| RRC ID |
38409
|
| 著者 |
Chen R, Guo L, Chen Y, Jiang Y, Wierda WG, Plunkett W.
|
| タイトル |
Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia.
|
| ジャーナル |
Blood
|
| Abstract |
Homoharringtonine (HHT) is a plant alkaloid that inhibits the elongation phase of translation that is currently in clinical trials. Because the intrinsically short-lived antiapoptotic protein myeloid cell leukemia-1 (Mcl-1) has been reported to support the survival of chronic lymphocytic leukemia (CLL) cells, we hypothesized that inhibition of protein synthesis by HHT would decrease Mcl-1 expression and induce apoptosis in CLL. In primary CLL cells, HHT induced significant apoptosis independent of the prognostic characteristics of the patients. This was associated with inhibition of translation and decreased Mcl-1 levels in CLL cells. Mcl-1 reduction was evident as early as 2 hours and continued to decrease in the next 6-8 hours, whereas cell death started in 2 hours and continued to increase for 24 hours. Reduction of the Mcl-1 level was due to translation inhibition and proteasome degradation rather than to transcription inhibition or caspase cleavage. HHT and the transcription inhibitor SNS-032 induced synergistic cell killing. Although stromal cells induced Mcl-1 expression and protected CLL cells from the toxicity of fludarabine, this induction was reversed by HHT, which overcame stromal cell-mediated protection. Thus, these results provide a rationale for clinical development of HHT in CLL as single agent or in combinations.
|
| 巻・号 |
117(1)
|
| ページ |
156-64
|
| 公開日 |
2011-1-6
|
| DOI |
10.1182/blood-2010-01-262808
|
| PII |
S0006-4971(20)60151-3
|
| PMID |
20971952
|
| PMC |
PMC3037741
|
| MeSH |
Adult
Aged
Aged, 80 and over
Antineoplastic Agents, Phytogenic / pharmacology*
Apoptosis / drug effects*
Blotting, Western
Cell Proliferation / drug effects
Drug Synergism
Drug Therapy, Combination
Harringtonines / pharmacology*
Homoharringtonine
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
Lymphocytes / drug effects
Middle Aged
Mitochondrial Membranes / drug effects
Myeloid Cell Leukemia Sequence 1 Protein
Oxazoles / pharmacology
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism*
RNA, Messenger / genetics
Reverse Transcriptase Polymerase Chain Reaction
Stromal Cells / drug effects
Thiazoles / pharmacology
Tumor Cells, Cultured
|
| IF |
17.794
|
| 引用数 |
53
|
|
WOS 分野
|
HEMATOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
StromaNKtert(RCB2350)
KUSA-H1(RCB1990) |
