Current cancer drug targets最新文献

Background: Colorectal cancer (CRC) encompasses various cancers located in the rectosigmoid junction, rectum, and anus, as well as parts of the colon. Globally, CRC is the second leading cause of cancer-related mortality and the third most prevalent malignan-cy. The KRAS oncogene was found to be mutated in 30 to 50% of CRC cases, leading to dysregulated cellular functions. Furthermore, the connection between KRAS and P53 gene mutations and the incidence of both colorectal and breast cancer remains an area of interest.

Method: This comprehensive narrative review was carried out by mining data from recog-nized databases, such as PubMed, Google Scholar, and ResearchGate. The purpose was to extensively explore and understand the association between the KRAS and P53 gene muta-tions and the prevalence of colorectal and breast cancers.

Results: The mutation in the KRAS oncogene has been identified as a key player in cellular signaling pathways, including MAPK, PI3K, and PLD. Despite extensive research, gene therapies targeting these mutations have seen limited success, especially in codons 12, 13, 61, and 143.

Conclusion: Mutations in the KRAS and P53 genes, along with aberrant MDM2 expression, play pivotal roles in the onset and progression of colorectal cancer by disrupting key cellular signaling pathways, such as MAPK, PI3K, and PLD. Despite advancements in understand-ing these mechanisms, current gene therapy approaches have shown limited success, particu-larly in targeting KRAS codon mutations. This underscores the urgent need for innovative therapeutic strategies and further research to develop effective treatments for colorectal can-cer and its potential links to other malignancies, such as breast cancer.

Background: Gastric cancer is the third most lethal malignancy worldwide. While cisplatin has shown remarkable efficacy at a low cost, it is also associated with severe side effects. Exosomes play a key role in mediating the bystander effect of radiation and have the capacity to deliver apoptosis signals for targeted destruction of tumor cell. However, there remains a paucity of research on exosome-mediated bystander effects in the context of chemotherapeutic drugs.

Objective: This study aims to investigate the ability of cisplatin-induced exosomes to deliver apoptosis signals to gastric cancer cells, with the aim of mitigating the adverse effects associated with chemotherapy.

Methods: Differential ultracentrifugation was used to isolate apoptotic exosomes secreted by cisplatin-induced gastric cancer MKN-28 cells. Characterization and identification of these exosomes were performed by transmission electron microscopy, particle size analyzer, flow cytometry, and Western blotting. The transduction efficiency of the exosomes was confirmed through immunefluorescence. The effects of apoptotic exosomes on the proliferation, apoptosis, migration, cycle, senescence, and tumor formation of MKN-28 cells in vitro and in vivo were investigated by live cell workstation, flow cytometry, HE staining, and tumor-igenicity assays.

Results: Cisplatin-induced apoptotic exosomes, termed DDP-EXO, exhibited a significantly enhanced inhibitory effect on the proliferation of MKN-28 cells compared to gastric epithelial GES-1 cells. Moreover, DDP-EXO was able to deliver apoptotic signals to MKN-28 cells, leading to an increase in the apoptotic population in recipient cells, possibly through the involvement of Caspase-9. Furthermore, DDP-EXO showed limited impacts on cell migration, cell cycle, or cell senescence. In vivo, DDP-EXO effectively suppressed tumorigenesis in a subcutaneous tumor model without causing detectable pathological changes in main organs and blood samples, suggesting a favorable safety profile.

Conclusion: In summary, this study provides new perspectives on the potential application of exosomes as an innovative therapeutic approach for gastric cancer.

Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC), characterized by poor prognosis and limited treatment options.

Material and methods: This study investigated the expression patterns and functional roles of the CREC family genes (RCN1, RCN2, RCN3, SDF2, and CALU) in LUAD using vari-ous detailed molecular and in silico experiments.

