title: Combination therapy of an anticancer drug with the FNIII14 peptide of fibronectin effectively overcomes cell adhesion-mediated drug resistance of acute myelogenous leukemia.
abstract: We investigated whether FNIII14, a 22-mer peptide derived from fibronectin (FN) that potently impairs interaction of FN with beta1-integrin, could overcome cell adhesion-mediated drug resistance (CAM-DR) induced by very late antigen (VLA)-4-to-FN interaction in acute myelogenous leukemia (AML). Two AML cell lines, U937 cells and HL-60 cells, and fresh leukemic cells from six AML patients with high alpha4-integrin expression exhibited CAM-DR to cytosine arabinoside (Ara C) through VLA-4-to-FN interaction, while fresh leukemic cells from two AML patients with low alpha4-integrin expression did not display CAM-DR to Ara C. FNIII14 impaired VLA-4-to-FN interaction and restored sensitivity to Ara C in the CAM-DR leukemic cells. In these CAM-DR leukemic cells, upregulation of Bcl-2, which was induced through the focal adhesion kinase/Akt signal pathway upon VLA-4-to-FN interaction, was inhibited by FNIII14 treatment. In a mouse model of minimal residual disease (MRD) in bone marrow, 100% survival was achieved by combining FNIII14 with Ara C, whereas Ara C alone prolonged survival only slightly. The myelosuppression induced by Ara C was not augmented by the combination of FNIII14 in mouse experiments. Thus, the combination of anticancer drugs and FNIII14 holds promise to eradicate MRD in bone marrow after chemotherapy.
authors.affiliation: Fourth Department of Internal Medicine, Sapporo Medical University, School of Medicine, Sapporo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Matsunaga
authors.forename: F
authors.initials: F
authors.lastname: Fukai
authors.forename: S
authors.initials: S
authors.lastname: Miura
authors.forename: Y
authors.initials: Y
authors.lastname: Nakane
authors.forename: T
authors.initials: T
authors.lastname: Owaki
authors.forename: H
authors.initials: H
authors.lastname: Kodama
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Nagaya
authors.forename: R
authors.initials: R
authors.lastname: Takimoto
authors.forename: T
authors.initials: T
authors.lastname: Takayama
authors.forename: Y
authors.initials: Y
authors.lastname: Niitsu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology / Q000627:therapeutic use; D004351:Drug Resistance / Q000187:drug effects*; D004359:Drug Therapy, Combination; D005353:Fibronectins / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D019012:Integrin beta1; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D018365:Neoplasm, Residual / Q000188:drug therapy*; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D005353:Fibronectins; D019012:Integrin beta1; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D003561:Cytarabine