共查询到20条相似文献,搜索用时 10 毫秒
1.
Dinis J Silva V Gromicho M Martins C Laires A Tavares P Rendeiro P Torres F Rueff J Rodrigues A 《Leukemia & lymphoma》2012,53(10):2004-2014
Abstract Resistance to imatinib in patients with chronic myeloid leukemia can lead to advanced disease and blast crisis. Conventional chemotherapy with DNA damaging agents is then used, alone or in combination with other tyrosine kinase inhibitors (TKIs). Our aim was to assess whether imatinib resistant K562 cells were also resistant to DNA damaging agents. After treatment with H(2)O(2) and doxorubicin, but not camptothecin, cell survival was higher in imatinib resistant cells compared to parental cells. DNA damage, measured by comet and γ-H2AX assays, was lower in imatinib resistant cells. mRNA expression levels of 50 genes of the DNA damage response pathway showed increased expression of the base excision repair (BER) genes MBD4 and NTHL1. Knockdown of MBD4 and NTHL1 expression in resistant cells using siRNA decreased cell survival after treatment with H(2)O(2) and doxorubicin. Our results indicate that imatinib resistant cells display cross-resistance to oxidative agents, partly through up-regulation of BER genes. Expression of these genes in imatinib resistant patients was not significantly different compared to sensitive patients. However, the strategy followed in this study could help identify chemotherapeutic agents that are more effective as alternative agents in cases of resistance to TKIs. 相似文献
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Jian Wang Hua XuHairui Zhang Qi WangChijuan Wang Hongju ZhangYani Lin Yongxin RuHaoyue Liang Qinghua LiTianxiang Pang 《Leukemia research》2014
CIAPIN1 (cytokine-induced antiapoptotic inhibitor 1) was recently identified as an essential downstream effector of the Ras signaling pathway. However, its potential role in regulating myeloid differentiation remains unclear. In this study, we found depletion of CIAPIN1 by shRNAs led to granulocytic differentiation of K562 cells. Meanwhile, the decrease of NHE1 and up-regulation of phosphorylated ERK1/2 were observed after CIAPIN1 depletion. Interestingly, targeted inhibition of NHE1 further promoted the differentiation of K562 cells with CIAPIN1 silencing. Accordingly, ectopic expression of NHE1 reversed this phenotype. Furthermore, ERK1/2 inhibition with the chemical inhibitor, PD98059, abolished CIAPIN1 silencing-induced differentiation of K562 cells after NHE1 inhibition. Thus, our results revealed important mechanism that CIAPIN1 targeted NHE1 to mediate differentiation of K562 cells via ERK1/2 pathway. Our findings implied CIAPIN1 and NHE1 could be new targets in developing therapeutic strategies against leukemia. 相似文献
4.
Nuria Ferrandiz Juan M. Caraballo Marta Albajar M. Teresa Gomez-Casares Carmen E. Lopez-Jorge Rosa Blanco M. Dolores Delgado Javier Leon 《Cancer letters》2010
Imatinib is a Bcr-Abl inhibitor used as first-line therapy of chronic myeloid leukemia (CML). p21Cip1, initially described as a cell cycle inhibitor, also protects from apoptosis in some models. We describe that imatinib down-regulates p21Cip1 expression in CML cells. Using K562 cells with inducible p21 expression and transient transfections we found that p21 confers partial resistance to imatinib-induced apoptosis. This protection is not related to the G2-arrest provoked by p21, a decrease in the imatinib activity against Bcr-Abl or a cytoplasmic localization of p21. The results suggest an involvement of p21Cip1 in the response to imatinib in CML. 相似文献
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Karina Lani Silva Paloma Silva de Souza Gabriela Nestal de Moraes Arthur Moellmann-Coelho Flavia da Cunha Vasconcelos Raquel Ciuvalschi Maia 《Leukemia research》2013
P-glycoprotein (Pgp) and XIAP co-expression has been discussed in the process of the acquisition of multidrug resistance (MDR) in cancer. Here, we evaluated XIAP and Pgp expression in chronic myeloid leukemia (CML) samples, showing a positive correlation between them. Furthermore, we evaluated the effects of imatinib in XIAP and Pgp expression using CML cell lines K562 (Pgp−) and K562-Lucena (Pgp+). Imatinib increased XIAP and Pgp expression in K562-Lucena cells, while in K562 cells a downregulation of these proteins was observed, suggesting that imatinib induces an increment of MDR phenotype of CML cells that previously exhibit high levels of Pgp/XIAP co-expression. 相似文献
7.