Results: RT-qPCR analysis revealed significant upregulation of all five genes in LUAD cell lines compared to normal controls, with ROC curve analysis suggesting their potential as di-agnostic biomarkers. Validation using independent datasets (Oncomine, UALCAN, and HPA) confirmed these findings at both the transcript and protein levels. Stage-specific ex-pression and promoter methylation analyses demonstrated that RCN1 and CALU exhibit higher expression in advanced stages, while promoter hypomethylation correlated with gene overexpression in LUAD. Mutation and copy number variation (CNV) analyses indicated that CREC gene alterations are common in LUAD, with CALU and RCN3 frequently mu-tated. Functional assays revealed that knockdown of SDF2 and CALU significantly reduced cell proliferation, colony formation, and wound healing abilities in A549 cells, suggesting their roles in promoting LUAD progression. Gene enrichment and miRNA interaction anal-yses highlighted the involvement of CREC genes in processes like calcium binding, oxida-tive stress response, and immune regulation. CALU emerged as a potential prognostic mark-er, showing a significant association with poorer survival outcomes.

Conclusion: Together, the findings of this study suggested that CREC family genes may serve as promising diagnostic and therapeutic targets in LUAD.

Breast cancer is a heterogeneous disease driven by complex molecular signaling pathways that influence tumor progression, metastasis, and treatment resistance. This review provides a comprehensive analysis of the molecular mechanisms underlying breast cancer, with a focus on key pathways such as EGFR, ESR1, BCL2, and TP53. We examine the roles of these pathways in regulating critical cellular processes, including proliferation, survival, apoptosis, and migration. EGFR's involvement in cell proliferation and migration, as well as its overexpression and mutations in breast cancer, are discussed, alongside the impact of ESR1 signaling in hormone-receptor-positive breast cancer and resistance to endocrine ther-apies. Additionally, the review highlights the function of BCL2 in apoptosis regulation and its overexpression in conferring resistance while also exploring the role of TP53 in cell cycle control and apoptosis, particularly its mutations that contribute to poor prognosis. Further-more, the interplay between these molecular pathways-such as the crosstalk between EGFR and ESR1, BCL2-TP53 interactions, and the EGFR-TP53 mutational relationships-illustrates the complexity of resistance mechanisms and the need for multi-targeted thera-peutic strategies. The concept of synergistic targeting, including the integration of the PI3K/AKT/mTOR pathway, is explored, with evidence supporting the potential for over-coming resistance and improving therapeutic outcomes. We also discuss the emerging role of personalized medicine, emphasizing biomarker-driven approaches for patient selection and tailored treatments. Finally, advancements in nanoparticle-based drug delivery systems are reviewed, addressing their potential to enhance therapeutic efficacy and address current challenges in cancer therapy. This review highlights the critical importance of understanding the molecular underpinnings of breast cancer and the need for integrated, multi-targeted ap-proaches to overcome therapeutic resistance, offering insights into future directions for im-proving clinical outcomes in breast cancer treatment.

Aim: This comprehensive assessment and quantitative synthesis aimed to assess the effectiveness and safety profile of pembrolizumab, an antagonist of the programmed cell death protein 1 [PD-1] pathway, for individuals with metastatic colorectal carcinoma [mCRC].

Methods: A comprehensive search of scholarly articles was performed using the PubMed and Web of Science [WOS] databases from January 2015 to August 2024. The scope of the search was limited to randomized controlled trials and clinical studies that reported the effectiveness of pembrolizumab in patients with metastatic colorectal cancer [mCRC], which emphasized critical indicators, such as overall survival, progression-free survival, objective response rate, and disease control rate. The research also considered secondary outcomes, including the incidence of severe adverse events and mortality rates. Data ex-traction was performed by two independent reviewers, who employed a standardized data collection form. The subsequent meta-analysis was performed using RevMan 5.0, a soft-ware tool for statistical analysis.

