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PubMed2025

Multi-Step Synthesis of Chimeric Nutlin-DCA Compounds Targeting Dual Pathways for Treatment of Cancer.

Chimeric compounds represent a promising strategy in cancer therapy by simultaneously targeting multiple pathways responsible for tumour growth and survival. Their structure comprises two or more pharmacophores connected through suitable chemical linker. These dual or multi-functional drugs can interact with several biological targets for a more pronounced pharmacological effect. In order to identify new multi-targeting agents with anticancer efficacy, we designed and synthesised a series of novel multi-functional molecules by covalently linking antitumor compounds dichloroacetate (DCA) and Nutlin-3a. The design was aimed at addressing two critical events in cancer: (1) the Warburg effect and (2) the dysregulations of protein p53 pathway, both of which are directly linked to the predominant survival and aggressive proliferation of malignant cells. DCA reactivate oxidative phosphorylation by inhibiting mitochondria pyruvate dehydrogenase kinase (PDK), thereby unlocking the Warburg metabolism of cancer cells and its antiapoptosis state. Concurrently, Nutlin-3a restores the protective function of the "genome guardian" p53 protein, by blocking its antagonist oncoprotein E3 ligase MDM2. Chimeric compounds were obtained using a chemoenzymatic multi-step procedure that included a key lipase-catalysed asymmetric reaction. Biological evaluation of the synthesised Nutlin-DCA chimeras in a panel of three cancer cell lines demonstrated promising results in vitro. Specifically, compounds rac-19a, rac-19b, rac-20a, rac-20b and enantioenriched 20a caused a statistically significant reduction in cell viability at micromolar concentrations. These findings suggest that targeting both the Warburg effect and the p53 pathway with a single molecule is a viable approach for future cancer therapeutic development.

Humans↗

PubMed2025

Genome-wide screening in human embryonic stem cells identifies genes and pathways involved in the p53 pathway.

BACKGROUND: The tumor suppressor protein, p53, which is mutated in half of human tumors, plays a critical role in cellular responses to DNA damage and maintenance of genome stability. Therefore, increasing our understanding of the p53 pathway is essential for improving cancer treatment and diagnosis. METHODS: This study, which aimed to identify genes and pathways that mediate resistance to p53 upregulation, used genome-wide CRISPR-Cas9 loss-of-function screening done with Nutlin-3a, which inhibits p53-MDM2 interaction, resulting in p53 accumulation and apoptotic cell death. We used bioinformatics analysis for the identification of genes and pathways that are involved in the p53 pathway and cell survival assays to validate specific genes. In addition, we used RNA-seq to identify differentially expressed p53 target genes in gene knockout (KO) cell lines. RESULTS: Our screen revealed three significantly enriched pathways: The heparan sulfate glycosaminoglycan biosynthesis, diphthamide biosynthesis and Hippo pathway. Notably, TRIP12 was significantly enriched in our screen. We found that TRIP12 is required for the p53-dependent transcription of several pro-apoptotic genes. CONCLUSION: Our study has identified two novel pathways that play a role in p53-mediated growth restriction. Moreover, we have highlighted the interaction between the Hippo and the p53 pathways. Interestingly, we have shown that TRIP12 plays an important function in the p53 pathway by selectively affecting its role as a transcription factor.

Humans↗

PubMed2025

Identification and external validation of a prognostic signature based on myeloid-derived suppressor cells-related LncRNAs to evaluate survival prognosis and treatment efficacy in invasive breast carcinoma.

