Adhesion-induced drug resistance in leukemia stem cells.
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.
Funayama
Keiji
K
Department of Integrative Bioscience and Biomedical Engineering, Waseda University, Shinjuku-ku, Tokyo, Japan.
Murai
Fumihiko
F
Shimane
Miyuki
M
Nomura
Hitoshi
H
Asano
Shigetaka
S
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
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