Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was aimed to investigate the expression of neuropilin-1 (NRP-1) and NRP-2 mRNA in myeloid leukemia cells and the effect of NRP-1 on cell proliferation and migration. The expressions of NRP-1 and NRP-2 mRNA in bone marrow mononuclear cells of 24 patients with acute myeloid leukemia and in 7 myeloid leukemic cell lines (HL-60, KGIa, NB4, U937, HEL MEG01 and K562) were detected by RT-PCR. The effects of NRP-1 interfered with siRNA on proliferation and migration in leukemic cell line HEL were examined by MTT and migration test. The results showed that the expression of NRP-1 mRNA was found in bone marrow mononuclear cells (BMMNCS) of 24 AML patients, the positive rate was 100% and significantly higher than that in control group (positive rate 67%). The expressions of NRP-2 mRNA were seen in 79% AML patients and in 67% health control, there was no significant difference between them. The increased NRP-1 expression was directly correlated with the blast percentage in both peripheral blood and bone marrow of AML patients (r=05, r=0.4, p<0.05). The expressions of NRP-1 and NRP-2 mRNA were observed in 6/7 and 3/7 myeloid leukemic cell lines respectively. After HEL cells were transfected with siRNA for 24 hours, the expression levels of NRP-1 mRNA and protein decreased obviously. Under VEGF action, the cell number in control group significantly increased, while the cell proliferation in interfered group had been not changed. After being transfected for 24 hours, the migration in interfered group decreased significantly. It is concluded that the higher level of NRP-1 mRNA is expressed in bone marrow mononuclear cells of leukemia patients and plays a pivotal role in proliferation and migration of myeloid leukemic cells. Inhibition of NRP-1 functions may provide a new therapeutic strategy for AML.
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PMID:[Expression and effect of neuropilin-1 in acute myeloid leukemic cells]. 1808 55

Traditional cytotoxic chemotherapy is effective at temporizing AML in the majority of patients but cures a small minority. Thus, enrollment in clinical trials remains a recommended approach for nearly all patients. While signal transduction inhibition is a promising area to advance AML therapy, no agent as monotherapy has demonstrated obvious clinical benefit over traditional cytotoxic chemotherapy. Tipifarnib is perhaps an exception as it is the only signal transduction inhibitor in AML that reproducibly shows clinical benefit using traditional chemotherapy response criteria. Due to toxicity and low response rates, however, the potential advantages of tipifarnib over either traditional cytotoxic chemotherapy or best supportive care alone await confirmation from phase III studies. Available data suggest that combining signal transduction inhibitors with chemotherapy will improve response rates. Clinical trials to test this hypothesis are ongoing using various agents directed against targets such as FLT3, ras/raf/MAPK, mTOR, KIT, and VEGF, but the optimal approach is yet to be defined. Similarly unclear is the benefit of a potent specific kinase inhibitor versus a broad inhibitor of multiple kinases that could prove relevant to leukemia biology. In general, the incomplete understanding of many signal transduction inhibitors' true mechanism of action limits our ability to identify pretreatment predictors of response. To this end, the extensive measures applied to correlate the biologic activity of FLT3 inhibitors with clinical responses are noteworthy and provide useful lessons for clinical trial design and drug development both in leukemia and other cancers.
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PMID:Exploiting signal transduction pathways in acute myelogenous leukemia. 1809 42

Neoangiogenesis plays an important role in leukemogenesis. We investigated the in vivo anti-leukemic effect of ABT-869 against AML with wild-type FLT3 using RFP transfected HL60 cells with in vivo imaging technology on both the subcutaneous and systemic leukemia xenograft models. ABT-869 showed a five-fold inhibition of tumor growth in comparison with vehicle control. IHC analysis revealed that ABT-869 decreased p-VEGFR1, Ki-67 labeling index, VEGF and remarkably increased apoptotic cells in the xenograft models. ABT-869 also reduced the leukemia burden and prolonged survival. Our study supports the rationale for clinically testing an anti-angiogenesis agent in AML with wild-type FLT3.
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PMID:In vivo activity of ABT-869, a multi-target kinase inhibitor, against acute myeloid leukemia with wild-type FLT3 receptor. 1816 Jan 2