Results: Six studies with 1,634 patients were included, and of these patients, 812 were in the pembrolizumab group, and 822 were in the control group. The results of the meta-analysis indicated via the standard mean difference [SMD] that the overall survival [OS] of patients in the pembrolizumab group was significantly different from that of patients in the control group [SMD = 0.21, 95% CI [0.09, 0.32], P = 0.0005]. The progression-free survival [PFS] of patients in the pembrolizumab group was slightly longer than that of pa-tients in the control group according to the SMD, and this difference was statistically sig-nificant [SMD = 0.11, 95% CI [0.01, 0.22], P = 0.03]. Compared with the objective re-sponse rate [ORR] of patients in the control group, that of patients in the pembrolizumab group was significantly higher [OR = 1.71, 95% CI [1.34, 2.17], P < 0.0001]. The mortali-ty rate in the pembrolizumab group was also significantly different from that in the control group [OR = 0.67, 95% CI [0.52, 0.87], P = 0.002].

Conclusion: Pembrolizumab may help improve overall survival [OS] and progression-free survival [PFS] in patients with metastatic colorectal cancer, which can potentially reduce the mortality rate. More research using larger, well-designed studies is needed to further confirm these findings.

Objective: Hepatocellular carcinoma (HCC) is a highly prevalent malignant tumor, ranking as the third leading cause of cancer-related deaths worldwide. Despite advances in chemotherapy, many patients exhibit limited therapeutic efficacy, ultimately leading to cisplatin resistance. Thus, an in-depth investigation into the molecular mechanisms underlying cisplatin resistance is critically needed.

Materials and methods: This study utilized the GEPIA dataset to analyze MED10 expression and its association with HCC. MED10 expression levels in normal and HCC tissues were quantified via PCR and immunohistochemistry. HCC cell proliferation was assessed through cell viability and colony formation assays, while apoptosis rates were measured using flow cytometry. To examine PTEN ubiquitination, Western blot analysis was conducted in vitro. Additionally, xenograft tumor models were employed using BALB/c nude mice (male/female, 6 weeks old, 18-22 g) to evaluate cellular proliferation in vivo.

Results: The findings reveal a pivotal role for MED10 in driving cisplatin resistance in HCC by promoting PTEN ubiquitination. MED10 expression correlated with HCC malignancy, and MED10 knockdown significantly reduced the IC50 of cisplatin in SMMC-7721, HepG2, and MHCC97-H cell lines. MED10 overexpression significantly decreased PTEN protein levels, which was reversed by the ubiquitination inhibitor TAK-243, while PTEN mRNA levels remained unaffected by MED10 overexpression or TAK-243. Both in vitro and in vivo, MED10 enhanced cisplatin resistance by promoting PTEN ubiquitination in HCC cells. These results offer valuable insights into the molecular mechanisms underlying MED10 expression and its role in cisplatin resistance in HCC.

Conclusions: MED10 enhances cisplatin resistance by promoting PTEN ubiquitination in HCC cells.

Background: The causal relationship between lipoprotein traits and the risk of pancre-atic cancer (PC) remains unclear. In this study, we employed a two-sample Mendelian randomiza-tion (MR) approach to explore the untangled relationship between lipoprotein traits and PC.

Methods: Univariable MR analyses were used to determine the causal connection between lipo-protein traits and PC. Instrumental variables corresponding to lipoprotein traits were taken from the Global Lipids Genetics Consortium (GLGC) (n = 188,578). The outcome dataset was created from PC summary-level data (n case = 1896, n control = 1939) from a genome-wide association study of European ancestry. Causal effects were evaluated using the inverse variance weighted (IVW) method. For sensitivity analysis, both the weighted median (WM) and MR-Egger methods, among others, were utilized. We also conducted multivariable MR analyses to examine potential confounders.

Results: In univariable MR, IVW methods supported evidence that HDL cholesterol (OR = 0.463, 95% CI: 0.313-0.685; P = 1.10×10-4) was linked with a decreased risk of PC. These findings were consistent across other MR methods, including MR-Egger (OR = 0.340, 95% CI: 0.182-0.638; P = 1.30×10-3) and WM (OR = 0.367, 95% CI: 0.195-0.692; P = 1.90×10-3). Our results displayed no significant heterogeneity or horizontal pleiotropy. Furthermore, these associations persisted in the multivariable MR analysis after adjusting for confounding factors such as smok-ing, alcohol consumption, and body mass index (BMI).

