Neoamphimedine, a Lead Anti-Metastatic Agent for the Treatment of Drug Resistant and Metastatic Colorectal Cancer

Aberrant regulation of epithelial-mesenchymal transition (EMT) is a driving force in the most prominent human diseases, including: cancer, organ fibrosis, and diabetes. In particular, EMT driven tumor progression promotes the expansion of cancer stem cells, drug resistance, and the mesenchymal phenotype, which is invasive with a high metastatic potential. Therefore, one therapeutic strategy to prevent metastatic dissemination is to develop small molecule drugs that can revert the mesenchymal phenotype to the more benign epithelial state. We have identified topoisomerase IIα (TopoIIα) as a key regulator of the mesenchymal phenotype in colorectal cancer. Specifically, we show that TopoIIα is required for TCF/Lef/β-catenin (TCF) transcription, which is primarily activated through Wnt signaling. This pathway regulates/activates normal adult stem cells, but aberrant regulation of TCF transcription promotes a tumor-initiating cell (TIC) phenotype. Importantly aberrant TCF-activity is linked to 80% of sporadic colorectal carcinomas, and familial adenomatous polyposis (FAP) tumors and metastasis. We have identified neoamphimedine (neo), a marine alkaloid and ATP-competitive inhibitor of TopoIIα that blocks TCF-activity in CRC cells. In contrast, the conventionally used TopoIIα drug, etoposide, was ineffective. Finally, we show that knockdown of TopoIIα expression also blocks TCF-activity indicating that TopoIIα is required for TCF-mediated transcription.