Repurposing veratridine, a previously used antihypertensive supplement, for effective treatment of metastatic colorectal cancer

Despite significant advances in improving colorectal cancer (CRC) survival over the past decade, therapeutic challenges persist due to the rapid spread of primary tumors. The rising incidence of early-onset colorectal cancer (patients under age 50) across all ethnicities has created another major health concern, as these patients are often diagnosed with advanced, metastatic disease, leading to higher mortality rates. This highlights the urgent need to develop more effective targeted therapies to fight metastatic CRC. The mTORC2 signaling pathway plays a key tumorigenic role in CRC by driving processes such as metastasis and drug resistance. The objective of this study is to develop a selective mTORC2 inhibitor that prevents tumor growth and metastasis without harming normal cells. This project aims to advance Veratridine (VTD), a small plant-derived molecule that transcriptionally upregulates UBXN2A, a colon-specific tumor-suppressor protein. UBXN2A's E3 ubiquitin ligase partners enable it to specifically target and degrade mitochondrial HSP70 (mortalin) oncoprotein and Rictor protein in the mTORC2 pathway. This study demonstrates the dual-action mechanisms of the VTD-UBXN2A axis in patient-derived xenograft (PDX) cell lines. Acute and sub-chronic VTD treatment using both two-dimensional (2D) and three-dimensional (3D) PDX cells, assessed using real-time cell analysis via xCELLigence and Cytation visualizing technologies, revealed that VTD effectively suppresses cell migration and metastatic features of human CRC cells. Our genetic and pharmacological tools have established a platform for repurposing Veratridine, a previously used anti-hypertensive supplement, into a new generation of anti-metastatic drugs that function mechanistically through a ubiquitin-like protein, while simultaneously providing greater safety and therapeutic efficacy in patients with metastatic CRC.