2004 Fiscal Year Final Research Report Summary
Analysis of the mechanisms of drug resistance in leukemia cells
| Project/Area Number |
15591020
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Hematology
|
|---|
| Research Institution | Jichi Medical School |
|---|
Principal Investigator |
NAGAI Tadashi Jichi Medical School, Faculty of Medicine, Associate Professor, 医学部, 助教授 (40237483)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
OHMINE Ken Jichi Medical School, Faculty of Medicine, Research Associate, 医学部, 助手 (90316521)
|
|---|
| Project Period (FY) |
2003 – 2004
|
| Keywords | Chronic myeloid leukemia / Drug resistance / Imatinib / Heme / Farnesyltransferase inhibitor / Tipifarnib / K562 / RR / β-globin |
|---|
| Research Abstract |
1.Drug resistance is a major problem for patients with chronic myeloid leukemia who are being treated with imatinib. In this study, we investigated the role of heme in the determination of sensitivity to imatinib. Addition of hemin to BCR/ABL-positive cell line KCL22 resulted in significant increases in the IC_<50> values of imatinib in accordance with the abrogation of imatinib-mediated induction of apoptosis. Furthermore, inhibition of intracellular heme synthesis by succinylacetone increased the sensitivity to imatinib in imatinib-resistant cell lines, KCL22/SR and KU812/SR. Hemin increased activity of human γ-glutamylcystein synthetase (γ-GCS) light subunit gene promoter containing MARE, which is recognized by Nrf2 transcription factor. The results suggest that heme is critically involved in the sensitivity to imatinib, at least in part, through regulation of Nrf2 function.
2.The farnesyltransferase inhibitor Tipifarnib has shown effects in some cases of hematological disorders incl
… More
uding chronic myeloid leukemia. Combined treatment of imatinib-resistant cells with imatinib and Tipifarnib resulted in synergistic growth inhibition. Induction of apoptosis and blockage of the cell cycle were major mechanisms of the synergistic inhibitory effect of the combination treatment, but the relative importance of these mechanisms differed among cell types.
3.Acquisition of resistance is also an important problem in Tipifarnib treatment. To examine the mechanisms of Tipifarnib-resistance, we have cloned a Tipifarnib-resistant BCR/ABL-positive cell line, K562/RR. The IC_<50> of Tipifarnib was 7.4-fold higher in K562/RR than in the parental cell line K562. Induction of apoptosis by Tipifarnib is much less in K562/RR than in K562 cells. The level of unprocessed HDJ-2, which is a substrate of farnesyltransferase, was increased by Tipifarnib treatment, suggesting that mechanisms independent of farnesyltransferase activity are involved in the acquisition of resistance in K562/RR cells. DNA microarray analyses demonstrated that cell cycle-regulating factors and erythroid specific genes such as β-globin were preferentially expressed in K562/RR cells. Less
|
