Frontiers in Oncology (Oct 2020)

Metronomic Celecoxib Therapy in Clinically Available Dosage Ablates Hepatocellular Carcinoma via Suppressing Cell Invasion, Growth, and Stemness in Pre-Clinical Models

  • Chun-Chieh Yeh,
  • Chun-Chieh Yeh,
  • Pei-Ying Liao,
  • Pei-Ying Liao,
  • Sudhir Pandey,
  • Su-Yung Yung,
  • Hsueh-Chou Lai,
  • Hsueh-Chou Lai,
  • Long-Bin Jeng,
  • Long-Bin Jeng,
  • Wei-Chun Chang,
  • Wei-Chun Chang,
  • Wen-Lung Ma,
  • Wen-Lung Ma,
  • Wen-Lung Ma,
  • Wen-Lung Ma

DOI
https://doi.org/10.3389/fonc.2020.572861
Journal volume & issue
Vol. 10

Abstract

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ObjectiveTo investigate the anti-carcinogenic effect of metronomic Celecoxib (i.e., frequent administration in clinically available doses) against hepatocellular carcinoma (HCC) in the perspective of metastasis, spontaneous hepatocarcinogenesis, cancer invasion, proliferation, and stemness in vivo and in vitro.BackgroundCelecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is known to cause anti-carcinogenic effects for HCC in suprapharmacological doses. However, the effects of metronomic Celecoxib treatment on HCC cells remain unclear.MethodsThe in vivo chemopreventive effect of metronomic Celecoxib (10mg/kg/d) was investigated by the syngeneic HCC implantation model and spontaneous hepatocarcinogenesis in HBV-transgenic(HBVtg) mice individually. HCC cell lines were treated by either suprapharmacological (100 μM) or metronomic (4 μM) Celecoxib therapy. Anti-carcinogenic effects were evaluated using cell invasion, cancer proliferation, angiogenesis, and phenotype of cancer stem/progenitor cells (CSPC). The molecular mechanism of metronomic Celecoxib on HCC was dissected using Luciferase assay.ResultsIn vivo metronomic Celecoxib exerted its chemopreventive effect by significantly reducing tumor growth of implanted syngeneic HCC and spontaneous hepatocarcinogenesis in HBVtg mice. Unlike suprapharmacological dose, metronomic Celecoxib can only inhibit HCC cell invasion after a 7-day course of treatment via NF-κB/MMP9 dependent, COX2/PGE2 independent pathway. Metronomic Celecoxib also significantly suppressed HCC cell proliferation after a 7-day or 30-day culture. Besides, metronomic Celecoxib reduced CSPC phenotype by diminishing sphere formation, percentage of CD90+ population in sphere cells, and expression of CSPC markers.ConclusionsMetronomic Celecoxib should be investigated clinically as a chemopreventive agent for selected high-risk HCC patients (e.g., HCC patients after curative treatments).

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