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ABSTRACT: Signal transducers and activators of transcription (STAT) proteins function in the JAK/STAT signaling pathway and are activated by phosphorylation. As a result of this signaling event, they affect many cellular processes including cell growth, proliferation, differentiation, and survival. Increases in the expressions of STAT5A and STAT5B play a remarkable role in the development of leukemia in which leukemic cells gain uncontrolled proliferation and angiogenesis ability. At the same time, these cells acquire ability to escape from apoptosis and host immune system. In this study, we aimed to suppress STAT-5A and -5B genes in K562 CML cells by siRNA transfection and antisense oligonucleotides (ODN) targeting and then to evaluate apoptosis rate. Finally, we compared the transfection efficiencies of these approaches. Quantitative RT-PCR and Western blot results indicated that STAT expressions were downregulated at both mRNA and protein levels following siRNA transfection. However, electroporation mediated ODN transfection could only provide limited suppression rates at mRNA and protein levels. Moreover, it was displayed that apoptosis were significantly induced in siRNA treated leukemic cells as compared to ODN treated cells. As a conclusion, siRNA applications were found to be more effective in terms of gene silencing when compared to ODN treatment based on the higher apoptosis and mRNA suppression rates. siRNA application could be a new and alternative curative method as a supporting therapy in CML patients.
American journal of blood research. 01/2013; 3(1):58-70.
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Ozlem Purclutepe,
Guniz Iskender,
Hatice Demet Kiper,
Burcin Tezcanli,
Nur Selvi,
Cigir Biray Avci,
Buket Kosova,
Aysun Adan Gokbulut, Fahri Sahin,
Yusuf Baran,
Guray Saydam
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ABSTRACT: In this study, we aimed at evaluating the cytotoxic and apoptotic effects of enalapril on human HL60 acute promyelocytic leukaemia cells and at clarifying the roles of signal transducers and activator of transcription proteins (STATs) on enalapril-induced cell death.
Cell viability and cytotoxicity tests were conducted by Trypan blue dye exclusion and 2,3-Bis[2-methoxy-4-nitro-5-sulphophenyl]-2H-tetrazolium-5-carboxanilide inner salt (XTT) assays, respectively. Apoptotic analyses were performed by the AnnexinV-enhanced green fluorescent protein (EGFP) staining method and by fluorescence microscopy. Expression levels of STAT3, -5A and -5B genes were analysed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR).
The results showed that enalapril reduced viability and proliferation, and induced apoptosis in HL60 cells in a dose- and time-dependent manner as compared to untreated controls. The expression levels of STAT5A gene were significantly reduced in enalapril-treated HL60 cells as compared to untreated controls.
Taken together, all data showed for the first time that enalapril has significant anticancer potential for the treatment of acute premyelocytic leukaemia.
Anticancer research 07/2012; 32(7):2885-93. · 1.73 Impact Factor
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ABSTRACT: To determine the gene expression profiles of the JAK/STAT pathway members STAT3, STAT5A, STAT5B at both mRNA and protein levels in HL-60 and K-562 leukemia cells that were undergoing apoptosis following high-dose methylprednisolone (MP) treatment.
HL-60 cells were treated with 0.1 mM MP and K-562 cells were treated with 0.4 mM MP according to their IC(50) values. STAT3, STAT5A, and STAT5B mRNA relative expression levels were determined by qRT-PCR whereas the protein levels were detected via western-blot analysis and apoptosis was evaluated by Annexin V method.
A significant decrease was seen in STAT5A mRNA relative expression level at 48 hours of MP treatment (P < 0.05) both in HL-60 and K-562 cells. Other STATs showed a lower downregulation in their relative expressions at 48 hours at mRNA level for both of the cell lines. STAT proteins showed no expression change in K-562 cells in time course experiments but while STAT5A expression was downregulated; STAT5B showed an increase at 96 hours in HL-60 cells. Apoptosis was triggered by high-dose MP treatment that was evaluated by fluorescent microscopy.
The JAK/STAT pathway components may play an important role in the apoptosis mechanism of leukemic cells under MP treatment in HL-60 and K-562 cells. Other pathways may also be involved with a post-translational modification seen in the HL-60 cell line, with both upregulation and downregulation of protein expression levels of STAT5B and STAT5A, respectively.
