Effect of notch ligands on in vitro sensitivity to chemo-therapeutic drugs in leukemia and lymphoma cells.
The effect of the recombinant Notch ligand proteins Jagged1 and Delta1 on drug-sensitivity of leukemia and lymphoma cells was examined. Four acute myeloid leukemia (AML) cell lines were cultured in ligand-coated wells and control wells, with cytosine arabinoside (Ara-C), doxorubicin, or mitoxantrone, and nine lymphoid leukemia or lymphoma cell lines were cultured with dexamethasone. The growth was evaluated with a colorimetric assay. The drug-induced growth suppression was slightly reduced by the ligand stimulation in 4 out of 17 combinations of cells versus drugs, such as NB4 cells versus Ara-C. In the remainder, the ligands did not significantly affect the drug-sensitivity. To investigate the possible molecular mechanism of the protective effect, the influence of Jagged1 on Ara-C-induced activation of caspase-3 and PARP, and dephosphorylation of NF-kappaB was examined in NB4 cells. However, Jagged1 did not obviously affect the activation and dephosphorylation. It is known that stromal cells reduce drug-induced cytotoxicity of leukemia cells. According to our results, the role of Notch ligands in the stroma-mediated resistance seems to be minor and occurs only in a limited context. However, the ligand-coated culture-plates are more similar to the microenvironment in human bone marrow than ordinary plates. We will further examine the clinical usefulness of the drug-sensitivity test using the ligand-coated plates.
Kogoshi
Hanae
H
Department of Laboratory Medicine, Tokyo Medical and Dental University, Bunkyo-Ku, Tokyo 113-8519, Japan.
Tohda
Shuji
S
Fu
Lu
L
Koyama
Takatoshi
T
Nara
Nobuo
N
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002135:Calcium-Binding Proteins; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003561:Cytarabine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism / Q000494:pharmacology*; D008942:Mitoxantrone / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051880:Receptors, Notch; D011994:Recombinant Proteins / Q000494:pharmacology; D000072099:Serrate-Jagged Proteins; D020298:U937 Cells
D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D016328:NF-kappa B; D051880:Receptors, Notch; D011994:Recombinant Proteins; D000072099:Serrate-Jagged Proteins; C064045:delta protein; D003561:Cytarabine; D003907:Dexamethasone; D004317:Doxorubicin; D008942:Mitoxantrone; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases