Highly and uncontrolled cell proliferation on cancer cells may boost ROS level intracellular accumulation up significantly. Sappan heartwood (Caesalpinia sappan L.) have been known to have cytotoxicity effect toward several cancer cells. This research was conducted to develop Caesalpinia sappan L. heartwood ethanolic extract (CSE) as chemopreventive agent which can be used as cancer therapy, looked from antioxidant and anti-senescence activity toward 4T1 breast cancer cell. CSE was obtained through maceration using ethanol 70% as solvent. Cytotoxicity activity of CSE was done by using MTT assay with IC50 as parameter. This IC50 was used as basic to the next assay, ROS assay by using DCFDA staining flowcytometry to look ROS level intracellular of CSE toward 4T1 cell and senescence assay by using senescence associated β-galactosidase (SA β-gal) assay with % cell senescence as their parameter. CSE toxic to 4T1 cell that proved from IC50 value of 25 µg/mL. Single treatment of CSE on concentration 12,5; 25; and 37.5 µg/mL able to suppress ROS level intracellular. If compared with untreated cell, single treatment of CSE on concentration 6 and 12 µg/mL showed % cell senescence not significantly different. Based on this result, CSE is cytotoxic, has antioxidant and antisenescence activity, so it has great potential to developed as chemoprevention agent on cancer therapy.Keywords : Caesalpinia sappan L., 4T1 breast cancer line, Reactive Oxygen Species (ROS), anti-senescence

Agents that target metastasis are important to improve treatment efficacy in patients with breast cancer. Tangeretin, a citrus flavonoid, exhibits antimetastatic effects on breast cancer cells, but its molecular mechanism remains unclear. Tangeretin targets were retrieved from PubChem, whereas metastatic breast cancer regulatory genes were downloaded from PubMed. In total, 58 genes were identified as potential therapeutic target genes of tangeretin (PTs). GO and KEGG pathway enrichment analyses of PTs were performed using WebGestalt (WEB-based Gene SeT AnaLysis Toolkit). The PPI network was analyzed using STRING-DB v11.0 and visualized by Cytoscape software. Hub genes were selected on the basis of the highest degree score as calculated by the CytoHubba plugin. Genetic alterations of the PTs were analyzed using cBioPortal. The prognostic values of the PTs were evaluated with the Kaplan–Meier plot. The expression of PTs across breast cancer samples was confirmed using GEPIA. The reliability of the PTs in metastatic breast cancer cells was validated using ONCOMINE. Molecular docking was performed to foresee the binding sites of tangeretin with PIK3Cα, MMP9, PTGS2, COX-2, and IKK. GO analysis showed that PTs participate in the biological process of stimulus response, are the cellular components of the nucleus and the membrane, and play molecular roles in enzyme regulation. KEGG pathway enrichment analysis revealed that PTs regulate the PI3K/Akt pathway. Genetic alterations for each target gene were MTOR (3%), NOTCH1 (4%), TP53 (42%), MMP9 (4%), NFKB1 (3%), PIK3CA (32%), PTGS2 (15%), and RELA (5%). The Kaplan–Meier plot showed that patients with low mRNA expression levels of MTOR, TP53, MMP9, NFKB1, PTGS2, and RELA and high expression of PIK3CA had a significantly better prognosis than their counterparts. Further validation of gene expression by using GEPIA revealed that the mRNA expression of MMP9 was significantly higher in breast cancer tissues than in normal tissues, whereas the mRNA expression of PTGS2 showed the opposite. Analysis with ONCOMINE demonstrated that the mRNA expression levels of MMP9 and NFKB1 were significantly higher in metastatic breast cancer cells than in normal tissues. The results of molecular docking analyses revealed the advantage of tangeretin as an inhibitor of PIK3CA, MMP9, PTGS2, and IKK. Tangeretin inhibits metastasis in breast cancer cells by targeting TP53, PTGS2, MMP9, and PIK3CA and regulating the PI3K/Akt signaling pathway. Further investigation is needed to validate the results of this study.