Hematology (Amsterdam, Netherlands) 03/2012; 17(2):93-9. · 1.33 Impact Factor
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01/2012; , ISBN: 978-953-307-768-0
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ABSTRACT: We aimed to examine the growth suppressive effects of quercetin on acute promyelocytic and lymphoblastic leukemia and chronic myeloid leukemia, and to find out whether the growth suppression is related to the blocking of telomerase enzyme activity. Cytotoxic effects of quercetin were shown by trypan blue analyses. Apoptotic effects of quercetin were examined by acridine orange and ethidium bromide staining by fluorescence microscopy. The effects of quercetin on telomerase enzyme activity were shown by hTERT Quantification Kit. Our results demonstrated that quercetin has antiproliferative and apoptotic effects on T-cell acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia, and chronic myeloid leukemia (CML) cells. We also showed for the first time by this study that quercetin suppresses the activity of telomerase in ALL and CML cells. The results of this study show the importance of quercetin for its therapeutic potential in treatment of leukemias.
Hematology (Amsterdam, Netherlands) 09/2011; 16(5):303-7. · 1.33 Impact Factor
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ABSTRACT: Thrombus in sinus of Valsalva is unusual reason for acute myocardial infarction. We demonstrated a case with floating thrombus in sinus of Valsalva obstructing the right coronary ostium intermittently, and causing cardiogenic shock. The patient was diagnosed with multiplane transesophageal echocardiography and treated successfully with surgical removal of mass. A homozygote polymorphism of plasminogen activator inhibitor (PAI) 1 4G/5G was found. This is the first report demonstrating a patient with PAI 1 polymorphism and thrombus of Valsalva complicated with cardiogenic shock.
Echocardiography 05/2011; 28(8):E164-7. · 1.24 Impact Factor
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ABSTRACT: Resveratrol, an important phytoalexin in many plants, has been reported to have cytotoxic effects on various types of cancer. Ceramide is a bioactive sphingolipid that regulates many signaling pathways, including cell growth and proliferation, senescence and quiescence, apoptosis, and cell cycle. Ceramides are generated by longevity assurance genes (LASS). Glucosylceramide synthase (GCS) and sphingosine kinase-1 (SK-1) enzymes can convert ceramides to antiapoptotic molecules, glucosylceramide, and sphingosine-1-phosphate, respectively. C8:ceramide, an important cell-permeable analogue of natural ceramides, increases intracellular ceramide levels significantly, while 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) and SK-1 inhibitor increase accumulation of ceramides by inhibiting GCS and SK-1, respectively. Chronic myelogenous leukemia (CML) is a hematological disorder resulting from generation of BCR/ABL oncogene. In this study, we examined the roles of ceramide metabolizing genes in resveratrol-induced apoptosis in K562 CML cells. There were synergistic cytotoxic and apoptotic effects of resveratrol with coadministration of C8:ceramide, PDMP, and SK-1 inhibitor. Interestingly, there were also significant increases in expression levels of LASS genes and decreases in expression levels of GCS and SK-1 in K562 cells in response to resveratrol. Our data, in total, showed for the first time that resveratrol might kill CML cells through increasing intracellular generation and accumulation of apoptotic ceramides.
Nutrition and Cancer 05/2011; 63(4):637-44. · 2.78 Impact Factor
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ABSTRACT: Primary diffuse large B-cell lymphoma of the lacrimal sac is rare. Herein we report a 55-year-old female presented with epiphora in the right eye. Distention of the lacrimal sac secondary to nasolacrimal duct obstruction was observed. She was scheduled for external dacryocystorinostomy for the next month. When she came for surgery, a growing mass was recognised over the lacrimal sac region. On computer tomography scan, a subdermal mass causing nasal bone destruction was detected. Excisional biopsy of the mass was performed. Histopathologic and immunohistochemical evaluations revealed primary diffuse large B-cell non-Hodgkin lymphoma of the lacrimal sac. She was treated with cyclophospamide, vincristine, adriablastine and prednisone for eight courses combined with rituximab for 6 months. During a follow-up period of 25 months, patient is stable with no systemic disease. Although rare, lacrimal sac tumors can mimic dacryocystitis and must be considered in differential diagnosis. In suspicious cases incisional biopsy is recommended.
