Current cancer drug targets最新文献

Introduction: Single-nucleotide polymorphisms (SNPs) are the major source of attraction for researchers as they significantly contribute to an individual's susceptibility to various diseases, as well as provide an insight into new diseases associated with a particular gene.

Methods: In this study, the data were retrieved from dbSNP till July 2021. DbSNP showed 103738 total SNPs in the human ERG gene, and out of them, 377 missense SNPs were selected for analysis. Twenty-six missense SNPs were found to be deleterious in all five SNP tools (SIFT, PolyPhen-2, Condel, PHD-SNP, SNPs&GO). These 26 SNPs were further checked for protein stability by iStable, I-Mutant, and MuPro. Collectively, 23 SNPs showed to decrease the protein stability. A comparison of the 3D structures of the wild type (predicted by trRosetta) and the mutated type was visualized using the Chimera tool.

Results: Post-translational modifications identified T180, R302, S356, and Y452 as clinically significant sites, as they were involved in phosphorylation and methylation.

Discussion: In this study, in silico SNP analysis was performed on the human ERG gene. ERG's involvement in various types of diseases, as well as cancer, has made it a source of interest. It is an oncogene that is not only involved in the germ line differentiation of hemo-poietic stem cells, but is also involved in cell proliferation, embryonic development, angiogenesis, inflammation, and apoptosis.

Conclusion: This study has provided detailed information on missense SNPs of the ERG gene. This work can be significant in the detection of genetic diseases and drug discovery, as it has shown involvement of the ERG gene.

Introduction: Liver Hepatocellular Carcinoma (LIHC) poses a significant global health burden, necessitating comprehensive molecular investigations to elucidate its pathogenesis and identify potential biomarkers and therapeutic targets.

Methods: This study utilized Bioinformatics and detailed molecular experiments to delve into the expression profiling and epigenetic regulation of PIAS family genes in LIHC, shedding light on their diagnostic, prognostic, and therapeutic implications.

Results: Analysis of clinical specimens revealed a pronounced up-regulation of PIAS1, PIAS2, PIAS3, and PIAS4 genes in LIHC cell lines and tissue samples compared to normal controls, emphasizing their potential as diagnostic biomarkers for LIHC. Furthermore, promoter methylation profiling unveiled significant hypomethylation of PIAS1, PIAS2, PIAS3, and PIAS4 genes in LIHC samples, implicating epigenetic dysregulation in LIHC pathogenesis. Validation using independent TCGA datasets corroborated these findings, emphasizing the robustness of PIAS family genes as diagnostic markers for LIHC. Functional analyses revealed that PIAS1 knockdown in HepG2 cells significantly impaired proliferation and colony formation, while paradoxically enhancing cell migration. These results suggest a dual role for PIAS1 in promoting tumor growth while inhibiting metastatic potential. Prognostic modeling demonstrated the collective impact of dysregulated PIAS family genes on overall survival outcomes in LIHC patients, emphasizing their clinical relevance in prognostic assessments. Furthermore, correlation analysis with immune infiltrates and drug sensitivity profiling revealed intricate interactions and therapeutic implications of PIAS family genes in LIHC.

Discussion: The upregulation and hypomethylation of PIAS1-4 in LIHC suggest their role in tumor initiation and progression. PIAS1 knockdown impaired proliferation but increased migration, indicating a dual role in growth and metastasis. These findings align with poor patient survival linked to PIAS dysregulation. Their association with immune infiltration and drug sensitivity highlights potential for targeted therapies.

Conclusion: This study provides valuable insights into the multifaceted roles of PIAS family genes in LIHC pathogenesis and paves the way for personalized diagnostic and therapeutic interventions.

Introduction: Ovarian cancer (OV) is one of the most malignant gynecological cancers. Poly(ADP-ribose) polymerase inhibitors (PARPi) represent the first-line maintenance therapy, effectively prolonging patient survival; however, the development of PARPi resistance poses a significant challenge for OV maintenance therapy. Previous studies have indicated that HNF4G functions as an oncogene in various tumors, but its role in OV development and Olaparib resistance remains unexplored.