Chronic myeloid leukemia (CML) is a progressive and often fatal malignancy of the blood. The harbinger of CML is a chromosomal
translocation that results in the synthesis of the BCR-ABL fusion protein, a constitutively active tyrosine kinase. The advent
of imatinib, an inhibitor targeted specifically for BCR-ABL, represented a significant medical advance in CML therapy. However,
patients with CML can exhibit varying responses to first-line treatment with imatinib. While most patients respond to treatment,
some may experience a loss of response or require treatment discontinuation due to toxicity. Frequent monitoring for resistance
or intolerance is a requirement for recognition of suboptimal response. Mutational analysis of the patient’s BCR-ABL alleles
is also informative and may be predictive of a response to therapy. Published physician guidelines have highlighted these
recommendations, but it is not clear if these guidelines are universally followed. One option in patients showing poor response
to standard-dose imatinib of 400 mg is to escalate the dose. However, this option should be reserved for patients with minimal
disease burden. Clinically available options mainly include second-generation tyrosine kinase inhibitors, such as dasatinib
and nilotinib. Allogenic stem cell transplantations (for eligible patients) also should be considered. The disease and patient
characteristics at the time of imatinib failure should be evaluated before choosing second-line therapy to optimize the therapeutic
benefit without unnecessary delay. 相似文献
8.
Imatinib was the first treatment for chronic myeloid leukemia (CML) that specifically targeted the causative BCR-ABL oncoprotein, and represented a major therapeutic advance in this disease; however, some patients develop resistance or intolerance. Resistance can be classified as BCR-ABL-dependent (e.g., mutation in the BCR-ABL gene) or BCR-ABL-independent (alternative pathways of disease progression, e.g., SRC-family tyrosine kinases). The investigation of therapeutic options post-imatinib failure resulted in the development and regulatory approval of dasatinib, a BCR-ABL and SRC-family kinase inhibitor. Dasatinib is active across all phases of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia, and demonstrates activity in almost all imatinib-resistant mutations. Other therapeutic options are also under investigation, with nilotinib being the most clinically advanced. Nilotinib is an analog of imatinib with similar multiple kinase targets, but without inhibition of SRC, and reduced in vitro activity against BCR-ABL P-loop mutations compared with dasatinib. Similar to dasatinib, nilotinib has no activity against T315I mutations. The availability of dasatinib and development of other tyrosine kinase inhibitors provide positive prospects for patients with imatinib-resistant or -intolerant CML. Here, we discuss several of these new strategies for treating patients after imatinib failure. 相似文献
9.
目的: 探讨靶向干扰细胞因子诱导凋亡抑制因子1 (cytokine induced apoptosis inhibitor 1,CIAPIN1)基因表达后慢性
粒细胞性白血病K562细胞对伊马替尼的敏感性。 方法 :构建靶向CIAPIN1基因的shRNA干扰载体;使用实时定量PCR、West-
ern blotting以及免疫荧光评价CIAPIN1-shRNA组(CIAPIN1-shRNA转染)和scramble-shRNA组(scramble-shRNA转染K562细
胞)干扰效率;伊马替尼(imatinib)处理两组K562细胞后,MTT法检测其增殖能力,集落形成实验检测细胞克隆形成能力,流式细
胞术和Western blotting检测细胞周期、凋亡及凋亡相关蛋白的变化。 结果: shRNA干扰可有效抑制CIAPIN1表达,CIAPIN1-
shRNA组的CIAPIN1 mRNA表达量为scramble-shRNA组的(29.74±4.03)%、CIAPIN1蛋白表达量前者为后者的(21.57±2.18)%。
CIAPIN1表达下调能显著抑制伊马替尼对K562细胞的增殖和克隆形成,CIAPIN1-shRNA+imatinib组的细胞克隆形成数为
(15.60±1.03)个/视野,克隆半径为(2.63±0.55)μm,均小于scramble-shRNA+imatinib组(P<0.05或P<0.01)。CIAPIN1-shRNA+
imatinib组的细胞G1期细胞比例比scramble-shRNA+imatinib组明显增多,S期细胞比例较scramble-shRNA+imatinib组明显减少
(均P<0.01)。CIAPIN1-shRNA+imatinib组K562细胞凋亡率明显增加(P<0.01)。敲除CIAPIN1能抑制细胞周期相关蛋白Cyclin
D1、Bcl-xl、Bcl-2、Mcl-1表达,诱导细胞内细胞凋亡相关蛋白p21、Bid、Bim表达,且与伊马替尼具有协同作用。 结论: CIAPIN1表
达下调可明显提高K562细胞对伊马替尼的敏感性,该作用主要通过阻滞K562细胞周期及诱导凋亡相关蛋白表达实现。 相似文献
10.