Auris, nasus, larynx 02/2011; 38(5):643-5. · 0.58 Impact Factor
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ABSTRACT: Acute promyelocytic leukemia results from a translocation between 15 and 17 chromosomes that produce PML/RARα fusion protein. PML/RARα inhibits differentiation of myeloid precursor cells at stem cell level. Resveratrol is a phytoalexin that exerts cytotoxic effects on cancer cells. Ceramides have crucial roles in cell growth, proliferation, differentiation, drug resistance, and apoptosis. In this study, we examined the possible cytotoxic effects of resveratrol on acute myeloid leukemia cells and determined the roles of ceramide-metabolizing genes in resveratrol-induced apoptosis, in addition to investigating the possibility of increasing the sensitivity of HL60 cells to resveratrol by manipulating sphingolipids.
Cytotoxic effects of resveratrol, C8:ceramide, PDMP, and SK-1 inhibitor were determined by XTT cell proliferation assay. Changes in caspase-3 enzyme activity and mitochondrial membrane potential (MMP) were measured using caspase-3 colorimetric assay and JC-1 MMP detection kit. Expression levels of ceramide-metabolizing genes were examined by RT-PCR.
The results revealed that manipulations of ceramide metabolism toward generation or accumulation of apoptotic ceramides increased apoptotic effects of resveratrol in HL60 cells, synergistically. More importantly, gene expression analyses revealed that resveratrol-induced apoptosis via increasing expression levels of ceramide-generating genes and decreasing expression levels of antiapoptotic sphingosine kinase-1 and glucosylceramide synthase genes.
These results showed for the first time that increasing intracellular levels of ceramides by biochemical approaches has also increased sensitivity of HL60 cells to resveratrol. We also showed that resveratrol induces apoptosis through manipulating ceramide-metabolizing genes that resulted in the accumulation of ceramides in HL60 cells.
Journal of Cancer Research and Clinical Oncology 02/2011; 137(2):279-86. · 2.56 Impact Factor
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ABSTRACT: In this study, we aimed to investigate the potential relationship between gossypol-induced cytotoxicity of human promyelocytic leukemia cell line (HL-60) leukemic cells and intracellular serine/threonine protein phosphatase (PP) dynamics and human telomerase reverse transcriptase (hTERT) activity. Gossypol was found to be cytotoxic in HL-60 cells with the IC(50) dose of 4.5 microM. The combination of gossypol and okadaic acid in IC(50) doses revealed the increased cytotoxicity in a time-dependent manner. Treatment of cells with gossypol has shown significant decrease in PP2A activity. The expression of the PP2A catalytic subunit was downregulated in gossypol-treated cells with 24 hours' intervals. hTERT mRNA levels were gradually decreased. In conclusion, during gossypol-induced cytotoxicity, intracellular activity and expression of PP2A was decreased as well as the activity of hTERT. The variation of hTERT activity in gossypol-treated HL-60 cells may be the potential reason for the phosphatase interaction during the gossypol treatment of leukemic cells resulting in cellular cytotoxicity.
Hematology (Amsterdam, Netherlands) 06/2010; 15(3):144-50. · 1.33 Impact Factor
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ABSTRACT: CAPE (caffeic acid phenethyl ester) is one of the most valuable and investigated component of propolis which is composed by honeybees. In the current study, we aimed at examining apoptotic effects of CAPE on CCRF-CEM leukemic cells and at determining the roles of mitochondrial membrane potential (MMP) in cell death.
Trypan blue and XTT methods were used to evaluate the cytotoxicity. Apoptosis was examined by ELISA-based oligonucleotide and acridine orange/ethidium bromide dye techniques. Loss of mitochondrial membrane potential was evaluated using JC-1 dye by flow cytometric analysis and under fluorescent microscope.
We detected the time- and dose-dependent increases in cytotoxic effect of CAPE on CCRF-CEM cells. ELISA and acridine orange/ethidium bromide results showed that apoptotic cell population increased significantly in CCRF-CEM cells exposed to increasing concentrations of CAPE. On the other hand, there was significant loss of MMP determined in response to CAPE in CCRF-CEM cells.
This in vitro data by being supported with clinical data may open the way of the potential use of CAPE for the treatment of leukemia.
Journal of Cancer Research and Clinical Oncology 03/2010; 137(1):41-7. · 2.56 Impact Factor
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ABSTRACT: Anti-TNF drugs may increase lymphoma risk in autoimmune rheumatic diseases, such as rheumatoid arthritis, but there have been no reports stating increased risk of lymphoma in ankylosing spondylitis (AS). Before 2 years, we had presented a case with AS developing Hodgkin's lymphoma following 6 months of etanercept treatment. Hereby, we present another case with AS developing non-Hodgkin's lymphoma (NHL), subsequent to 11 months of etanercept treatment. Pathological analysis revealed diffuse large B cell NHL. Although this is a report of a single case, cautious use of anti-TNF drugs is strongly recommended as they might cause lymphoma development even in AS.