Methods: We established an Olaparib-resistant OV cell line, SKOV3-PARPi, from the parental SKOV3 cell line. The impact of HNF4G on SKOV3 cell resistance to Olaparib was investigated using qRT-PCR, CCK-8 assay, Transwell assay, colony formation assay, scratch assay, Western blot, flow cytometry, as well as a nude mouse xenograft tumor model and immuno-histochemistry. The function of HNF4G in SKOV3-Olaparib resistant cells was elucidated and subsequently validated through the animal tumor model.

Results: Prolonged Olaparib exposure induced acquired resistance in SKOV3 cells. Compared to parental OV cells, HNF4G expression was upregulated in Olaparib-resistant cells. Overexpression of HNF4G enhanced Olaparib resistance in OV cells, whereas HNF4G knockdown diminished it. Furthermore, increased protein levels of components within the PI3K-AKT signaling pathway were observed in Olaparib-resistant cells. Knocking down HNF4G expression in resistant cells significantly slowed tumor growth under Olaparib treatment. Changes in the protein levels of HNF4G and PI3K-AKT pathway components in the in vivo xenograft tumor tissues were consistent with the cellular observations.

Conclusion: Overexpression of HNF4G plays a crucial role in conferring Olaparib resistance in OV by activating the PI3K-AKT signaling pathway. HNF4G may serve as a potential therapeutic target for patients with Olaparib-resistant OV.

Central nervous system (CNS) metastasis represents a severe complication in pa-tients with advanced non-small cell lung cancer (NSCLC), significantly impacting both quality of life and prognosis. Immune checkpoint inhibitor (ICI)-based regimens have emerged as promising therapeutic options for NSCLC patients lacking actionable genetic alterations. Large-scale clinical trials and real-world studies are progressing in this field. Increasing clini-cal evidence suggests that ICIs exhibit favorable efficacy and safety in treating NSCLC with CNS metastasis, particularly showing enhanced activity in patients with high programmed death-ligand 1(PD-L1) expression levels (≥50%). This article aimed to review the therapeutic progress of ICI-based management of NSCLC with CNS involvement, covering systemic treatment strategies of ICIs combined with chemotherapy and multimodal treatment plans combining ICIs with radiotherapy and chemotherapy. By summarizing the results of existing large-scale clinical studies, the goal was to provide a phased summary for the clinical treatment of advanced NSCLC with CNS metastasis and propose ideas for future research directions.

Introduction: Thiazolidinedione (TZD) derivatives have gained significant attention as anti-cancer agents due to their diverse biological activities. The objective of the research was to investigate the potential of thiazolidine derivatives as inhibitors of Carbonic anhydrase XII, an isoform overexpressed in hypoxic tumor environments, to explore their application as anticancer agents targeting breast cancer.

Methods: The study employed a computational approach to evaluate thiazolidine derivatives as potential CA XII inhibitors. Acute toxicity and safety were evaluated using ProTox 3.0. Molecular docking was conducted to study interactions with the zinc-bound active site of CA XII. Molecular dynamics simulations were performed to validate the stability of the ligand-enzyme complex over 250 ns.

Results: TZD derivatives demonstrated favorable physicochemical properties, high gastrointestinal absorption, and low toxicity risks. Molecular docking studies showed strong binding affinities with key hydrogen bonding and zinc coordination at the CA XII active site. Toxicity predictions indicated that most compounds had acceptable safety margins, reinforcing their potential as safe and effective CA XII inhibitors.

Discussion: The findings suggest that thiazolidine scaffolds could serve as promising small-molecule inhibitors of CA XII by targeting its zinc-bound catalytic site, a mechanism consistent with previously reported CA inhibitor pharmacology.

Conclusion: The study demonstrates that TZD derivatives possess promising characteristics as CA XII inhibitors, with favorable physicochemical properties, strong binding affinity, stable ligand-protein interactions, and acceptable safety profiles. These findings highlight their potential for further in vitro and in vivo validation, supporting the continued exploration of thiazolidinedione scaffolds in the development of targeted anticancer therapies.

