Current Medicinal Chemistry - Online First

The aim of this study is the evaluation of an Azomethine derivative, BCS2, for its antioxidant and anti-tumor activities against mammary carcinoma through the Nrf2-Keap1-HO-1 pathway.

The global prevalence of breast cancer is rising at an alarming rate. The facilitation of abnormal cell proliferation in mammary carcinoma occurs due to the disruption of signaling pathways that balance pro- and antioxidant status, thereby producing oxidative stress that disrupts genomic stability. Therefore, introducing a potent antioxidant molecule with antitumor activity is of paramount importance for treating breast cancer.

Synthesis, characterization, and in-vitro, in-vivo, and in-silico evaluation of an Azomethine derivative, BCS2, for its antioxidant and anti-tumor activities against chemical carcinogen-induced mammary carcinogenesis in Sprague-Dawley rats.

An azomethine derivative, 1-(4-nitrophenyl)-N-phenylmethanimine (BCS2), was synthesized and characterized based on its spectral data. The cytotoxic potential was observed on breast cancer cells, MCF-7, MDA-MB-231, and MDA-MB-468. The in vivo chemotherapeutic potential of BCS2 was established on 7,12-dimethylbenz(a)anthracene (DMBA) induced breast cancer in Sprague-Dawley (SD) rats. The effect of BCS2 on kelch-like ECH-associated protein-1 (Keap1), Nrf2, heme oxygenase-1 (HO-1), mitogen-activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated-B (NF-κB) was evaluated through ELISA and qPCR techniques. Furthermore, the binding potential and stability of BCS2 with Keap-1, HO-1, and MAPK were predicted using in silico molecular docking and dynamics studies. Additionally, drug-likeness properties of BCS2 were evaluated using in silico ADMET tools.

BCS2 showed remarkable cytotoxic activity on MCF-7 cells followed by MDA-MB-231 and MDA-MB-468 cells having an IC50 of 2.368 µM, 4.843 µM and 6.472 µM respectively, without affecting normal breast cells, MCF-10A. In the DMBA-induced animal model, BCS2 showed potent antitumor potential and showed protective action on endogenous-enzymatic and non-enzymatic antioxidants in cancer-bearing animals. Marked improvement in cellular architecture and ultrastructure of breast/tumor tissues excised from experimental animals was noted through histopathological and field emission scanning electron microscopy (FESEM) analyses. Significant upregulation of antioxidant proteins, Keap1 and HO-1, and downregulation of inflammatory proteins, MAPK, and NF-κB was observed after BCS2 treatment. The in silico computational studies predicted the potent binding of BCS2 with the active pockets of Keap1, HO-1, and MAPK proteins that validated the biological findings.

The study revealed BCS2's potent antioxidant and antitumor potential against mammary carcinoma through the Nrf2-Keap1-HO-1 signaling pathway.

A series of benzylidene derivatives of fenobam and its thio analogues (1-22) have been evaluated for their cytotoxicity against breast cancer (MCF-7, MDA-MB-231), ovarian cancer (A2780, SKOV-3) and cervical cancer (HELA) cell lines.

These compounds (1-22) exhibited 72-83% inhibition of Erk activity against the ovarian cancer cell line (A2780). Compounds 3 and 20 showed the highest DNA damage effect in Comet Assay against the A2780 cancer cell line as compared to the other tested analogues (4, 8, 11, 12, and 13) by using % Tail DNA and OTM. Compounds 3, 4, and 11 showed significant activities and selectivity towards COX-2 with 78%, 97%, and 89% inhibition, as compared to 17%, 57%, and 26% inhibition against COX-1 isoenzyme, respectively.

Interestingly, molecular docking scores were also in very good agreement with the experimental results regarding discriminating the selectivity index of the tested compounds against COX-1 & COX-2 enzymes. Further molecular dynamics (MD) simulation study revealed that the most selective compound, 13, binds with the COX-2 enzyme in a similar fashion to that of Rofecoxib, which was further supported by their MD-based free binding energies (MM-GBSA) of -49.76 ± 4.27 kcal/mol, and -44.84 ±3.78 kcal/mol, respectively.

Moreover, in silico ADMET predictions showed adequate properties for these compounds, making them promising leads worthy of further optimization.

Globally, one of the main causes of cancer-related mortality is Colon Adenocarcinoma (COAD). In this study, a new special Immune Cell Functions (ICF) risk model was constructed using single-cell and bulk RNA sequencing data to develop a new understanding and clinical applications for COAD.

The immune function gene sets were downloaded from a literature reference, and the COAD single-cell dataset GSE146771 was downloaded from the Tumour Immune Single Cell Hub database. Using Lasso analysis, a multiple gene signature was made from the enrichment scores of immune function gene sets that were enriched in different ways. Robust validation of the signature was then performed in multiple independent cohorts. After that, we built the model using a 10-fold cross-test and evaluated its independence for clinical usage using a nomogram. We also investigated the connection between signature and immune function, genetic variation, immunotherapy, and the cancer immunological microenvironment. Lastly, we used qPCR and immunohistochemistry to examine the expression of the unreported model genes. To find the regulatory functions of unreported model genes, an EdU assay was employed.

