title: Adhesion-induced drug resistance in leukemia stem cells.
abstract: The co-culture of TF-1 leukemia cells and MS-5 stromal cells produces a cobblestone area which partially mimics the leukemia stem cell niche. The adhering leukemia cells are shown to become less sensitive to cytarabine, etoposide and daunorubicin. These changes are associated with an increased proportion of the G0/G1 phase, increased upregulation of cyclin-dependent kinase inhibitors, and increased levels of Bcl-2, but not with any change in the expression of BAX or drug transporters such as ABCG2 and MDR1, compared to monocultured leukemic cells. In addition, we demonstrate using a bioimaging technique that daunorubicin accumulates in the lysosomes of the adherent leukemic cells and that V-ATPase is activated. These findings suggest that adhesion alone can lead to drug resistance in leukemic stem cells by various mechanisms.
authors.affiliation: Department of Integrative Bioscience and Biomedical Engineering, Waseda University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Funayama
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Murai
authors.forename: Miyuki
authors.initials: M
authors.lastname: Shimane
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nomura
authors.forename: Shigetaka
authors.initials: S
authors.lastname: Asano
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000502:physiology; D002448:Cell Adhesion; D002453:Cell Cycle; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology; D003630:Daunorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008247:Lysosomes / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000502:physiology*; D009994:Osmolar Concentration; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D055153:Stem Cell Niche / Q000503:physiopathology*; D017154:Stromal Cells / Q000502:physiology*; D015854:Up-Regulation; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D003561:Cytarabine; D005047:Etoposide; D025262:Vacuolar Proton-Translocating ATPases; D003630:Daunorubicin