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造血组织群体的稳定取决于造血细胞增殖和凋亡的动态平衡。细胞凋亡的抑制可能是多种疾病,包括血液系统恶性肿瘤致病的主要原因,而如何诱导细胞的凋亡则成为白血病治疗的新途径,本文就近年来该领域的有关研究作一综述。1细胞凋亡的基因调控近年来研究发现细胞凋亡受多... 相似文献
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WT1基因是转录因子白血病发病机制的研究热点之一。通过选择性剪接可以产生四种主要转录本,各转录本表达水平差异及相互之间比例改变可能与细胞增生、分化及凋亡等过程有关。WT1在正常骨髓中低表达而在白血病细胞中异常表达,提示其在造血分化过程中可能起重要作用。 相似文献
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白血病,俗称血癌,是一类造血干细胞恶性克隆性疾病。克隆性白血病细胞因为增殖失控、分化障碍、凋亡受阻等机制在骨髓和其他造血组织中大量增殖累积,并浸润其他组织和器官,同时使正常造血受抑制。人类白血病的确切病因至今未明,许多因素被认为和白血病的发病有关, 相似文献
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骨髓增生异常综合征(myelodysplastic syndrome,MDS)是一组获得性造血干/祖细胞克隆增殖性疾病,是良性多克隆造血由于多次基因损伤而逐步被恶性单克隆造血替代的过程。当其尚未发展为急性白血病之前,MDS的基本病理特征是骨髓的无效造血。造血组织处于高增殖、高凋亡状态,而反映在细胞形态学上的变化提示着DNA复制紊乱的病态造血以及后期不同程度的原始细胞增多。 相似文献
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鞠佃文 《中国肿瘤生物治疗杂志》1994,1(1):79-79
集落刺激因子(CSFs)能促使化疗引起的骨髓抑制尽早恢复正常。但最近研究发现,G-CSF、GM-CSF等不仅能恢复放疗、化疗导致的造血功能抑制,还能促使带有CSF受体的白血病细胞和非造血系统肿瘤细胞的增殖。因此,CSF并不是用于化疗中恢复造血功能的最佳方案。本文研究发现rhG-CSF能促使鼠白血病细胞L1210增殖,减轻体内、体外阿霉素和VP-16对L1210的抗肿瘤及诱导细胞凋亡作用。用~(125)I-rhG-CSF进行放射配基结合试验发现L1210细胞上有特异性rhG-CSF受体(398/细胞)。作者以MPZen Neo(bcl-2)逆转录病毒为载体,将人的原癌基因bcl-2基因转入BALB/C× 相似文献
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肿瘤干细胞学说认为肿瘤组织中存在极少量瘤细胞,在肿瘤中充当干细胞的角色,具有无限增生的潜能,在启动肿瘤形成和生长中起着决定性的作用。肿瘤干细胞的研究最初在白血病中获得突破,寻找到急性粒细胞白血病的干细胞表型,随后的研究证明白血病干细胞的免疫表型在许多方面与造血干细胞相似。随着对干细胞研究的深入,研究领域已经扩展到实体瘤,首次寻找和证实实体瘤肿瘤干细胞的实验是在乳腺癌的研究中进行的,研究发现了具备干细胞特性的细胞表面抗原。随后实体瘤的干细胞研究在脑肿瘤及前列腺肿瘤等中开展,并得到了初步的结果。近来肿瘤干细胞的研究集中到针对肿瘤干细胞的治疗中。本文对肿瘤干细胞最近的研究情况进行综述。 相似文献
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Yamaguchi Y Shiraki K Fuke H Inoue T Miyashita K Yamanaka Y Saitou Y Sugimoto K Nakano T 《Oncology reports》2005,14(5):1311-1316
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Expression of IAP family proteins in myelodysplastic syndromes transforming to overt leukemia 总被引:11,自引:0,他引:11
Yamamoto K Abe S Nakagawa Y Suzuki K Hasegawa M Inoue M Kurata M Hirokawa K Kitagawa M 《Leukemia research》2004,28(11):1203-1211
Bone marrow cells of patients with myelodysplastic syndromes (MDS) frequently undergo apoptosis, though the apoptotic cell ratio decreases when overt leukemia (OL) develops. Thus, we compared the expression of the inhibitor of apoptosis protein (IAP) gene family proteins in bone marrow samples from control, MDS, OL transformed from MDS (MDS --> OL), and de novo acute myelogenous leukemia (AML) subjects by the quantitative real-time RT-PCR method and an immunohistochemical approach. Overexpression of mRNA for survivin, cIAP1, NAIP and XIAP was significant in MDS bone marrow cells compared with control samples. However, the expression of mRNA for survivin, cIAP1 and cIAP2 exhibited a remarkable decrease after the development of OL (MDS --> OL). By immunohistochemistry, survivin was found to localize to the nucleus of myeloid cells in the majority of MDS cases. Next, the chronological changes in the expression of IAPs were determined in cases of MDS with evolution of OL. Although the expression of cIAP1 and cIAP2 revealed a sudden or gradual decrease as OL developed, survivin in many cases and XIAP in the majority of cases exhibited a peak of expression before a decline, indicating that these IAPs could be associated with the early events in the development of OL. 相似文献
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We have shown previously that garlic constituent diallyl trisulfide (DATS) inhibits growth of cultured and xenografted human prostate cancer cells in association with apoptosis induction, but the mechanism of cell death is not fully understood. The present study systematically investigates the role of inhibitor of apoptosis (IAP) family proteins in the regulation of DATS-induced apoptosis using cultured PC-3 and LNCaP human prostate cancer cells and dorsolateral prostate from control and DATS-treated transgenic adenocarcinoma of mouse prostate (TRAMP) mice. Level of X-linked inhibitor of apoptosis (XIAP) protein was decreased on 8-hour treatment with 20 and 40 μmol/L DATS, but this effect was partially attenuated at the 16-hour time point. DATS-mediated decline in XIAP protein level was partially