The treatment of glioblastoma multiforme (GBM) is challenging owing to its localization in the brain, the limited capacity of brain cells to repair, resistance to conventional therapy, and its aggressiveness. Curcumin has anticancer activity against aggressive cancers, such as leukemia, and GBM; however, its application is limited by its low solubility and bioavailability. Chemoprevention curcumin analog 1.1 (CCA-1.1), a curcumin analog, has better solubility and stability than those of curcumin. In this study, we explored potential targets of CCA-1.1 in GBM (PTCGs) by an integrated computational analysis and in vitro study. Predicted targets of CCA-1.1 obtained using various databases were subjected to comprehensive downstream analyses, including functional annotation, disease and drug association analyses, protein–protein interaction network analyses, analyses of genetic alterations, expression, and associations with survival and immune cell infiltration. Our integrative bioinformatics analysis revealed four candidate targets of CCA-1.1 in GBM: TP53, EGFR, AKT1, and CASP3. In addition to targeting specific proteins with regulatory effects in GBM, CCA-1.1 has the capacity to modulate the immunological milieu. Cytotoxicity of CCA-1.1 was lower than TMZ with an IC50 value of 9.8 μM compared to TMZ with an IC50 of 40 μM. mRNA sequencing revealed EGFR transcript variant 8 was upregulated, whereas EGFRvIII was downregulated in U87 cells after treatment with CCA-1.1. Furthermore, a molecular docking analysis suggested that CCA-1.1 inhibits EGFR with various mutations in GBM, which was confirmed using molecular dynamics simulation, wherein the binding between CCA-1.1 with the mutant EGFR L861Q was stable. For successful clinical translation, the effects of CCA-1.1 need to be confirmed in laboratory studies and clinical trials.

BackgroundHonokiol (HON) inhibits epidermal growth factor receptor (EGFR) signaling and increases the activity of erlotinib, an EGFR inhibitor, in human head and neck cancers. In this study, using a bioinformatics approach and in vitro experiments, we assessed the target genes of HON against breast cancer resistance to tamoxifen (TAM).Materials and methodsMicroarray data were obtained from GSE67916 and GSE85871 datasets to identify differentially expressed genes (DEGs). DEGs common between HON-treated and TAM-resistant cells were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and protein-protein interaction (PPI) networks were constructed. Selected genes were analyzed for genetic alterations, expression, prognostic value, and receiver operating characteristics (ROC). TAM-resistant MCF-7 (MCF-7 TAM-R) cells were generated and characterized for their resistance toward TAM. A combination of HON and TAM was used for cytotoxicity and gene expression analyses. Molecular docking was performed using the Molecular Operating Environment software.ResultsPPI network analysis revealed that FN1, FGFR2, and RET were the top three genes with the highest scores. A genetic alteration study of potential target genes revealed MMP16 and ERBB4 as the genes with the highest alterations among the breast cancer samples. Pathway enrichment analysis of FGFR2, RET, ERBB4, SOX2, FN1, and MMP16 showed that the genetic alterations herein were likely to impact the RTK-Ras pathway. The expression levels of RET, MMP16, and SOX2 were strongly correlated with prognostic power, with areas under the ROC curves (AUC) ​​of 1, 0.8, and 0.8, respectively. The HON and TAM combination increased TAM cytotoxicity in MCF-7 TAM-R cells by regulating the expression of potential target genes ret, ERBB4, SOX2, and FN1, as well as the TAM resistance regulatory genes including HES1, VIM, PCNA, TP53, and CASP7. Molecular docking results indicated that HON tended to bind RET, ErbB4, and the receptor protein Notch1 ankyrin domain more robustly than its native ligand.ConclusionHON could overcome breast cancer resistance to TAM, potentially by targeting FGFR2, RET, ERBB4, MMP16, FN1, and SOX2. However, further studies are required to validate these results.

Background Tamoxifen resistance in estrogen receptor positive (ER+) breast cancer therapy increases, which is the leading cause of cancer treatment failure, as it can impair patients’ prognoses, cause cancer recurrence, metastasis, and death. Combination therapy with compounds is needed to overcome tamoxifen resistance. Oleanolic acid (OA) was known to increase tamoxifen sensitivity in tamoxifen-resistant breast cancer; however, the molecular mechanism of OA and its involvement in overcoming tamoxifen resistance remain unknown and need further investigation. This study was conducted to identify the potential gene targets and molecular mechanisms of OA in overcoming tamoxifen resistance. Results A bioinformatic approach for functional network analysis was used in silico by utilizing secondary data in the Gene Expression Omnibus (GEO) database and analyzing them with GEO2R to obtain data on differentially expressed genes (DEGs). The DEG data were further examined with Database for Annotation, Visualization, and Integrated Discovery (DAVID), STRING, cBioPortal website, and Cytoscape with its plugin CytoHubba. Molecular docking was performed to predict the binding properties of OA on the protein encoded by the potential gene. CD44, FGFR2, PIK3R1, and MDM2 were designated as potential target genes (PTGs), and PIK3R1 was suspected as the potential gene for OA to overcome tamoxifen resistance. Molecular docking confirms that OA can inhibit p85 activation. PIK3R1 is suggested to be the potential gene for OA in overcoming tamoxifen resistance in breast cancer therapy. Conclusion The predicted molecular mechanism of OA in overcoming tamoxifen resistance involves inhibiting p85 activation, leading to the inhibition of the downstream activity of the PI3K signaling pathway, causing breast cancer to respond to tamoxifen therapy once again. Results of this study need to be validated by further studies, including in vitro and in vivo.