A Drug Screening Reveals Minocycline Hydrochloride as a Therapeutic Option to Prevent Breast Cancer Cells Extravasation across the Blood-Brain Barrier.
Joana Godinho-PereiraMargarida Dionísio LopesAna Rita GarciaHugo M BotelhoRui MalhóInês FigueiraMaria Alexandra BritoPublished in: Biomedicines (2022)
Among breast cancer (BC) patients, 15-25% develop BC brain metastases (BCBM), a severe condition due to the limited therapeutic options, which points to the need for preventive strategies. We aimed to find a drug able to boost blood-brain barrier (BBB) properties and prevent BC cells (BCCs) extravasation, among PI3K, HSP90, and EGFR inhibitors and approved drugs. We used BCCs (4T1) and BBB endothelial cells (b.End5) to identify molecules with toxicity to 4T1 cells and safe for b.End5 cells. Moreover, we used those cells in mixed cultures to perform a high-throughput microscopy screening of drugs' ability to ameliorate BBB properties and prevent BCCs adhesion and migration across the endothelium, as well as to analyse miRNAs expression and release profiles. KW-2478, buparlisib, and minocycline hydrochloride (MH) promoted maximal expression of the junctional protein β-catenin and induced 4T1 cells nucleus changes. Buparlisib and MH further decreased 4T1 adhesion. MH was the most promising in preventing 4T1 migration and BBB disruption, tumour and endothelial cytoskeleton-associated proteins modifications, and miRNA deregulation. Our data revealed MH's ability to improve BBB properties, while compromising BCCs viability and interaction with BBB endothelial cells, besides restoring miRNAs' homeostasis, paving the way for MH repurposing for BCBM prevention.
Keyphrases
- blood brain barrier
- endothelial cells
- induced apoptosis
- high throughput
- cell cycle arrest
- small cell lung cancer
- cerebral ischemia
- high glucose
- end stage renal disease
- drug induced
- brain metastases
- chronic kidney disease
- breast cancer cells
- nitric oxide
- ejection fraction
- single cell
- emergency department
- endoplasmic reticulum stress
- newly diagnosed
- binding protein
- cell proliferation
- escherichia coli
- body composition
- signaling pathway
- prognostic factors
- pi k akt
- young adults
- blood pressure
- heart rate
- mass spectrometry
- machine learning
- early onset
- diabetic rats
- biofilm formation
- optical coherence tomography
- cell migration
- stress induced