XX Peng Z Shi AK Tiwari VL Damaraju L Fu CE Cass CR Ashby GD Kruh ZS Chen 《Oncology letters》2011,2(3):549-556
To investigate the mechanisms of cellular resistance to 6-mercaptopurine (6-MP) in chronic myeloid leukemia (CML), a 6-MP resistant cell line (K562-MP5) was established by stepwise selection of the CML cell line (K562). The results of the drug sensitivity analysis of the K562-MP5 cell line revealed the cells to be 339-fold more resistant to 6-MP compared with the parental K562 cells. K562-MP5 cells exhibited decreased accumulation and increased efflux of [(14)C]6-MP and its metabolites. In addition, K562-MP5 cells showed increased [(3)H]MTX transport. K562-MP5 cells over-expressed P-glycoprotein (P-gp) and up-regulated MDR1 mRNA levels. Taken together, these results suggest that the up-regulation of P-gp, which contributes to the decreased accumulation by increasing the efflux of 6-MP and its metabolites, underlies the mechanism of 6-MP resistance in K562 cells. 相似文献
11.
Fenouille N Puissant A Dufies M Robert G Jacquel A Ohanna M Deckert M Pasquet JM Mahon FX Cassuto JP Raynaud S Tartare-Deckert S Auberger P 《Cancer research》2010,70(23):9659-9670
SPARC is an extracellular matrix protein that exerts pleiotropic effects on extracellular matrix organization, growth factor availability, cell adhesion, differentiation, and immunity in cancer. Chronic myelogenous leukemia (CML) cells resistant to the BCR-ABL inhibitor imatinib (IM-R cells) were found to overexpress SPARC mRNA. In this study, we show that imatinib triggers SPARC accumulation in a variety of tyrosine kinase inhibitor (TKI)-resistant CML cell lines. SPARC silencing in IM-R cells restored imatinib sensitivity, whereas enforced SPARC expression in imatinib-sensitive cells promoted viability as well as protection against imatinib-mediated apoptosis. Notably, we found that the protective effect of SPARC required intracellular retention inside cells. Accordingly, SPARC was not secreted into the culture medium of IM-R cells. Increased SPARC expression was intimately linked to persistent activation of the Fyn/ERK kinase signaling axis. Pharmacologic inhibition of this pathway or siRNA-mediated knockdown of Fyn kinase resensitized IM-R cells to imatinib. In support of our findings, increased levels of SPARC mRNA were documented in blood cells from CML patients after 1 year of imatinib therapy compared with initial diagnosis. Taken together, our results highlight an important role for the Fyn/ERK signaling pathway in imatinib-resistant cells that is driven by accumulation of intracellular SPARC. 相似文献
12.
Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells 总被引:5,自引:0,他引:5
Mukai M Che XF Furukawa T Sumizawa T Aoki S Ren XQ Haraguchi M Sugimoto Y Kobayashi M Takamatsu H Akiyama S 《Cancer science》2003,94(6):557-563
STI571, an Abl-specific tyrosine kinase inhibitor, selectively kills Bcr-Abl-containing cells in vitro and in vivo . However, some chronic myelogenous leukemia (CML) cell lines are resistant to STI571. We evaluated whether STI571 interacts with P-glycopro-tein (P-gp) and multidrug resistance protein 1 (MRP1), and examined the effect of agents that reverse multidrug resistance (MDR) on the resistance to SI571 in MDR cells. STI571 inhibited the [125 l]azidoagosterol A-photolabeling of P-gp, but not that of MRP1. K562/MDR cells that overexpress P-gp were 3.67 times more resistant to STI571 than the parental Philadelphia-chromosome-positive (Ph+) CML K562 cells, and this resistance was most effectively reversed by cepharanthine among the tested reversing agents. The concentration of STI571 required to completely inhibit tyrosine phosphorylation in K562/MDR cells was about 3 times higher than that in K562 cells, and cepharanthine abolished the difference. In KB-G2 cells that overexpress P-gp, but not Bcr-Abl, 2.5 μM STI571 partly reversed the resistance to vincristine (VCR), paclitaxel, etoposide (VP-16) and actinomycin D (ACD) but not to Adriamycin (ADM) or colchicine. STI571 increased the accumulation of VCR, but not that of ADM in KB-G2 cells. STI571 did not reverse resistance to any agent in KB/MRP cells that overexpress MRP1. These findings suggest that STI571 is a substrate for P-gp, but is less efficiently transported by P-gp than VCR, and STI571 is not a substrate for MRP1. Among the tested reversing agents that interact with P-gp, cepharanthine was the most effective agent for the reversal of the resistance to STI571 in K562/ MDR cells. Furthermore, STI571 itself was a potent reversing agent for MDR in P-gp-expressing KB-G2 cells. 相似文献
13.