Conclusions: Our comprehensive MR analyses consistently demonstrate a protective association between higher HDL cholesterol levels and decreased PC risk, even after adjustments for key life-style factors and BMI.

Introduction: Yippee Like 1 (YPEL1) is a nuclear protein involved in various cellular processes, including cell cycle regulation, senescence, and mammalian develop-ment. It plays a dual role in cancer, functioning as either an antitumor or tumor-promoting factor.

Methods: In the current study, via The Cancer Genome Atlas (TCGA) search, we found that YPEL1 is aberrantly expressed in various cancers. High expression of YPEL1 corre-lated with poorer survival outcomes, whereas low expression of YPEL1 was associated with improved overall survival of patients. YT cell lines and gemcitabine-resistant YT cell line (YT/Gem-R) exhibit elevated levels of the YPEL1 protein.

Result: Furthermore, we determined that knocking down YPEL1 in both YT cell and YT/Gem-R induces apoptosis and autophagy. Additionally, silencing YPEL1 significantly reduced the tumor growth the xenograft model.

Conclusion: These findings suggest that YPEL1 exhibits the potential for being used as a target for NK / T cell lymphoma treatment.

The development of targeted drug delivery systems has transformed modern medicine, offering novel approaches to improve the efficacy and safety of therapeutic agents. Nanomaterials, due to their unique physicochemical properties, have emerged as pivotal contributors to this transformation. This paper aimed to explore recent advance-ments in nanomaterials for targeted drug delivery, highlighting emerging trends and pro-spects in nanodrug development. Nanomaterials, including polymers, liposomes, metal-based nanoparticles, dendrimers, and carbon-based structures, possess high surface area, tunable surface chemistry, and biocompatibility, which enable precise drug delivery, en-hanced solubility, improved stability, and controlled release profiles. These characteristics allow for the targeting of specific tissues or cells, thereby maximizing therapeutic efficacy while minimizing systemic side effects. The objective of this review was to provide a comprehensive analysis of the role of these nanomaterials in improving drug bioavailabil-ity, targeting specificity, and controlled release, with particular emphasis on their applica-tions in cancer therapy, antibiotic delivery, and gene therapy. This paper addresses critical challenges associated with the use of nanomaterials, including toxicity, potential immuno-genicity, regulatory hurdles, and the complexities involved in large-scale manufacturing and clinical translation. Strategies to overcome these barriers, such as surface modifica-tion, optimization of nanomaterial properties, and the development of multifunctional and smart nanocarriers, are discussed. The review concludes by emphasizing the potential of nanomaterials to revolutionize drug delivery systems, contributing to the development of more effective, personalized, and patient-friendly therapeutic options, thereby paving the way for next-generation treatments for a wide range of diseases.

Background: Prior research has demonstrated that proteins play a significant role in the prognosis and treatments of various sarcomas, including Ewing sarcoma through the interplay of downstream signaling cascades. However, there is limited understanding about the strcucture conformation of EWSR1 and its structural implication in the prognosis of Ews-ing Sarcoma by interaction with RNA molecules.

Aims: The primary goal of ongoing research is to determine how EWSR1 contributes to Ewing sarcoma.

Objective: The current study explores the complexity of EWSR1 structure and its conforma-tional interactions with RNA in relation to Ewing sarcoma.

Methods: Here, we employed a comparative modeling approach to predict EWSR1 domains separately and assembled them into one structural unit using a DEMO server. Additionally, the RNA motifs interacting with EWSR1 were predicted, and the 3D model was built using RNAComposer. Protein-RNA docking and MD simulation studies were carried out to check the intermolecular interactions and stability behavior of docked EWSR1-RNA complexes.

Results: The overall results explore the structural insights into EWSR1 and their interactions with RNA, which may play a momentous role in co- and post-transcriptional regulation to control gene expression.

Conclusion: Taken togather, our findings suggest that EWSR1 may be a useful therapeutic target for the diagnosis and management of Ewing sarcoma.