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

Arjanneke F Van De Merbel,Jack A Schalken,Maaike H Van Der Mark,Henry Cheung,Cindy C M Van Rijt-Van De Westerlo,Geertje Van Der Horst,Henk Viëtor,Gabri Van Der Pluijm,Jan Kroon,Antoine Wellink,Peter Maas,Gerald W Verhaegh,Johan Tijhuis,Onno Van Hooij

doi:10.3390/ijms22041688

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.

Highlights

We identified multiple candidate low molecular weight (LMW) compounds that block the acquisition of an invasive phenotype
After dose-response reporter assays and cell invasion assays in the third screening round, 63 compounds were selected that both increased
PROAM02-0008 significantly reduced the intraosseous growth of human prostate cancer cells (p = 0.0049) (Figure 4D). These results indicate that LMW compounds can inhibit tumor aggressiveness and metastatic behavior in human prostate and breast cancers in vivo

Summary

Introduction

The formation of metastases represents a major problem in the treatment of solid cancers, and 90% of patients suffering from epithelial cancers will eventually die from metastatic disease [1]. The treatment and management of advanced disease in cancer patients are mainly palliative, and new treatment modalities are urgently needed. The progression from primary, localized cancer to advanced metastatic disease is a complex, multistep process. Oncological EMT is reactivated, resulting in a switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype [3,4,5,6]. One of the key features of EMT is the loss of the epithelial marker E-cadherin and the upregulation of mesenchymal markers (e.g., vimentin and N-cadherin). E-cadherin is encoded by the CDH1 gene and functions as a homotypic cell–cell adhesion receptor

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Results

Discussion

Conclusion