The Identification of Small Molecule Inhibitors That Reduce Invasion and Metastasis of Aggressive Cancers

• Published in: International journal of molecular sciences Vol. 22; no. 4; p. 1688
• Main Authors: van de Merbel, Arjanneke F, van Hooij, Onno, van der Horst, Geertje, van Rijt-van de Westerlo, Cindy C M, van der Mark, Maaike H, Cheung, Henry, Kroon, Jan, Verhaegh, Gerald W, Tijhuis, Johan, Wellink, Antoine, Maas, Peter, Viëtor, Henk, Schalken, Jack A, van der Pluijm, Gabri
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08.02.2021; MDPI
• Subjects: Animal models; Animals; Antitumor activity; Apoptosis; Bioavailability; Bladder cancer; Bone growth; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell adhesion & migration; Cell Movement; Cell Proliferation; Drug Discovery; E-cadherin; Epithelial cells; Female; Gene Expression Regulation, Neoplastic - drug effects; Genotype & phenotype; High-Throughput Screening Assays; Humans; Inhibitors; Invasiveness; Libraries; Low molecular weights; Male; Mesenchyme; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular weight; Neoplasm Invasiveness; Phenotypes; Physiology; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; small molecule inhibitors; Small Molecule Libraries - pharmacology; Transcription factors; Tumor cell lines; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Xenografts; small molecule inhibitors; invasiveness; prostate cancer; metastasis; bladder cancer; breast cancer; E-cadherin
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22041688

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.