Breast cancer (BC) represents a complex malignancy shaped by both genetic pre-disposition and environmental influences, with growing evidence implicating the gut micro-environment in its pathogenesis. While the therapeutic potential of gut-targeted interventions has gained attention, the precise molecular mechanisms remain poorly characterized. Tradi-tional Chinese medicine (TCM) has emerged as a valuable therapeutic approach due to its widespread availability and demonstrated clinical efficacy, particularly through its capacity to modulate gut homeostasis and exert systemic effects across multiple disease states, including breast cancer. Specific TCM formulations, including CCM, CMM, and MBC, have shown significant potential to reshape gut microbial composition, influence microbial metabolite pro-duction, restore immune homeostasis, enhance short-chain fatty acid biosynthesis, regulate estrogen metabolism, and induce beneficial epigenetic modifications, thereby offering a mul-tifaceted therapeutic strategy against breast cancer. This review systematically examines the pharmacological mechanisms, molecular targets, and clinical implications of TCM-based in-terventions in breast cancer management, highlighting their potential to open new avenues in oncological therapeutics.

Introduction: Enhanced angiogenesis and impaired vascular integrity facilitate cancer metastasis. There is accumulating evidence that cancer-derived exosomes take a functional role in these processes. In our previous study, we revealed that Golgi Membrane protein 1 (GOLM1) can promote metastasis of Hepatocellular Carcinoma (HCC), and miRNAs can modulate angiogenesis and vascular permeability in HCC. The objective is to reveal that GOLM1 can promote HCC progression in an exosomal miRNA-dependent way.

Methods: Comprehensive bioinformatics analysis and experiments were conducted to associate GOLM1 expression with angiogenesis in HCC. The effect of hepatoma cell-derived exosomes on Human Umbilical Vein Endothelial Cells (HUVEC) was tested. Exosomal miRNA expression was profiled and validated in GOLM1-knockdown HCC cells. Targets of miR-4449 and miR-3651 were predicted with online tools and validated in vitro. Correlation between miR-4449/miR-3651 and microvascular invasion or recurrence in HCC was assessed.

Results: GOLM1 correlated with angiogenesis in HCC. HCC cell-derived exosomes can be transferred to endothelial cells, and GOLM1 can regulate exosome-induced angiogenesis and vascular permeability. In vitro experiments showed that GOLM1 knockdown reduced exosomal abundance of miR-4449 and miR-3651, which target KEAP1 and ZO-1, respectively. Elevated miR-4449 and miR-3651 expression were correlated with microvascular invasion and recurrence in HCC patients.

Discussion: We demonstrated that GOLM1 can promote HCC progression independent of its role in modulating EGFR/RTK cell-surface recycling, indicating that patients with high GOLM1 expression may benefit more from anti-angiogenic drugs and highlighting the potential of targeting miR-4449 and miR-3651 to prevent angiogenesis and vascular leakiness in HCC. However, in vivo studies are further needed to validate the effect of miR-4449 and miR-3651 inhibitors in compromising angiogenesis and vascular permeability. Besides, a larger validation cohort is indispensable for establishing the correlation between miR-4449/miR-3651 expression and microvascular invasion and tumor recurrence in HCC.

Conclusions: Our findings suggest that, under the control of GOLM1, HCC cell-derived exosomal miR-4449 and miR-3651 increase angiogenesis and vascular permeability by targeting KEAP1 and ZO-1, highlighting the potential of exosomal miRNAs as promising therapeutic targets for HCC.

Introduction: Hepatocellular carcinoma (HCC) is one of the leading causes of global cancer death. The phosphatidylinositol-3-kinase/ protein kinase B/ mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway is one of the highly regulated signalling transduction pathways in cells promoting cell survival, growth, motility, metabolism, and proliferation. This signalling axis is aberrantly activated in a wide variety of tumours, such as breast, cervical, colon, gastric, liver, lung, ovarian, and prostate. The PI3K/AKT/mTOR (PAM) signalling axis is the most pivotal and overactivated signalling pathway in ⁓50% of HCC cases. Phytochemicals, such as flavonoids, have been identified and isolated to date and are reported to have anticancer, cardioprotective, anti-inflammatory, anti-oxidant, and hepato-protective properties.

Methods: Studies discussed in this review were obtained from PubMed, Scopus, and Google Scholar databases using combinations of the terms related to HCC and flavonoids.

Results: This review summarizes the mechanism of action of flavonoids to get a better understanding of their role in HCC. It also discusses mechanistic approaches for targeting the PAM pathway using various flavonoid moieties.