TNFalpha levels are elevated in the marrows of patients with myelodysplastic syndrome (MDS) and are associated with high rates of apoptosis, which contributes to hematopoietic failure. We observed that exposure of human marrow stroma cell lines HS5 and HS27a to TNFalpha increases levels of IL-32 mRNA. IL-32, in turn, induces TNFalpha. Marrow stroma from patients with MDS expressed 14- to 17-fold higher levels of IL-32 mRNA than healthy controls. In contrast, cells from patients with chronic myelomonocytic leukemia (CMML) expressed only one tenth the level of IL-32 measured in healthy controls. Human KG1a leukemia cells underwent apoptosis when cocultured with HS5 stromal cells, but knockdown of IL-32 in the stromal cells by using siRNA abrogated apoptosis in the leukemia cells. IL-32 knockdown cells also showed dysregulation of VEGF and other cytokines. Furthermore, CD56(+) natural killer cells from patients with MDS and CMML expressed IL-32 at lower levels than controls and exhibited reduced cytotoxic activity, which was unaffected by IL-2 treatment. We propose that IL-32 is a marrow stromal marker that distinguishes patients with MDS and CMML. Furthermore, IL-32 appears to contribute to the pathophysiology of MDS and may be a therapeutic target.
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PMID:Dysregulation of IL-32 in myelodysplastic syndrome and chronic myelomonocytic leukemia modulates apoptosis and impairs NK function. 1828 21

Cancer is primarily a disease of old age, and that life style plays a major role in the development of most cancers is now well recognized. While plant-based formulations have been used to treat cancer for centuries, current treatments usually involve poisonous mustard gas, chemotherapy, radiation, and targeted therapies. While traditional plant-derived medicines are safe, what are the active principles in them and how do they mediate their effects against cancer is perhaps best illustrated by curcumin, a derivative of turmeric used for centuries to treat a wide variety of inflammatory conditions. Curcumin is a diferuloylmethane derived from the Indian spice, turmeric (popularly called "curry powder") that has been shown to interfere with multiple cell signaling pathways, including cell cycle (cyclin D1 and cyclin E), apoptosis (activation of caspases and down-regulation of antiapoptotic gene products), proliferation (HER-2, EGFR, and AP-1), survival (PI3K/AKT pathway), invasion (MMP-9 and adhesion molecules), angiogenesis (VEGF), metastasis (CXCR-4) and inflammation (NF-kappaB, TNF, IL-6, IL-1, COX-2, and 5-LOX). The activity of curcumin reported against leukemia and lymphoma, gastrointestinal cancers, genitourinary cancers, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, melanoma, neurological cancers, and sarcoma reflects its ability to affect multiple targets. Thus an "old-age" disease such as cancer requires an "age-old" treatment.
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PMID:Curcumin and cancer: an "old-age" disease with an "age-old" solution. 1846 66

Sulforaphane (SFN) is a biologically active compound extracted from cruciferous vegetables, and possessing potent anti-cancer and anti-inflammatory activities. Here, we show that tumor necrosis factor-alpha (TNF-alpha), in combination with a sub-toxic dose of SFN, significantly triggered apoptosis in TNF-alpha-resistant leukemia cells (THP-1, HL60, U937, and K562), which was associated with caspase activity and poly (ADP-ribose)-polymerase cleavage. We also report that SFN non-specifically inhibited TNF-alpha-induced NF-kappaB activation through the inhibition of IkappaBalpha phosphorylation, IkappaBalpha degradation, and p65 nuclear translocation. This inhibition correlated with the suppression of NF-kappaB-dependent genes involved in anti-apoptosis (IAP-1, IAP-2, XIAP, Bcl-2, and Bcl-xL), cell proliferation (c-Myc, COX-2, and cyclin D1), and metastasis (VEGF and MMP-9). These effects suggest that SFN inhibits TNF-alpha-induced NF-kappaB activation through the suppression of IkappaBalpha degradation, leading to reduced expression of NF-kappaB-regulated gene products. Combined treatment with SFN and TNF-alpha was also accompanied by the generation of reactive oxygen species (ROS). Pre-treatment with N-acetyl-l-cysteine significantly attenuated the combined treatment-induced ROS generation and caspase-3-dependent apoptosis, implying the involvement of ROS in this type of cell death. In conclusion, the results of the present study indicate that SFN suppresses TNF-alpha-induced NF-kappaB activity and induces apoptosis through activation of ROS-dependent caspase-3.
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PMID:Sulforaphane suppresses TNF-alpha-mediated activation of NF-kappaB and induces apoptosis through activation of reactive oxygen species-dependent caspase-3. 1895 68

