The Identification of Small Molecule Inhibitors That Reduce Invasion and Metastasis of Aggressive Cancers.
Arjanneke F van de MerbelOnno van HooijGeertje van der HorstCindy C M van Rijt-van de WesterloMaaike H van der MarkHenry CheungJan KroonGerald W VerhaeghJohan TijhuisAntoine WellinkPeter MaasHenk ViëtorJack A SchalkenGabri van der PluijmPublished in: International journal of molecular sciences (2021)
Transformed epithelial cells can activate programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype. This process is linked to the acquisition of an invasive phenotype and the formation of distant metastases. The development of compounds that block the acquisition of an invasive phenotype or revert the invasive mesenchymal phenotype into a more differentiated epithelial phenotype represent a promising anticancer strategy. In a high-throughput assay based on E-cadherin (re)induction and the inhibition of tumor cell invasion, 44,475 low molecular weight (LMW) compounds were screened. The screening resulted in the identification of candidate compounds from the PROAM02 class. Selected LMW compounds activated E-cadherin promoter activity and inhibited cancer cell invasion in multiple metastatic human cancer cell lines. The intraperitoneal administration of selected LMW compounds reduced the tumor burden in human prostate and breast cancer in vivo mouse models. Moreover, selected LMW compounds decreased the intra-bone growth of xenografted human prostate cancer cells. This study describes the identification of the PROAM02 class of small molecules that can be exploited to reduce cancer cell invasion and metastases. Further clinical evaluation of selected candidate inhibitors is warranted to address their safety, bioavailability and antitumor efficacy in the management of patients with aggressive cancers.
Keyphrases
- papillary thyroid
- endothelial cells
- high throughput
- small molecule
- squamous cell
- induced pluripotent stem cells
- small cell lung cancer
- stem cells
- pluripotent stem cells
- prostate cancer
- mouse model
- childhood cancer
- squamous cell carcinoma
- dna methylation
- bone marrow
- gene expression
- lymph node metastasis
- risk factors
- postmenopausal women
- bone mineral density
- body composition
- bioinformatics analysis
- single cell
- breast cancer risk