目的:探讨水通道蛋白1(aquaporin-1,AQP1)过表达对人慢性髓细胞白血病(chronic myeloidleukemia,CML) K562细胞红系分化和增殖的影响.方法:以人脑cDNA文库为模板,通过PCR扩增出AQP1基因的编码序列,构建pBABE-puro-AQP1真核表达载体;感染K562细胞,筛选建立稳定过表达AQP1基因的K562细胞株(命名为K562-AQP1);实时荧光定量PCR法、细胞免疫荧光染色法及蛋白质印迹法分别检测AQP1转录和蛋白表达水平.通过MTT法检测细胞生长增殖、实时荧光定量PCR法检测γ珠蛋白表达和分光光度法检测血红蛋白含量,研究AQP1过表达对K562细胞红系分化和增殖的影响.结果:与空载体对照组相比,pBABE-puro-AQP1转染入K562细胞后AQP1 mRNA和蛋白表达水平皆有显著升高(P<0.01),K562-AQP1细胞中红系分化指标γ珠蛋白和血红蛋白表达水平明显增加,同时细胞生长速度明显降低(P<0.05).结论:AQP1过表达可以显著促进K562细胞向红系分化,同时抑制细胞增殖.推测AQP1可能成为临床诱导分化治疗CML的基因靶点之一. 相似文献
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The cyclic lipopeptide (CLP) has been known to inhibit proliferation and induce apoptosis in cancer cells. However, the molecular mechanisms involved in CLP-induced apoptosis are still uncharacterized in human leukemic K562 cells. The current study investigated the molecular mechanism of action of CLP, purified from Bacillus natto T-2. CLP-induced a sustained increase in concentration of intracellular Ca2+. This increase in [Ca2+]i was associated with CLP-induced cell apoptosis and ERK phosphorylation. CLP-induced cell apoptosis was reversed by PD98059 (an inhibitor of ERK), but not by SB203580 (an inhibitor of p38) and SP200125 (an inhibitor of JNK), suggesting that the action of CLP on K562 cells was via ERK, but not via p38 and JNK. On the other hand, pretreatment with Bapta-AM, a well-known calcium chelator, partially blocked CLP-induced apoptosis, indicating that the elevation of [Ca2+]i may play an important role in the apoptosis. Collectively, in K562 cells, CLP-induced an increase in [Ca2+]i which evoked ERK phosphorylation. This ERK phosphorylation subsequently activated Bax, cytochrome c and caspase-3 leading to apoptosis. 相似文献
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CUEDC2, a newly reported protein, has been found to be ubiquitously expressed in human tissues and repress NF-κB activity. To study the role of CUEDC2 in chronic myeloid leukemia (CML), we explored the function of CUEDC2 in CML cells through using the CML cell line K562 and its imatinib resistant cells K562/G01. K562 cells expressed a relatively higher level of CUEDC2 compared to K562/G01 cells. Knockdown of CUEDC2 in K562 cells resulted in decreased cell apoptosis after imatinib treatment; when CUEDC2 was overexpressed in K562/G01 cells, imatinib induced more cell apoptosis. By analyzing the activity of NF-κB, the results indicated a negative association between the expression of CUEDC2 and NF-κB signaling pathway in these CML cells. Our data suggested that the expression level of CUEDC2 has an inverse correlation with imatinib resistance and activity of NF-κB signaling pathway in CML cells, CUEDC2 could regulate imatinib sensitivity in CML cells at least partially through NF-κB signaling pathway. 相似文献
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Ling-Na Ni Jian-Yong Li Kou-Rong Miao Chun Qiao Su-Jiang Zhang Hai-Rong Qiu Si-Xuan Qian 《Medical oncology (Northwood, London, England)》2011,28(1):265-269
The human multidrug resistance gene (MDR1, ABCB1) codes for P-glycoprotein (P-gp) that affects the pharmacokinetics of many drugs. MDR1 single nucleotide polymorphisms (SNPs)
are associated with drug clearance. Imatinib is a substrate of P-gp-mediated efflux. We investigated the MDR1 T1236C, G 2677T/A,
and C3435T polymorphism in 52 patients with chronic myeloid leukemia treated with imatinib. The distribution of MDR1 1236,
2677, or 3435 genotypes was significantly different between the resistance patients and sensitivity patients. The resistance