reversible in the presence of proteasomal inhibitor MG132. In contrast, DATS-treated PC-3 and LNCaP cells exhibited marked induction of survivin and cellular inhibitor of apoptosis protein 1 (cIAP1) proteins. Induction of survivin protein expression resulting from DATS exposure was associated with an increase in its mRNA level. Dorsolateral prostates from DATS-treated TRAMP mice exhibited statistically significant downregulation of XIAP and induction of survivin protein compared with those of control mice. Ectopic expression of XIAP conferred partial but significant protection against DATS-induced apoptosis. On the other hand, DATS-induced apoptosis was only marginally affected by RNA interference of survivin or cIAP1. In conclusion, the present study indicates that the DATS-induced apoptosis in prostate cancer cells is mediated in part by suppression of XIAP protein expression, and that XIAP represents a viable biomarker of DATS response for future clinical investigations. 相似文献
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目的 研究XIAP在弥漫性大B细胞淋巴瘤(DLBCL)中的表达及其与Suvivin表达的相关性,并探讨其与临床预后的关系。方法 采用免疫组织化学法检测49例DLBCL中XIAP与Suvivin蛋白的表达水平。结果 XIAP、Suvivin蛋白在DLBCL中的阳性表达率分别为40.8 %(20/49)和44.9 %(22/49),高于良性淋巴结病变中阳性表达率,分别为15 %(3/20)和10 %(2/20),差异均有统计学意义(P<0.05);XIAP与Suvivin表达呈正相关(r=0.382,P=0.01);XIAP表达的DLBCL患者的平均生存时间明显短于无表达的患者(P<0.02)。结论 XIAP蛋白表达上调可能是DLBCL发生、发展的重要因素,并可能在抑制细胞凋亡过程中与Suvivin起协同作用,并可能是DLBCL一个新的预后不良因子。 相似文献
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Ingo Tamm Stephan Richter Doreen Oltersdorf Ursula Creutzig Jochen Harbott Frank Scholz Leonid Karawajew Wolf-Dieter Ludwig Christian Wuchter 《Clinical cancer research》2004,10(11):3737-3744
PURPOSE: Apoptosis-related proteins are important molecules for predicting chemotherapy response and prognosis in adult acute myeloid leukemia (AML). However, data on the expression and prognostic impact of these molecules in childhood AML are rare. EXPERIMENTAL DESIGN: Using flow cytometry and Western blot analysis, we, therefore, investigated 45 leukemic cell samples from children with de novo AML enrolled and treated within the German AML-BFM93 study for the expression of apoptosis-regulating proteins [CD95, Bcl-2, Bax, Bcl-xL, procaspase-3, X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein-1 (cIAP-1), survivin]. RESULTS: XIAP (P < 0.002) but no other apoptosis regulators showed maturation-dependent expression differences as determined by French-American-British (FAB) morphology with the highest expression levels observed within the immature M0/1 subtypes. XIAP (P < 0.01) and Bcl-xL (P < 0.01) expression was lower in patients with favorable rather than intermediate/poor cytogenetics. After a mean follow-up of 34 months, a shorter overall survival was associated with high expression levels of XIAP [30 (n = 10) versus 41 months (n = 34); P < 0.05] and survivin [27 (n = 10) versus 41 months (n = 34); P < 0.05]. CONCLUSIONS: We conclude that apoptosis-related molecules are associated with maturation stage, cytogenetic risk groups, and therapy outcome in childhood de novo AML. The observed association of XIAP with immature FAB types, intermediate/poor cytogenetics, and poor overall survival should be confirmed within prospective pediatric AML trials. 相似文献
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In TNF-related apoptosis-inducing ligand (TRAIL)-resistant glioma cells, co-treatment with nontoxic doses of sodium butyrate and TRAIL resulted in a marked increase of TRAIL-induced apoptosis. This combined treatment was also cytotoxic to glioma cells overexpressing Bcl-2 or Bcl-xL, but not to normal human astrocytes, thus offering an attractive strategy for safely treating resistant gliomas. Cotreatment with sodium butyrate facilitated completion of proteolytic processing of procaspase-3 that was partially blocked by treatment with TRAIL alone. We also found that treatment with sodium butyrate significantly decreased the protein levels of survivin and X-linked inhibitor of apoptosis protein (XIAP), two major caspase inhibitors. Overexpression of survivin and XIAP attenuated sodium butyrate-stimulated TRAIL-induced apoptosis, suggesting its involvement in conferring TRAIL resistance to glioma cells. Furthermore, the kinase activities of Cdc2 and Cdk2 were significantly decreased following sodium butyrate treatment, accompanying downregulation of cyclin A and cyclin B, as well as upregulation of p21. Forced expression of Cdc2 plus cyclin B, but not Cdk2 plus cyclin A, attenuated sodium butyrate/TRAIL-induced apoptosis, overriding sodium butyrate-mediated downregulation of survivin and XIAP. Therefore, Cdc2-mediated downregulation of survivin and XIAP by sodium butyrate may contribute to the recovery of TRAIL sensitivity in glioma cells. 相似文献
