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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
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Ivermectin synergizes sorafenib in hepatocellular carcinoma via targeting multiple oncogenic pathways

Haofeng Lu1,2, Lin Zhou1, Hongping Zuo1

  • 1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, China.

Pharmacology Research & Perspectives
|May 15, 2022
PubMed

Insights

Ivermectin shows promise in treating advanced hepatocellular carcinoma (HCC) by inhibiting cancer cell growth, metastasis, and stem cell functions. This anti-parasitic drug, when combined with sorafenib, offers a synergistic therapeutic strategy for HCC, warranting clinical trials.

Area of Science:

  • Oncology
  • Pharmacology

Background:

  • Advanced hepatocellular carcinoma (HCC) presents significant therapeutic challenges with poor clinical outcomes.
  • Ivermectin, an established anti-parasitic agent, is emerging as a potential anti-cancer therapeutic.
  • Novel treatment strategies are crucial for improving outcomes in advanced HCC.

Purpose of the Study:

  • To investigate the anti-cancer potential of ivermectin in advanced hepatocellular carcinoma (HCC).
  • To evaluate the efficacy of ivermectin in inhibiting HCC cell growth, metastasis, and stem cell properties.
  • To explore the synergistic effects of ivermectin in combination with sorafenib for HCC treatment.

Main Methods:

  • In vitro studies on multiple HCC cell lines to assess ivermectin's effects on growth, survival, and stem cell markers.
  • Mechanism of action studies including pathway analysis (mTOR/STAT3), epithelial-mesenchymal transition (EMT) assessment, and stem cell marker evaluation.
  • In vivo studies using an HCC xenograft mouse model to evaluate ivermectin's efficacy and toxicity.
  • Combination index (CI) analysis to determine synergistic effects of ivermectin and sorafenib in vitro and in vivo.

Main Results:

  • Ivermectin demonstrated significant activity against HCC cell growth and survival at clinically relevant concentrations.
  • Ivermectin inhibited metastasis, targeted HCC stem cell functions, suppressed EMT, and reduced stem cell markers.
  • Ivermectin effectively inhibited tumor formation and growth in an HCC xenograft model with minimal toxicity.
  • A synergistic effect was observed when ivermectin was combined with sorafenib in both in vitro and in vivo HCC models.

Conclusions:

  • Ivermectin exhibits potent anti-HCC activities by targeting key oncogenic pathways including mTOR/STAT3.
  • The combination of ivermectin and sorafenib shows synergistic efficacy in preclinical HCC models.
  • These findings provide strong preclinical evidence supporting the initiation of clinical trials for advanced HCC using ivermectin and sorafenib.
Keywords:
HCCcancer stem cellivermectinmTOR/STAT3sorafenibsynergism

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