Small Molecules as Drugs to Upregulate Metastasis Suppressors in Cancer Cells

It is well-recognized that the majority of cancer-related deaths is attributed to metastasis, which can arise from virtually any type of tumor. Metastasis is a complex multistep process wherein cancer cells must break away from the primary tumor, intravasate into the circulatory or lymphatic systems, extravasate, proliferate and eventually colonize secondary sites. Since these molecular processes involve the coordinated actions of numerous proteins, targeted disruptions of key players along these pathways represent possible therapeutic interventions to impede metastasis formation and reduce cancer mortality. A diverse group of proteins with demonstrated ability to inhibit metastatic colonization have been identified and they are collectively known as metastasis suppressors. Given that the metastasis suppressors are often downregulated in tumors, drug-induced re-expression or upregulation of these proteins represents a promising approach to limit metastasis. Indeed, over 40 compounds are known to exhibit efficacy in upregulating the expression of metastasis suppressors via transcriptional or post-transcriptional mechanisms, and the most promising ones are being evaluated for their translational potentials. These small molecules range from natural products to drugs in clinical use and they apparently target different molecular pathways, reflecting the diverse nature of the metastasis suppressors. In this review, we provide an overview of the different classes of compounds known to possess the ability to upregulate one or more metastasis suppressors, with an emphasis on their mechanisms of action and therapeutic potentials.