BACKGROUND: Originating in the hematopoietic tissue, myeloid-derived suppressor cells (MDSCs) significantly contribute to tumor-related immunological processes. However, their relationship with long noncoding RNAs (lncRNAs) and breast cancer remains incompletely understood. In this study, we introduced MDSCs-associated lncRNAs as novel prognostic biomarkers to assess outcomes in patients with invasive breast carcinoma (BRCA). METHODS: Information regarding BRCA cases, including clinical and genomic details, was obtained from the TCGA repository. Predictive indicators were discovered, and their reliability underwent thorough verification. A clinically useful nomogram was developed following application-based validation. Additional investigations encompassed functional analysis, TMB assessment, TME profiling, immunotherapy efficacy forecasting, and drug sensitivity testing along with target identification. Long non-coding RNA expression was measured using reverse transcription quantitative PCR. RESULTS: A risk stratification model incorporating eight MDSCs-related lncRNAs effectively predicted patient outcomes. Kaplan-Meier (K-M) survival analysis clearly indicated a much worse prognosis among patients classified as high-risk (p < 0.001). The nomogram accurately forecasted overall survival (OS). Analysis of functional enrichment revealed that pathways associated with epithelial cells showed activity among patients at higher risk. Characterization of the tumor microenvironment showed increased immune cell presence in those classified as low-risk. Conversely, individuals with greater risk displayed higher tumor mutational burden. TIDE and IPS analyses indicated superior immunotherapy responsiveness in the low-risk BRCA subgroup. Among 47 drugs with notable IC50 variations, Ribociclib, PD173074, KU-55933, NU7441, and nutlin-3a exhibited lower IC50 values within the low-risk group, whereas Lapatinib demonstrated greater efficacy among the high-risk group. Moreover, 10 potential therapeutic agents and their targets were predicted for high-risk patients. RT-qPCR validation confirmed the robustness of the model. CONCLUSIONS: We successfully verified a new model of molecular markers of MDSCs-related lncRNAs, offering critical insights for predicting outcomes and guiding therapeutic decisions in BRCA cases.

Bioinformatics↗

PubMed2026

ZUP1 as a Novel Potential Oncogenic Driver and Prognostic Biomarker in Breast Cancer.

INTRODUCTION: Breast cancer is one of the main causes of cancer death in women globally. Identifying new predictive markers and therapeutic targets is important for improving patient outcomes. Zinc finger-containing U-rich RNA-binding protein 1 (ZUP1) is an RNA-binding protein containing a zinc finger structure that has not been systematically analyzed in breast cancer research. MATERIALS AND METHODS: The study used data from 1,231 samples from the Cancer Genome Atlas (TCGA) database. The ZUP1 expression in tumor tissues and normal tissues was compared. Its predictive value was assessed using survival analysis and regression models. Its biological role was explored through gene functional analysis. The immune cell analysis method was used to study the tumor immune environment, and the drug susceptibility database was used to predict drug responses. Predictive models were also built and validated. RESULTS: ZUP1 expression was significantly higher in breast cancer tissues than in normal tissues. High expression of ZUP1 is related to advanced tumor stage and is an independent indicator of poor survival prognosis in univariate and multivariate analyses. Functional enrichment revealed that ZUP1 is closely linked to cell cycle progression, DNA replication, and the Fanconi anemia (FA) pathway. Immune infiltration analysis demonstrated a significant negative link between ZUP1 levels and the abundance of resting mast cells and activated NK cells. Furthermore, high ZUP1 expression was associated with increased sensitivity to several targeted therapies, including Nutlin-3a and PD-0325901. A clinically applicable nomogram combining ZUP1 expression with key clinical factors (age, stage, T, N, M) was developed to predict 3- and 5-year OS with good calibration and discrimination. DISCUSSION: Our study identifies ZUP1 as a potential oncogenic factor and a robust independent prognostic biomarker in breast cancer. Its involvement in critical cellular processes and modulation of the tumor immune microenvironment highlights its potential as a novel therapeutic target. Functional experiments, including immunohistochemical staining and CCK8 proliferation assays, further supported the oncogenic role of ZUP1. The established nomogram provides a valuable tool for personalized risk assessment and clinical decision-making. CONCLUSION: Our findings suggest that ZUP1 is a novel multifaceted biomarker with significant implications for personalized treatment strategies in breast cancer.

ZUP1↗