Adult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). The activation of NF-kappaB by Tax has been reported to play a crucial role in HTLV-1-induced transformation. The HTLV-1 bZIP factor (HBZ), which is encoded by an mRNA of the opposite polarity of the viral genomic RNA, is involved in both T cell proliferation and suppression of Tax-mediated viral gene transcription, suggesting that HBZ cooperates closely with Tax. In the present study, we observed that HBZ specifically suppressed NF-kappaB-driven transcription mediated by p65 (the classical pathway) without inhibiting the alternative NF-kappaB signaling pathway. In an immunoprecipitation assay, HBZ bound to p65 and diminished the DNA binding capacity of p65. In addition, HBZ induced p65 degradation through increasing the expression of the PDLIM2 gene, which encodes a ubiquitin E3 ligase for p65. Finally, HBZ actually repressed the transcription of some classical NF-kappaB target genes, such as IL-8, IL2RA, IRF4, VCAM-1, and VEGF. Selective suppression of the classical NF-kappaB pathway by HBZ renders the alternative NF-kappaB pathway predominant after activation of NF-kappaB by Tax or other stimuli, which might be critical for oncogenesis.
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PMID:Human T-cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF-kappaB. 1906 27

Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment.
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PMID:Tyrosine kinase blockers: new hope for successful cancer therapy. 1914 83

Haematopoiesis and blood vessel formation are closely associated, with several molecules employed by both systems. Recently, vasohibin-1 (VASH1), an endothelium-derived negative feedback regulator of angiogenesis, has been isolated and characterized. VASH1 is induced by VEGF or bFGF in endothelial cells (ECs) and inhibits their proliferation and migration. However, there are no data on the induction and expression of VASH1 in haematopoietic cells (HCs). Here, we show that the haematopoietic stem cell (HSC) population, but not haematopoietic progenitors (HPs) or mature HCs from adult bone marrow (BM) constitutively express VASH1. However, HPs, but not HSCs, can be induced to express VASH1 after BM suppression by 5-FU. Knock-down of the VASH1 gene in VASH1(+) leukaemia cells induced cell proliferation. These results suggest a role for VASH1 in negative feedback regulation of HP proliferation during recovery following BM ablation.
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PMID:Induction and expression of anti-angiogenic vasohibins in the hematopoietic stem/progenitor cell population. 1917 60

The objective of this study was to investigate the effect of cyclooxygenase-2 (COX-2) in the angiogenesis of bone marrow in leukemia patients. 51 patients with newly diagnosed acute leukemia were taken as study objects, 18 healthy volunteers were enrolled in the control group. Bone marrow microvessel density (MVD) in bone marrow biopsy tissue section was determined with immunohistochemistry method, the vascular endothelial growth factor level in serum was detected with ELISA method and the expression of cyclooxygenase-2 in bone marrow cells was assayed by flow cytometry. The results showed that the MVD, VEGF level, positive rate of COX-2 expression in leukemia group all obviously increased as compared with the control group (p < 0.05). The correlative coefficients of MVD, VEGF level and COX-2 expression rate were 0.614, 0.423 and 0.577 respectively (p < 0.05). In conclusion, as well as solid tumors, leukemia may be also a angiogenesis-dependent malignant tumor. Coordination of COX-2 with VEGF may promote angiogenesis in bone marrow.
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PMID:[Expression of cyclooxygenase-2 in bone marrow cells of leukemia patients and its association with angiogenesis]. 1923 44


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