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Updated: Jun 4, 2025
Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Screening and identification of potential target of 1'-acetoxychavicol acetate (ACA) in acquired lapatinib-resistant
Febri Wulandari1, Ahmad Fauzi1, Muhammad Da'i1
1Faculty of Pharmacy, Universitas Muhammadiyah Surakarta, Surakarta, Indonesia.
Abstract:
1'-Acetoxychavicol acetate (ACA) eliminates breast cancer cells via the HER2/MAPK/ERK1/2 and PI3K/AKT pathways, and it also directly influences endocrine resistance by both enhancing pro-apoptotic signals and suppressing pro-survival molecules. This study utilized bioinformatics to assess ACA target genes for lapatinib-resistant breast cancer. We identified differentially expressed genes (DEGs) using GSE16179 microarray data. DEGs from ACA-treated and lapatinib-resistant cells were analyses using Panther DB, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and protein-protein interaction (PPI) network analysis. Genomic mutations, expression levels, prognostic significance, and ROC analysis were examined in selected genes. We used AutoDock Vina to conduct ACA molecular docking with potential target genes. In the PPI network analysis, BCL2, CXCR2, and CDC42 were the three highest-scoring genes. Genetic modification analysis identified PLAU and SSTR3 as the genes most frequently altered in breast cancer samples. The RTK-Ras pathway is likely to be affected by changes in BCL2, CXCR2, CDC42, SSTR3, PLAU, ICAM1, IGF1R, and MET genes. Patients with breast cancer who had lower levels of BCL2, SSTR3, PLAU, ICAM1, IGF1R, and MET had worse overall survival compared to other groups. ACA exhibited moderate binding affinity to BCL2, SSTR3, PLAU, ICAM1, IGF1R, and MET. Overall, ACA might counteract breast cancer resistance to lapatinib by targeting BCL2, SSTR3, PLAU, ICAM1, IGF1R, and MET. Further in vitro studies involving gene silencing could provide more detailed insights into the mechanism by which ACA combats lapatinib resistance.
Insights
1'-Acetoxychavicol acetate (ACA) combats lapatinib resistance in breast cancer by targeting key genes like BCL2 and SSTR3. This natural compound may restore sensitivity to cancer therapies by influencing cell survival pathways.
Area of Science:
- Oncology
- Pharmacology
- Bioinformatics
Background:
- Breast cancer often develops resistance to therapies like lapatinib, necessitating novel treatment strategies.
- 1'-Acetoxychavicol acetate (ACA) has demonstrated anti-cancer properties, including effects on apoptosis and survival pathways.
Purpose of the Study:
- To investigate the potential of ACA in overcoming lapatinib resistance in breast cancer using bioinformatics.
- To identify ACA target genes involved in lapatinib resistance.
Main Methods:
- Bioinformatic analysis of microarray data (GSE16179) to identify differentially expressed genes (DEGs).
- Pathway enrichment analysis (Panther DB, KEGG) and protein-protein interaction (PPI) network analysis.
- Molecular docking (AutoDock Vina) to assess ACA binding affinity to potential targets.
Main Results:
- BCL2, CXCR2, and CDC42 were identified as key nodes in the PPI network.
- PLAU and SSTR3 showed frequent genetic alterations in breast cancer.
- ACA demonstrated moderate binding affinity to BCL2, SSTR3, PLAU, ICAM1, IGF1R, and MET, suggesting their role in combating lapatinib resistance.
- Lower expression of BCL2, SSTR3, PLAU, ICAM1, IGF1R, and MET correlated with poorer patient survival.
Conclusions:
- ACA may counteract lapatinib resistance in breast cancer by targeting genes within the RTK-Ras pathway, including BCL2, SSTR3, PLAU, ICAM1, IGF1R, and MET.
- These findings highlight ACA as a potential therapeutic agent for overcoming endocrine resistance in breast cancer.
