that the p53-signaling pathway is the most significant pathway responsive to INZ treatment as predicted, since a number of these p53 target genes have been previously reported and some of them were validated by RT-qPCR. Finally, among the 9 tested and highly expressed genes, ACBD4, APOBEC3C, and FLJ14327 could be novel p53 target genes, for they were up-regulated by INZ in HCT116(p53+/+) cells, but not in HCT116(p53-/-) cells.Conclusions/significanceFrom our whole genome microarray analysis followed by validation with RT-qPCR, we found that INZ can indeed induce the expression of p53 target genes at a larger scale or globally. Our findings not only verify that INZ indeed activates the p53 signaling pathway, but also provide useful information for identifying novel INZ and/or p53 targets. The global effect of INZ on human p53-responsive transcriptome could also be instrumental to the future design of INZ clinical trials.

Dataset Information

Nanoparticle encapsulation of non-genotoxic p53 activator Inauhzin-C for improved therapeutic efficacy.

Publications

Nanoparticle encapsulation of non-genotoxic p53 activator Inauhzin-C for improved therapeutic efficacy.

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