First, 20 differentially enriched immune function gene sets were identified. Ten genes can be used as a risk profile to assess the prognosis of colon cancer, according to Lasso regression analysis. Signature performance was stable in both the training cohort and two independent GEO external cohorts, and risk scores were confirmed as independent prognostic factors. At the same time, our risk model continued to be highly predictive across various clinical clusters and clinical characteristics, such as immune checkpoints, tumour genome mutations, and chemotherapeutic drug resistance. Patients in the low-risk group have exhibited a higher chance of benefiting from immunotherapy, according to immunotherapy response research. qPCR and immunohistochemistry analysis have revealed SIRP5 expression as high in COAD tissues, while CMC1 and ASAH1 expression has been found to be low. According to the findings of the functional experiment, SIRP5, CMC1, and ASAH1 may control the ability of CRC cells to proliferate.

In this study, using scRNA-seq and bulk RNA-seq data, we created a risk model to predict the prognosis and effectiveness of immunotherapy in patients with COAD. In addition, we have discovered three model genes (SIRP5, CMC1, and ASAH1) that have not been reported before. These genes have the potential to be novel therapeutic targets in Colorectal Cancer (CRC). These findings suggest that this model could be used to evaluate the prognostic risk and identify potential targets for COAD patient treatment.

The role of LNX1 antisense RNA 2 (LNX1-AS2) in lung adenocarcinoma (LUAD) remains unclear.

This study aimed to investigate the association between LNX1-AS2 and LUAD by employing bioinformatics analysis and experimental validation.

Statistical analysis and database interrogation were utilized to assess correlations among LNX1-AS2 expression, clinical characteristics of LUAD patients, prognostic factors, regulatory networks, and immune infiltration. LNX1-AS2 expression in LUAD cell lines was quantified using quantitative real-time polymerase chain reaction (qRT-PCR).

The study found significantly elevated levels of LNX1-AS2 expression in patients with LUAD. Furthermore, elevated LNX1-AS2 expression in LUAD patients did not significantly correlate with gender (p = 0.041) or race (p = 0.049). Importantly, high LNX1-AS2 expression levels were associated with poorer overall survival (OS, p = 0.042) and disease-specific survival (DSS, p = 0.040) in LUAD patients. Additionally, high LNX1-AS2 expression (p = 0.015) was independently correlated with OS in LUAD patients. The phenotype characterized by high LNX1-AS2 expression was also found to be enriched for asthma, allograft rejection, drug metabolism cytochrome P450, metabolism of xenobiotics by cytochrome P450, olfactory transduction, renin-angiotensin system, retinol metabolism, pentose and glucuronate interconversions, and porphyrin and chlorophyll metabolism. A significant correlation was identified between the expression levels of LNX1-AS2 and immune infiltration in the context of LUAD. Elevated expression of LNX1-AS2 was notably detected in LUAD cell lines as opposed to Beas-2B.

A noteworthy relationship was established among increased LNX1-AS2 expression in LUAD patients, unfavorable prognosis, and heightened immune infiltration. These findings suggest that the LNX1-AS2 gene could serve as a valuable prognostic indicator for LUAD and a potential predictor of response to immunotherapy.

Astragalus membranaceus has shown positive clinical efficacy in treating colorectal cancer (CRC).

This study aimed to identify the key active components of Astragalus and determine effective targets of these components in CRC patients.

We identified active components of Astragalus membranaceus and differentially expressed genes in traditional Chinese medicine systems pharmacology database and The Cancer Genome Atlas. Additionally, the enrichment analysis of differential target genes (DTGs) was performed using the R-package clusterProfiler. Immunocyte correlation analysis and non-coding regulatory network construction were performed for biomarkers using Spearman’s method and NetworkAnalyst. Finally, molecular docking of biomarkers and their corresponding molecule drugs was done with Autodock Vina software.

We identified 20 active components of Astragalus membranaceus and 1 403 target genes through screening. A total of 2 300 differentially expressed genes, and 3 035 hub genes in CRC were screened. The integration of the target genes with the significantly differentially expressed genes and Hub genes identified resulted in a total of 86 DTGs. Subsequently, the results showed 828 enriched GO biological processes, 184 enriched GO molecular functions, 59 enriched GO cellular components, and 46 enriched KEGG pathways. We also obtained a total of 143 PPI pairs involving 67 nodes. Additionally, we constructed 45 mRNA-TF pairs, 101 miRNA-mRNA pairs, and 200 miRNA-mRNA-TF triplets. Finally, molecular docking was performed for the active component quercetin with F2 and UGT1A1 and formic acid with FGA, AHSG, and KNG1.

This study identified the active components of Astragalus membranaceus and their corresponding targets in CRC. These findings provide robust evidence for precision drug therapy in patients with CRC.