Combination therapy of an anticancer drug with the FNIII14 peptide of fibronectin effectively overcomes cell adhesion-mediated drug resistance of acute myelogenous leukemia.
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.
Matsunaga
T
T
Fourth Department of Internal Medicine, Sapporo Medical University, School of Medicine, Sapporo, Japan.
Fukai
F
F
Miura
S
S
Nakane
Y
Y
Owaki
T
T
Kodama
H
H
Tanaka
M
M
Nagaya
T
T
Takimoto
R
R
Takayama
T
T
Niitsu
Y
Y
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
D000970:Antineoplastic Agents; D005353:Fibronectins; D019012:Integrin beta1; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D003561:Cytarabine