2. Academic Validation
  3. Niclosamide Revitalizes Sorafenib through Insulin-like Growth Factor 1 Receptor (IGF-1R)/Stemness and Metabolic Changes in Hepatocellular Carcinoma

Niclosamide Revitalizes Sorafenib through Insulin-like Growth Factor 1 Receptor (IGF-1R)/Stemness and Metabolic Changes in Hepatocellular Carcinoma

  • Cancers (Basel). 2023 Feb 1;15(3):931. doi: 10.3390/cancers15030931.
Syue-Wei Peng 1 2,  Mai-Huong T Ngo 2,  Yung-Che Kuo 2 3,  Ming-Hao Teng 2,  Chin-Lin Guo 4,  Hung-Cheng Lai 5 6,  Te-Sheng Chang 7 8,  Yen-Hua Huang 1 2 3 9 10 11
Affiliations

Affiliations

  • 1 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • 2 Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • 3 TMU Research Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • 4 Institute of Physics, Academia Sinica, Taipei 11529, Taiwan.
  • 5 Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan.
  • 6 Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • 7 School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33382, Taiwan.
  • 8 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan.
  • 9 Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan.
  • 10 International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • 11 PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
PMID: 36765890 DOI: 10.3390/cancers15030931
Abstract

Sorafenib is the first approved systemic targeting agent for advanced HCC; however, when used alone, drug resistance can result in considerably reduced efficacy. Here, we demonstrate that niclosamide, an antihelminthic agent approved by the US Food and Drug Administration, can be repurposed to increase sorafenib sensitivity in sorafenib-resistant HCC cells. We generated sorafenib-resistant HCC cell lines (HepG2215_R and Hep3B_R) with elevated IGF-1R levels and strong properties in terms of stemness and epithelial-mesenchymal transition. Niclosamide was found to increase sorafenib sensitivity effectively in both cell lines and their organoids. The underlying mechanism involves the modulation of Cancer stemness, IGF-1R/p-IGF1R/OCT4, and metabolic changes. The combination of sorafenib and niclosamide, but not linsitinib, effectively suppressed the IGF-1R/OCT4 expressions, yielded a synergistic combination index (CI), and attenuated stemness-related properties such as secondary tumor sphere formation and cell migration in sorafenib-resistant HCC cells. Notably, niclosamide significantly suppressed the sorafenib-induced IGF-1R phosphorylation prompted by IGF-1 treatment. Niclosamide effectively downregulated the sorafenib-induced gene expression associated with glycolysis (GLUT1, HK2, LDHA, and PEPCK), stemness (OCT4), and drug resistance (ABCG2) and enhanced the ability of sorafenib to reduce the mitochondrial membrane potential in vitro. The synergistic effect of a combination of niclosamide and sorafenib in vivo was further demonstrated by the decreased tumor size and tumor volume resulting from Apoptosis regulation. Our results suggest that niclosamide can enhance sorafenib sensitivity in sorafenib-resistant HCC cells through IGF-1R/stemness regulation and metabolic changes. Our findings highlight a practical clinical strategy for enhancing sorafenib sensitivity in HCC.

Keywords

HCC sorafenib resensitization; IGF-1R; metabolic change; niclosamide; organoid.

Figures
Products