title: Dual inhibition of αV integrins and Src kinase activity as a combination therapy strategy for colorectal cancer.
abstract: Both Src and αV integrins are important for tumor growth and angiogenesis. They are interconnected and responsible for important features of the tumor phenotype including invasiveness, metastasis, angiogenesis, and resistance to apoptosis. This study examines whether combinational inhibition of both integrin and Src pathways would exert greater antiangiogenesis and antitumor effects than either pathway alone. Using in-vitro cell culture systems, the activity of CNTO95 (Intetumumab), an αV integrin inhibitor, and dasatinib, an Src inhibitor, on proliferation, adhesion, and migration was evaluated in colon cancer cell lines, HCT-116 and RKO, as well as HUVEC cells. The antiangiogenic effect of this combinatory regimen was also tested using an in-vitro tubular network formation assay. The effects of CNTO95 and dasatinib on the activation of Src and integrin pathway signal transduction were also determined by western blotting. The combination of CNTO95 plus dasatinib inhibited adhesion, migration, and paxillin phosphorylation in both HCT-116 and RKO cells. CNTO95 and dasatinib also led to increased apoptosis of HCT-116 cells; however, similar effects were not observed in RKO cells. In addition, dual treatment of CNTO95 and dasatinib exerted enhanced effects on HUVEC cell proliferation, invasion, tubular network formation, and paxillin phosphorylation. In conclusion, our results suggest that concurrent inhibition of both the integrin and the Src pathways exert more pronounced antiangiogenic and antitumor effects than with either pathway being inhibited alone.
authors.affiliation: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Jingquan
authors.initials: J
authors.lastname: Jia
authors.forename: Alex
authors.initials: A
authors.lastname: Starodub
authors.forename: Ian
authors.initials: I
authors.lastname: Cushman
authors.forename: Yingmiao
authors.initials: Y
authors.lastname: Liu
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Marshall
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Nixon
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000069439:Dasatinib; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism*; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D039564:Integrin alphaV; C496061:PXN protein, human; D051419:Paxillin; D011743:Pyrimidines; D013844:Thiazoles; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases; C486839:intetumumab; D000069439:Dasatinib