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Sandra Loeder Annekathrin Drensek Irmela Jeremias Klaus‐Michael Debatin Simone Fulda 《International journal of cancer. Journal international du cancer》2010,126(9):2216-2228
Escape of apoptosis may contribute to treatment failure in childhood acute lymphoblastic leukemia (ALL) calling for new approaches to overcome apoptosis resistance. Here, we provide for the first time evidence that small molecule inhibitors that target the anti‐apoptotic protein X‐linked inhibitor of apoptosis (XIAP) sensitize ALL cells for CD95‐induced apoptosis. XIAP inhibitors at subtoxic concentrations, but not a structurally related control compound, act synergistically with agonistic anti‐CD95 antibodies or MegaFasL, a hexameric form of CD95 ligand, to induce apoptosis in ALL cells. Further, XIAP inhibitors co‐operate with MegaFasL to reduce clonogenic survival of ALL cells demonstrating their effect also on long‐term survival. In contrast, XIAP inhibitors show little effect on MegaFasL‐mediated apoptosis in normal peripheral blood lymphocytes (PBLs), pointing to some tumor selectivity. Molecular studies reveal that XIAP inhibitors enhance CD95‐induced activation of caspases, loss of mitochondrial membrane potential and cytochrome c release in a caspase‐dependent manner. Importantly, XIAP inhibitors sensitize primary leukemic blasts from children with ALL for MegaFasL‐induced apoptosis. Thus, small molecule XIAP inhibitors present a promising novel approach to enhance CD95‐induced apoptosis in childhood acute leukemia. 相似文献
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Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy 总被引:41,自引:0,他引:41
It is well known that dysfunction of the apoptotic pathway confers apoptosis resistance and results in a low sensitivity of human cancer cells to therapeutic agents. A novel strategy to overcome the resistance is to target the apoptotic pathway directly. To identify molecular targets in the apoptotic pathway that are differentially regulated in cancer and normal cells, we have examined the levels of apoptotic effectors and inhibitors in human tumor and normal cell lines as well as in cancer and normal tissues. These include three pancreatic cancer lines (BXPC-3, MIA PaCa-2, and Panc-1), four breast cancer cell lines (MDA-MB-231, MDA-MB-435, MDA-MB-361, and MCF-7), and colon carcinoma line (SW620). Additionally, breast carcinoma tissue specimens were examined. Compared with normal human fibroblast and mammary epithelial cell lines, we detected high basal levels of caspase-3 and caspase-8 activities and active caspase-3 fragments in the tumor cell lines and cancer tissues in the absence of apoptotic stimuli. Furthermore, the tumor cells expressed high levels of survivin and XIAP, two members of the inhibitor of apoptosis (IAP) protein family. When the activity of these IAPs was blocked by expression of dominant-negative mutant survivin (survivinT34A) and XIAP-associated factor 1, respectively, apoptosis was induced in tumor but not normal cell lines. Moreover, down-regulation of both survivin and XIAP significantly enhanced tumor-cell apoptosis as compared with inhibition of either survivin or XIAP alone. These results suggest that up-regulated IAP expression counteracts the high basal caspase-3 activity observed in these tumor cells and that apoptosis in tumor cells but not normal cells can be induced by blocking IAP activity. Therefore, IAPs are important molecular targets for the development of cancer-specific therapeutic approaches. 相似文献