Rheumatology International 12/2009; 31(12):1645-7. · 1.88 Impact Factor
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ABSTRACT: A 68-year-old woman presented with acute chest pain and a greatly increased platelet count. Cardiac catheterization revealed subtotal occlusion and a thrombus-like filling defect in the right coronary artery. The patient was successfully treated with intravenous tirofiban. Essential thrombocythemia was diagnosed based on bone marrow findings, clinical presentation and laboratory analysis. The relationship between intracoronary thrombus and essential thrombocythemia is discussed.
Thrombosis Journal 03/2009; 7:1. · 1.31 Impact Factor
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ABSTRACT: The aim of this study was to evaluate measures of insulin resistance and platelet function in postmenopausal women with oral or transdermal hormone replacement therapy (HRT).
Eighty women divided into four groups of 20 each were enrolled in the study. Group 1: postmenopausal hysterectomized women who received only transdermal estradiol (13.9 mg/12.5 cm(2)); group 2: women with intact uterus who were treated with estrogen-progestin combination (HRT); group 3: postmenopausal women who were treated with the selective estrogen receptor modulator tibolone, and group 4: women who were not taking any drugs for HRT were chosen as a control group (group 4).
In group 2, homeostasis model assessment of insulin resistance and fasting insulin levels were 2.90 +/- 0.37 and 9.3 +/- 3.0 microU/ml, respectively, prior to administration of HRT. These levels were reduced to 1.91 +/- 0.41 (p = 0.001) and 7.1 +/- 2.7 microU/ml (p = 0.002), respectively, after drug therapy. Mean levels of high-sensitivity C-reactive protein (hsCRP) were decreased with HRT only in group 2 (p = 0.002). No changes for biochemical and hematological parameters were observed in the other groups. Platelet function tests showed no differences after HRT in any group.
Estrogen-progestin combination HRT decreased measures of insulin resistance and hsCRP levels, but had no effect on platelet function tests in postmenopausal women.
Medical Principles and Practice 02/2009; 18(1):43-7. · 0.89 Impact Factor
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ABSTRACT: Paclitaxel and docetaxel (taxoids) are chemotherapy agents whose mode of action is through an effect on cellular microtubules. Several studies have investigated their potential in the treatment of myeloid malignancies. The aim of our study was to investigate the potential role of the serine/threonine protein phosphatase system in docetaxel/paclitaxel induced cytotoxicity on HL 60 cells. The IC50 dose of paclitaxel and docetaxel were found as 20 and 5 nM respectively using trypan blue dye exclusion and XTT assays. Treating HL 60 cells with docetaxel and paclitaxel resulted in dose and time dependent cytotoxicity. Docetaxel induced the decrease in the activity of protein phosphatase 1 (PP1) and increase in the activity of PP2 subgroups, while paclitaxel induced the increase in the activity of PP1 and decrease in the activity of PP2 subgroups. Potential use of specific protein phosphatase inhibitors or activators in combination with taxoids will open new windows in the treatment of myeloid leukemias.
Hematology (Amsterdam, Netherlands) 09/2008; 13(4):215-23. · 1.33 Impact Factor
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ABSTRACT: Caffeic acid phenethyl ester (CAPE) is one of the most effective components of propolis which is collected by honey bees. The aim of this study was to investigate the cytotoxic and apoptotic effects of CAPE in the CCRF-CEM cell line and to clarify the role of serine/threonine protein phosphatase 2A (PP2A) and human telomerase reverse transcriptase (hTERT) activity as an underlining mechanism of CAPE-induced apoptosis. Trypan blue dye exclusion test and XTT methods were used to evaluate the cytotoxicity and ELISA based oligonucleotide detection, which can be seen during apoptosis, was used to determine apoptosis. Acridine orange/ethidium bromide dye technique was also used to evaluate apoptosis. The cytotoxic effect of CAPE was detected in a dose and time dependent manner with the IC(50) of 1 muM. ELISA and acridine orange/ethidium bromide methods have shown remarkable apoptosis at 48th hour in CAPE treated cells. To investigate the role of PP2A in CAPE-induced apoptosis of CCRF-CEM cells, we performed combination studies with CAPE and, Calyculin A and Okadaic acid, which are very well known inhibitors of PP2A, in IC(20) of inhibitors and IC(50) of CAPE. Combination studies revealed synergistic effect of both drugs by concomitant use. Western blot analyses of PP2A catalytic and regulatory subunits showed down-regulation of expression of PP2A catalytic subunit in CAPE treated cells at 48th hour. Since, PP2A is important in hTERT (telomerase catalytic subunit) activation and deactivation, we also performed hTERT activity in CAPE treated cells simultaneously. Treating cells with IC(50) of CAPE for 96 h with the intervals of 24 h showed marked reduction of hTERT activity. The reduction of hTERT activity in CAPE treated CCRF-CEM cells was more prominent in the initial 48 h. The variation of hTERT activity in CAPE treated CCRF-CEM cells may be the reason for the protein phosphatase interaction that occurred after treatment with CAPE.
