Potent salinomycin C20-O-alkyl oxime derivative SAL-98 efficiently inhibits tumor growth and metastasis by affecting Wnt/β-catenin signal pathway

Abstract

The dysregulation of Wnt/β-catenin signaling pathway is closely related to tumorigenesis, metastasis and cancer stem cell maintenance. Salinomycin is a polyether ionophore antibiotic that selectively eliminates cancer stem cells by inhibiting the Wnt/β-catenin signal pathway. Salinomycin selectively target cancer stem cells, but the toxicity limits its further use. In this study, we explore the anti-tumor mechanism of one most active salinomycin C20-O-alkyl oximederivative SAL-98 and found that SAL-98 exerts 10 times higher anti-tumor and anti-CSCs activities compared with salinomycin, which induces cell cycle arrest, ER stress and mitochondria dysfunction and inhibits Wnt/β-catenin signal pathway in vitro with high efficacy. Moreover, SAL-98 shows good anti-metastasis effect in vivo. In addition, SAL-98 demonstrates same anti-tumor activities as salinomycin with less 5 times concentration in vivo, the ER stress, autophagy and anti-CSCs effects were also confirmed in vivo. Mechanistically, SAL-98 inhibits the Wnt/β-catenin signaling pathway associated with CHOP expression induced by ER stress, the induced CHOP disrupts the β-catenin/TCF4 complex and represses the Wnt targeted genes. This study provides an alternative strategy for rational drug development to target Wnt/β-catenin signaling pathway.

Keywords: Anti-metastasis; C20-O-alkyl oxime derivative; ER stress; Salinomycin; Wnt/β-catenin signal pathway.