incidence correlated with the number of T alleles at locus 1236 and 3435. Resistance was higher for patients homozygous for
the 1236T allele when compared to patients with CT/CC genotype groups (75% vs. 31.3%, P = 0.004). For the G2677T/A polymorphism, a better complete cytogenetic remission was observed for patients with genotype
AG/AT/AA, when compared to other genotype groups (TT/GT/GG, P = 0.02). Patients with 3435 TT/CT genotypes showed a higher resistance when compared with patients with CC genotype (59.4%
vs. 25%, P = 0.023). In conclusion, determination of 1236T, C3435T, and G2677T MDR1 polymorphisms might be useful in response prediction
to therapy with imatinib in patients with CML. 相似文献
19.
Ju DS Kim MJ Bae JH Song HS Chung BS Lee MK Kang CD Lee HS Kim DW Kim SH 《Cancer letters》2007,252(1):75-85
In this study, we have tried to find new targets and effective drugs for imatinib-resistant chronic myelogenous leukemia (CML) cells displaying loss of Bcr-Abl kinase target dependence. The imatinib-resistant K562/R1, -R2 and -R3 cells showed profound declines of Bcr-Abl level and concurrently exhibited up-regulation of Bcl-2 and Ku70/80, and down-regulation of Bax, DNA-PKcs and BRCA1, suggesting that loss of Bcr-Abl after exposure to imatinib might be accompanied by other cell survival mechanism. K562/R3 cells were more sensitive to camptothecin (CPT)- and radiation-induced apoptosis than K562 cells, indicating hypersensitivity of imatinib-resistant cells to DNA damaging agents. Moreover, when K562 cells were treated with the combination of imatinib with CPT, the level of Bax and the cleavage of PARP-1 and DNA-PK were significantly increased in comparison with the effects of each drug. Therefore, our study suggests that CPT can be used to treat CML with loss of Bcr-Abl expression. 相似文献
20.
Dihydroartemisinin downregulates vascular endothelial growth factor expression and induces apoptosis in chronic myeloid leukemia K562 cells 总被引:19,自引:0,他引:19
Dihydroartemisinin (DHA), a more water-soluble active metabolite of artemisinin derivatives, is safe and the most effective
antimalarial analog of artemisinin. In the present investigation, we assessed the effect of DHA on vascular endothelial growth
factor (VEGF) expression and apoptosis in chronic myeloid leukemia (CML) K562 cells. The results demonstrated that in addition
to its antiproliferation effect on CML cells, DHA was also found to induce K562 cells apoptosis. The percentage of apoptotic
cells was increased to 6.9 and 15.8% after being treated with 5 and 10 μmol/l DHA for 48 h, respectively (P<0.001). In order
to analyze the effect of DHA on VEGF expression in K562 cells, we assessed the level of VEGF expression by western blot; detected
the form of VEGF mRNA by RT-PCR and examined the level of VEGF secreted in conditioned media (CM) by ELISA assay. All these
experiments suggested that DHA could inhibit the VEGF expression and secretion effectively in K562 cells, even at a lower
concentration (2 μmol/l, P<0.05). Moreover, we further assessed the stimulating angiogenic activity of CM from K562 cells on CAM model. The angiogenic
activity was decreased in response to the CM from K562 cells pretreated with DHA in a dose-dependent manner. Taken together,
these results from our study together with its known low toxicity make it possible that DHA might present potential antileukemia
effect as a treatment for CML therapy, or as an adjunct to standard chemotherapeutic regimens. 相似文献