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


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.


CONCLUSIONS
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.
Oscar Lambret Centre, Lille, France French National Institute of Health and Medical Research (INSERM U.837), Institute for Cancer Research of Lille, Lille, France Laboratory of Therapeutic Drug Monitoring, Platform for Peptidomic, Metabolomic and Drug Measurements, Saint Antoine Hospital, Paris, France Medical Oncology and Cellular Therapy Department, Tenon Hospital, Public Assistance-Hospitals of Paris, Alliance for Cancer Research, Paris, France minh-hien.pham@aphp.fr.
Minh Hien
MH
Pham
French National Institute of Health and Medical Research (INSERM U.837), Institute for Cancer Research of Lille, Lille, France University of Lille, Lille, France.
Laure
L
Delestre
Oscar Lambret Centre, Lille, France French National Institute of Health and Medical Research (INSERM U.837), Institute for Cancer Research of Lille, Lille, France.
Amelie
A
Dewitte
Oscar Lambret Centre, Lille, France French National Institute of Health and Medical Research (INSERM U.837), Institute for Cancer Research of Lille, Lille, France.
Nicole
N
Wattez
University of Lille, Lille, France Lille Regional University Hospital Centre, Structural and Functional Genomics Core Facility, Lille, France.
Frederic
F
Lepretre
Oscar Lambret Centre, Lille, France French National Institute of Health and Medical Research (INSERM U.837), Institute for Cancer Research of Lille, Lille, France Hospital Group of Lille Catholic Institute, Lille Catholic University, Lille, France.
Amelie
A
Lansiaux
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000068818:Cetuximab / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D004357:Drug Synergism; D005434:Flow Cytometry; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects*; D006801:Humans; D000077146:Irinotecan; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
D000077146:Irinotecan; D000068818:Cetuximab; D002166:Camptothecin
SN-38; anti-angiogenesis; anti-invasion; cetuximab; colon cancer; irinotecan