Effect of Notch ligands on in vitro sensitivity to chemotherapeutic 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-kappa B 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.