Synergistic Effect of SN-38 in Combination with Cetuximab on Angiogenesis and Cancer Cell Invasion

Anticancer Res. 2015 Nov;35(11):5983-91.

Abstract

Background: The combination of irinotecan, a topoisomerase I inhibitor with cetuximab, an antibody against epidermal growth factor receptor, produces synergistic and beneficial effects in patients with irinotecan-refractory colorectal cancer. Our hypothesis was that synergistic effects could be due to anti-angiogenesis and anti-invasion, but not to cytotoxicity.

Materials and methods: Cytotoxicity was assessed by viability test and flow cytometry. Anti-angiogenesis, anti-invasion were studied by the endothelial cell capillary-like network formation and transmigration through an extracellular matrix. Protein kinase B (PKB, frequently cited as AKT), and extracellular signal-regulated kinases (ERK) activation was assayed by cell-based enzyme-linked immunosorbent assay (ELISA).

Results: Combinations of SN-38 (the active of irinotecan) and cetuximab did not induce any synergistic cytotoxicity confirmed by viability test and cell-cycle analyses. Interestingly, their combination produced synergistic anti-angiogenesis and anti-invasion activities revealed by endothelial cell capillary-like network formation and cell invasion tests. Subsequently, their combination attenuated either expression or phosphorylation of AKT and ERK1/2 using cell-based ELISA.

Conclusion: SN-38/cetuximab combination has synergistic anti-angiogenesis and anti-invasion activities mediated by down-regulation of phosphatidylinositol-3-kinases/AKT and mitogen-activated protein kinase/ERK pathways.

Keywords: SN-38; anti-angiogenesis; anti-invasion; cetuximab; colon cancer; irinotecan.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects
  • Blotting, Western
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives
  • Cell Adhesion / drug effects
  • Cell Cycle / drug effects
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cetuximab / administration & dosage
  • Colonic Neoplasms / blood supply
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / pathology
  • Drug Synergism*
  • Flow Cytometry
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Humans
  • Irinotecan
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / pathology
  • Phosphorylation / drug effects
  • Signal Transduction / drug effects*

Substances

  • Irinotecan
  • Cetuximab
  • Camptothecin