1. The Identification of Small Molecule Inhibitors That Reduce Invasion and Metastasis of Aggressive Cancers
- Author
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Cindy van Rijt-van de Westerlo, Arjanneke F. van de Merbel, Peter Maas, Johan Tijhuis, Gabri van der Pluijm, Onno van Hooij, Jan Kroon, Geertje van der Horst, Antoine Wellink, Gerald W. Verhaegh, Henry Cheung, Jack A. Schalken, Maaike H. van der Mark, and Henk Viëtor
- Subjects
Male ,0301 basic medicine ,Apoptosis ,Metastasis ,lcsh:Chemistry ,Mice ,Prostate cancer ,0302 clinical medicine ,Cell Movement ,Drug Discovery ,Tumor Cells, Cultured ,lcsh:QH301-705.5 ,Spectroscopy ,Mice, Inbred BALB C ,food and beverages ,General Medicine ,prostate cancer ,small molecule inhibitors ,Computer Science Applications ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,bladder cancer ,Female ,invasiveness ,Mice, Nude ,Breast Neoplasms ,Biology ,Article ,Catalysis ,Small Molecule Libraries ,Inorganic Chemistry ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,breast cancer ,Breast cancer ,In vivo ,Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15] ,medicine ,Animals ,Humans ,metastasis ,Neoplasm Invasiveness ,Physical and Theoretical Chemistry ,Molecular Biology ,Cell Proliferation ,Bladder cancer ,Cadherin ,Organic Chemistry ,Prostatic Neoplasms ,E-cadherin ,medicine.disease ,Xenograft Model Antitumor Assays ,High-Throughput Screening Assays ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cell culture ,Cancer cell ,Cancer research - Abstract
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.
- Published
- 2021