Transcriptomics analyses reveal the effects of Pentagamaboronon-0-ol on PI3K/Akt and cell cycle of HER2+ breast cancer cells.

Introduction: Monoclonal antibodies and targeted therapies against HER2+ breast cancer has improved overall and disease-free survival in patients; however, encountering drug resistance causes recurrence, necessitating the development of newer HER2-targeted medications. A curcumin analog PGB-0-ol showed most cytotoxicity against HCC1954 HER2+ breast cancer cells than against other subtypes of breast cancer cells. Objective: Here, we employed next-generation sequencing technology to elucidate the molecular mechanism underlying the effect of PGB-0-ol on HCC1954 HER2+ breast cancer cells. Methods: The molecular mechanism underlying the action of PGB-0-ol on HCC1954 HER2+ breast cancer cells was determined using next-generation sequencing technologies. Additional bioinformatics studies were performed, including gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, disease-gene, and drug-gene associations, network topology analysis (NTA), and gene set enrichment analysis (GSEA). Results: We detected 2,263 differentially expressed genes (DEGs) (1,459 upregulated and 804 downregulated) in the PGB-0-ol- and DMSO-treated HCC1954 cells. KEGG enrichment data revealed the control of phosphatidylinositol signaling system, and ErbB signaling following PGB-0-ol treatment. Gene ontology (GO) enrichment analysis demonstrated that these DEGs governed cell cycle, participated in the mitotic spindle and nuclear membrane, and controlled kinase activity at the molecular level. According to the NTA data for GO enrichment, GSEA data for KEGG, drug-gene and disease-gene, PGB-0-ol regulated PI3K/Akt signaling and cell cycle in breast cancer. Overall, our investigation revealed the transcriptomic profile of PGB-0-ol-treated HCC1954 breast cancer cells following PGB-0-ol therapy. Bioinformatics analyses showed that PI3K/Akt signaling and cell cycle was modulated. However, further studies are required to validate the findings of this study.

Development of curcumin-based amyloid ß aggregation inhibitors for Alzheimer's disease using the SAR matrix approach.

Amyloid ß (Aß) aggregation inhibitor activity cliff involving a curcumin structure was predicted using the SAR Matrix method on the basis of 697 known Aß inhibitors from ChEMBL (data set 2487). Among the compounds predicted, compound B was found to possess approximately 100 times higher inhibitory activity toward Aß aggregation than curcumin. TEM images indicate that compound B induced the shortening of Aß fibrils and increased the generation of Aß oligomers in a concentration dependent manner. Furthermore, compound K, in which the methyl ester of compound B was replaced by the tert-butyl ester, possessed low cytotoxicity on N2A cells and attenuated Aß-induced cytotoxicity, indicating that compound K would have an ability for preventing neurotoxicity caused by Aß aggregation.

Anti-proliferative and Anti-metastatic Potential of Curcumin Analogue, Pentagamavunon-1 (PGV-1), Toward Highly Metastatic Breast Cancer Cells in Correlation with ROS Generation.

Purpose: Pentagamavunon-1 (PGV-1) is a curcumin analogue that shows cytotoxic activity in various cancer cells. In this study, we evaluated the effect of PGV-1 on a highly metastatic breast cancer cell line, the 4T1 cells, as an anti-metastatic and anti-proliferative agent. Methods: Cell viability was evaluated using MTT assay; while cell cycle profile, apoptosis incidence, and ROS intracellular level were determined by flow cytometry. Cell senescence was observed under senescence-associated-ß-galactosidase (SA-ß-gal) staining assay. The expression of matrixmetalloproteinase-9 (MMP-9) was determined using immunoreaction based-ELISA, while other proteins expression were detected using immunoblotting. Results: Curcumin and PGV-1 showed cytotoxic effects on 4T1 cells with IC50 value of 50 and 4 µM, respectively. The cytotoxic activity of PGV-1 was correlated to the induction of G2/M cell cycle arrest and cell senescence. Furthermore, PGV-1 increased the accumulation of intracellular ROS level. We also revealed that PGV-1 bound to several ROS-metabolizing enzymes, including glyoxalase I (GLO1), peroxiredoxin 1 (PRDX1), N-ribosyldihydronicotinamide: quinone reductase 2 (NQO2), aldo-keto reductase family 1 member c1 (AKR1C1). As an antimetastatic agent, PGV-1 showed less inhibitory effect on cell migration compared to curcumin. However, PGV-1 significantly decreased MMP-9 protein expression in a dose-dependent manner suggesting it still potent to inhibit metastatic cells. Conclusion: Overall, our findings suggest that PGV-1 is potential to be developed as an antiproliferative and anti-metastatic agent.