Hematology (Amsterdam, Netherlands) 01/2008; 12(6):519-25. · 1.33 Impact Factor
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ABSTRACT: 8p11 myeloproliferative syndrome (EMS; also known as the stem cell leukemia syndrome-SCLL) is a rare atypical myeloproliferative disorder associated with chromosomal abnormalities involving the 8p11 chromosomal band. Translocations associated with this syndrome result in the fusion of the fibroblast growth factor receptor 1 (FGFR 1) gene with various partners, resulting in ligand independent FGFR activity. The most commonly observed translocation of this syndrome is t(8;13), which results in the expression of a chimeric ZNF198-FGFR1 tyrosine kinase. Disease phenotype associated with this translocation has some typical features such as poor prognosis, and transformation to mainly acute leukemia and non-Hodgkin lymphoma; commonly with a T-cell phenotype in which obtaining and maintenance of remission is difficult by conventional chemotherapy. We hereby present a case diagnosed as atypical chronic myeloproliferative disease with consistent t(8;13)(p12;q12) and transformed rapidly to pre-B-cell acute lymphoblastic leukemia which is a rare clinical presentation.
Hematology (Amsterdam, Netherlands) 01/2008; 12(6):489-92. · 1.33 Impact Factor
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Joint, bone, spine: revue du rhumatisme 04/2007; 74(2):209-11. · 2.25 Impact Factor
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ABSTRACT: Currently, autologous peripheral stem cell transplantation used as a therapeutic modality in the treatment of various hematological malignancies is gaining more popularity day by day. In this method, the patient's own peripheral stem cells are collected by a proper method and stored at -80 degrees C until they are reinfused into the patient after being rewarmed in water bath at 37 degrees C. A number of complications have been reported related to reinfusion of the cryopreserved cells into the patient. These may include noncardiovascular complications such as nausea, vomiting, flushing, abdominal pain, chest discomfort, and headache, as well as cardiovascular complications like arrhythmias, hypotension, and hypertension. Hypothermia related to rapid infusion has been reported as the main factor underlying the cardiovascular complications. Electrocardiographic findings of hypothermia include sinusal bradycardia, prolonged QT and PR intervals, widened QRS complexes, and J wave, which is a ECG abnormality characterized by supraventricular and ventricular arrhythmias. We here present two cases of giant J wave caused by hypothermia during infusion of cryopreserved autologous peripheral stem cell that is detected by ECG and regressed after infusion ceased.
American Journal of Hematology 09/2006; 81(8):627-30. · 4.67 Impact Factor
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ABSTRACT: Apart from calvarial infiltration, intracranial involvement in multiple myeloma is uncommon. Diffuse leptomeningeal invasion with or without parenchymal involvement is most common. Dural infiltration without involvement of the parenchyma, leptomeninges or skull is rare. The differential diagnosis of a dural plasmacytoma includes meningioma, which has a similar MRI appearance, metastasis, lymphoma and sarcoma of the dura mater. We present a patient with multiple myeloma presenting with an intracerebral mass mimicking a meningioma on MRI. Multiple myeloma had been diagnosed seven years previously. The patient presented with headache and speech disturbance 12 months after autologous peripheral stem cell transplantation for recurrence of multiple myeloma. MRI revealed a left temporal extra-axial mass with a dural tail mimicking meningioma. Histopathological examination of the mass after excision showed multiple myeloma immunopositive for IgG, kappa light chain and CD38. There was no recurrence after postoperative radiotherapy. Plasmacytoma should be considered in the differential diagnosis of a solitary dural mass, particularly in a patient with multiple myeloma.
Journal of Clinical Neuroscience 03/2006; 13(2):259-61. · 1.25 Impact Factor
