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A novel triple-action Pt(IV) prodrug presents multiple anti-cancer effects and overcomes cisplatin resistance [XR-seq]

ABSTRACT: Cisplatin is a widely used chemotherapeutic agent that is cytotoxic to cancer cells primarily by damaging their DNA. However, drug resistance limits its efficacy and significantly restricts its use. Cisplatin resistance is complex and multifactorial, as it involves numerous cellular pathways and activities. Among these are the constitutive activation of the nuclear factor erythroid 2 (NF-E2)-related factor 2 / Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Nrf2/Keap1) pathway, overexpression of histone deacetylases (HDACs), and increased nucleotide excision repair (NER). Simultaneous inhibition of both the Nrf2/Keap1 pathway and HDAC activity could be beneficial for addressing the challenge of cisplatin resistance and retrieve chemo-sensitivity. In this study, we synthesized a novel Pt(IV) derivative that is assembled from cisplatin, an Nrf2 inhibitor, and an HDAC inhibitor. This triple-action prodrug, cct-[Pt(NH3)2Cl2(VPA)(PhB)] (cPVP), enabled the parallel-targeting of multiple cancer-related pathways using a single agent. Compared to cisplatin, cPVP exhibited significantly enhanced damage-formation and cytotoxicity, and presented inhibitory effects on the Nrf2/Keap1 pathway, HDAC activity, and NER. Furthermore, the prodrug demonstrated improved efficacy against cisplatin-resistant cells. Most importantly, cPVP prevented the development of resistance to both cisplatin and itself in cancer cells. Together, our results suggest that the triple-action cPVP could be a feasible alternative to cisplatin in the clinic.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243354 | GEO | 2026/04/13

REPOSITORIES: GEO

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Project description:Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that induces a battery of cytoprotective genes in response to oxidative/electrophilic stress. Kelch-like ECH associating protein 1 (Keap1) sequesters Nrf2 in the cytosol. The purpose of this study was to investigate the role of Nrf2 in regulating the mRNA of genes encoding drug metabolizing enzymes and xenobiotic transporters. Microarray analysis was performed in livers of Nrf2-null, wild-type, Keap1-knockdown mice with increased Nrf2 activation, and Keap1-hepatocyte knockout mice with maximum Nrf2 activation. In general, Nrf2 did not have a marked effect on uptake transporters, but the mRNAs of organic anion transporting polypeptide 1a1, sodium taurocholate cotransporting polypeptide, and organic anion transporter 2 were decreased with Nrf2 activation. The effect of Nrf2 on cytochrome P450 (Cyp) genes was minimal, with only Cyp2a5, Cyp2c50, Cyp2c54, and Cyp2g1 increased, and Cyp2u1 decreased with enhanced Nrf2 activation. However, Nrf2 increased mRNA of many other phase-I enzymes, such as aldo-keto reductases, carbonyl reductases, and aldehyde dehydrogenase 1. Many genes involved in phase-II drug metabolism were induced by Nrf2, including glutathione S -transferases, UDP- glucuronosyltransferases, and UDP-glucuronic acid synthesis enzymes. Efflux transporters, such as multidrug resistance-associated proteins, breast cancer resistant protein, as well as ATP-binding cassette g5 and g8 were induced by Nrf2. In conclusion, Nrf2 markedly alters hepatic mRNA of a large number of drug metabolizing enzymes and xenobiotic transporters, and thus Nrf2 plays a central role in xenobiotic metabolism and detoxification. We used microarrays to detail the global programme of gene expression in response to Nrf2 activation and identified distinct classes of up- and down-regulated genes. process. Gene expression in livers of Nrf2-null, WT, Keap1-KD, and Keap1-HKO mice was determined using Affymetrix Mouse 430.20 arrays by the KUMC Microarray Core Facility. Biological cRNA replicates (n=3) of each genotype were hybridized to an individual array.

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A novel triple-action Pt(IV) prodrug presents multiple anti-cancer effects and overcomes cisplatin resistance [XR-seq]

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