Discussion: The scientific literature describes the pharmacological aspect of various flavonoids in targeting the "PAM axis" to manage hepatocarcinogenesis. These flavonoids chemo-sensitize the target, thus reducing the chance of resistance towards the chemotherapy, and also act as direct antioxidants, indirect antioxidants, or pro-oxidants.

Conclusion: Further studies are required to investigate the pharmacokinetic profile of flavonoids as they hold immense potential to inhibit the PAM pathway in the management of hepatocellular carcinoma.

Introduction: Epidermal Growth Factor Receptor (EGFR) is a well-established therapeutic target in cancer treatment. In this study, a novel N-phenylacetamide derivative of theobromine, designated as T-1-PA, was designed as a potential semisynthetic EGFR inhibitor.

Method: The 3D structure, stability, and electronic reactivity of T-1-PA were determined using Density Functional Theory (DFT) analyses. Molecular docking, molecular dynamics (MD) simulations, Molecular Mechanics Generalized Born Surface Area (MM-GBSA), Protein-Ligand Interaction Profiler (PLIP), and Principal Component Analysis of Trajectories (PCAT) were employed to evaluate the binding affinity and inhibitory potential of T-1-PA against EGFR. Computational ADMET profiling was conducted to predict drug-likeness and safety. Subsequently, T-1-PA was semisynthesized and subjected to in vitro biological evaluation.

Results: Computational analyses demonstrated a strong binding affinity of T-1-PA to EGFR. The compound exhibited favorable ADMET properties. In vitro assays revealed potent EGFR inhibition with an IC₅₀ of 0.736 ± 0.005 μM. T-1-PA also inhibited the proliferation of HepG2 and MCF7 cancer cell lines with IC₅₀ values of 0.88 ± 0.01 μM and 1.13 ± 0.01 μM, respectively. Flow cytometry analysis indicated induction of apoptosis and G1 phase cell cycle arrest in HepG2 cells. Additionally, T-1-PA significantly impaired HepG2 cell migration and wound-healing capacity.

Discussion: The results validate the computational predictions and highlight the anticancer potential of T-1-PA through EGFR inhibition and antiproliferative activity. The compound's favorable pharmacokinetic and safety profiles further support its therapeutic promise.

Conclusion: T-1-PA is a promising semisynthetic compound with selective antiproliferative activity mediated via EGFR inhibition. These findings encourage further preclinical investigation of T-1-PA as a novel candidate for EGFR-targeted cancer therapy.

Introduction: The Tumor microenvironment (TME) plays a crucial role in colorectal cancer (CRC) prognosis and treatment response. However, comprehensive understandings of TME-related immune subtypes and their mechanisms for precision medicine remain insufficient. This study aims to identify immune subtypes in CRC, develop a prognostic model, and explore the role of microbial diversity in tumor progression.

Methods: Multi-omics data and non-negative matrix factorization (NMF) were used to classify CRC into immune subtypes. Differentially expressed TME-related genes were identified, and a prognostic risk model was developed using Cox and LASSO regression. Single-cell RNA sequencing (scRNA-seq) assessed cellular interactions and gene set variations. Microbiome profiling was integrated to evaluate the impact of microbial diversity on CRC progression and immune modulation. Key findings were validated using immunohistochemistry, external datasets, and qPCR in patient-derived organoids.

Results: Four TME-related immune subtypes were identified: immune-exhausted C1 (poor prognosis, high immune infiltration), immune-activated C2/C3 (better prognosis), and immune-desert C4 (worst prognosis). A risk model based on genes (SOX9, CLEC10A, RAB15, RAB6B, PCOLCE2, FUT1) stratified patients into high- and low-risk groups. High-risk groups exhibited increased Enterobacteriaceae and Clostridium, while low-risk groups showed higher Porphyromonadaceae and Peptostreptococcaceae, correlating with better immunotherapy responses. scRNA-seq revealed distinct cell-cell communication patterns across subtypes.

Discussion: The study highlights the complexity of CRC's TME and its role in prognosis and treatment. Findings support personalized treatment strategies, considering immune and microbial factors.

Conclusion: This research integrates TME subtyping, risk modeling, single-cell analysis, and microbiome profiling to advance CRC prognosis and precision therapy, emphasizing personalized strategies for better outcomes.