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

  • Biochem Pharmacol. 2023 Jun 28;115666. doi: 10.1016/j.bcp.2023.115666.
Lei Tang  1 ,  Wenfang Duan  2 ,  Chi Zhang  3 ,  Yulu Shi  2 ,  Wenlian Tu  4 ,  Kangfan Lei  3 ,  Wenxuan Zhang  5 ,  Song Wu  6 ,  Jihong Zhang  7
Affiliations
  • 1. Faculty of Life Science, Kunming University of Science and Technology, Kunming 650500, China; Medical School, Kunming University of Science and Technology, Kunming, 650500, China.
  • 2. Medical School, Kunming University of Science and Technology, Kunming, 650500, China.
  • 3. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
  • 4. The First Hospital of Yunnan Province, the affiliated Hospital of Kunming University of Science and Technology, 650032, China.
  • 5. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China. Electronic address: [email protected].
  • 7. Medical School, Kunming University of Science and Technology, Kunming, 650500, China; Yunnan Province Clinical Research Center for Hematologic Disease, Kunming, 650032, China. Electronic address: [email protected].
PMID: 37391086 DOI: 10.1016/j.bcp.2023.115666
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.
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