title: Mechanisms responsible for nilotinib resistance in human chronic myeloid leukemia cells and reversal of resistance.
abstract: Multidrug resistance remains a significant obstacle to successful chemotherapy. The ability to determine the possible resistance mechanisms and surmount the resistance is likely to improve chemotherapy. Nilotinib is a very effective drug in the treatment of imatinib-sensitive or -resistant patients. Although very successful hematologic and cytogenetic responses have been obtained in nilotinib-treated patients, in recent years cases showing resistance to nilotinib have been observed. We aimed to examine the mechanisms underlying nilotinib resistance and to provide new targets for the treatment of chronic myeloid leukemia (CML). There was an up-regulation of antiapoptotic BCR/ABL, GCS and SK-1 genes and MRP1 transporter gene and down-regulation of apoptotic Bax and CerS1 genes in nilotinib-resistant cells. There was no mutation in the nilotinib-binding region of BCR/ABL in resistant cells. Inhibiton of GCS and SK-1 restored nilotinib sensitivity. Targeting the proteins that are involved in nilotinib resistance in addition to the inhibition of BCR/ABL could be a better method of treatment in CML.
authors.affiliation: Department of Molecular Biology and Genetics, Faculty of Science, İ zmir Institute of Technology, Izmir, Turkey.
authors.forename: Aylin
authors.initials: A
authors.lastname: Camgoz
authors.forename: Emel Basak
authors.initials: EB
authors.lastname: Gencer
authors.forename: Ali Ugur
authors.initials: AU
authors.lastname: Ural
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Baran
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D002518:Ceramides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016044:Fusion Proteins, bcr-abl; D053148:Caspase 3; C498826:nilotinib