Origanum vulgare extract induces apoptosis in Molt-4 leukemic cell line

2020 ◽  
pp. 1-8
Author(s):  
Nona Solouki ◽  
Ali Mohammadi-Gollou ◽  
Mohsen Sagha ◽  
Mohammad Mohammadzdeh-Vardin
Keyword(s):  
Cell Line ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Origanum Vulgare ◽  
Leukemia Treatment ◽  
Anti Oxidant ◽  
Induction Of Apoptosis ◽  
Apoptosis And Necrosis ◽  
Lymphoblastic Cells

OBJECTIVE: The purpose of this paper is to investigate the effect of Origanum vulgare extract as a plant with high anti-oxidant components on the induction of cell death in the Molt-4 cell line. BACKGROUND: Acute lymphocytic leukemia is characterized by the accumulation of a large number of lymphoblastic cells with high oxidant levels. METHODS: MTT assay was performed to determine the effect of O.vulgare extract on Molt-4 cells viability and the amount of 50%inhibitory concentration (IC50) was calculated. Changes in the expression of BAX and BCL-2 genes as involved in apoptosis and Nrf2 gene as a transcription factor of anti-oxidant genes in O.vulgare extract-treated Molt-4 cells were measured with Real-Time PCR. Treated Molt-4 cells were used to determine the stages of early and late apoptosis, and necrosis using acridine orange/ethidium bromide double staining. RESULTS: The results suggest survival inhibition and induction of apoptosis in Molt-4 cells treated with O.vulgare extract. Against Bax and Nrf2 genes expression, the expression of Bcl-2 gene has been reduced in Molt-4 cells following1/5 IC50 concentration of O. vulgare extract treatment. CONCLUSION: Given the oxidant drugs used in ALL treatment, and increased levels of oxidative stress in leukemic cells, induction of apoptosis by an anti-oxidant plant extract seems to be a promising way in leukemia treatment.

scholarly journals Comparative Activity of Melarsoprol and Arsenic Trioxide in Chronic B-Cell Leukemia Lines

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 562-570 ◽  
Author(s):  
Andrea König ◽  
Laura Wrazel ◽  
Raymond P. Warrell ◽  
Roberta Rivi ◽  
Pier Paolo Pandolfi ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Arsenic Trioxide ◽  
Cell Lines ◽  
Inorganic Arsenic ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Clinical Effects ◽  
Barr Virus

Inorganic arsenic trioxide (As2O3 ) was recently shown to induce apoptosis in NB4 promyelocytic leukemic cells. We have investigated the effects of the organic arsenical, melarsoprol (a drug used for treatment of trypanosomiasis), upon induction of apoptosis in cell lines representative of chronic B-cell lymphoproliferative disorders. An Epstein-Barr virus (EBV)-transformed B-prolymphocytic cell line (JVM-2), an EBV-transformed B-cell chronic lymphocytic leukemia (B-CLL) cell line (I83CLL), and one non–EBV-transformed B-CLL cell line (WSU-CLL) were used as targets. Dose-response experiments with melarsoprol (10−7 to 10−9 mol/L) were performed over 96 hours. Unexpectedly, we found that melarsoprol caused a dose- and time-dependent inhibition of survival and growth in all three cell lines. In contrast, As2O3 at similar concentrations had no effect on either viability or growth. After 24 hours, all three cell lines treated with melarsoprol (10−7 mol/L) exhibited morphologic characteristics of apoptosis. We also observed prominent concentration-dependent downregulation of bcl-2 mRNA after 24 hours of exposure to melarsoprol in WSU-CLL, I83CLL, and JVM-2 cells. Decrease of bcl-2 protein expression was also observed in all three cell lines, whereas As2O3 had no effect on this parameter. We conclude that melarsoprol may inhibit the growth of lymphoid leukemic cell by promoting programmed cell death. Results of these studies suggest that melarsoprol shows promising therapeutic activity in these diseases, and a study to evaluate clinical effects of this drug has been initiated.

scholarly journals Comparative Activity of Melarsoprol and Arsenic Trioxide in Chronic B-Cell Leukemia Lines

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 562-570 ◽  
Author(s):  
Andrea König ◽  
Laura Wrazel ◽  
Raymond P. Warrell ◽  
Roberta Rivi ◽  
Pier Paolo Pandolfi ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Arsenic Trioxide ◽  
Cell Lines ◽  
Inorganic Arsenic ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Clinical Effects ◽  
Barr Virus

Abstract Inorganic arsenic trioxide (As2O3 ) was recently shown to induce apoptosis in NB4 promyelocytic leukemic cells. We have investigated the effects of the organic arsenical, melarsoprol (a drug used for treatment of trypanosomiasis), upon induction of apoptosis in cell lines representative of chronic B-cell lymphoproliferative disorders. An Epstein-Barr virus (EBV)-transformed B-prolymphocytic cell line (JVM-2), an EBV-transformed B-cell chronic lymphocytic leukemia (B-CLL) cell line (I83CLL), and one non–EBV-transformed B-CLL cell line (WSU-CLL) were used as targets. Dose-response experiments with melarsoprol (10−7 to 10−9 mol/L) were performed over 96 hours. Unexpectedly, we found that melarsoprol caused a dose- and time-dependent inhibition of survival and growth in all three cell lines. In contrast, As2O3 at similar concentrations had no effect on either viability or growth. After 24 hours, all three cell lines treated with melarsoprol (10−7 mol/L) exhibited morphologic characteristics of apoptosis. We also observed prominent concentration-dependent downregulation of bcl-2 mRNA after 24 hours of exposure to melarsoprol in WSU-CLL, I83CLL, and JVM-2 cells. Decrease of bcl-2 protein expression was also observed in all three cell lines, whereas As2O3 had no effect on this parameter. We conclude that melarsoprol may inhibit the growth of lymphoid leukemic cell by promoting programmed cell death. Results of these studies suggest that melarsoprol shows promising therapeutic activity in these diseases, and a study to evaluate clinical effects of this drug has been initiated.

scholarly journals S-100 beta positive T cell leukemia

Blood ◽  
1988 ◽  
Vol 71 (5) ◽  
pp. 1299-1303
Author(s):  
K Takahashi ◽  
Y Ohtsuki ◽  
H Sonobe ◽  
K Hayashi ◽  
S Nakamura ◽  
...  
Keyword(s):  
T Cell ◽  
Human Peripheral Blood ◽  
Leukemic Cell ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
S 100 ◽  
T Cell Phenotypes

We reported a peculiar case with T cell leukemia. The patient was a 34- year-old woman showing extensive splenomegaly and marked leukemic cell proliferation and running a rapid fatal clinical course. The leukemic cells were morphologically ordinary lymphocytes showing suppressor/cytotoxic(s/c) T cell phenotypes and containing S-100b protein. Southern blot analysis revealed rearrangement of the beta chain genes of the T cell receptor (TcR) of the leukemic cells. Because these phenotypic and morphologic features were identical with those of S-100 beta+T lymphocytes (S-100 beta +TL) in normal human peripheral blood, we regarded this case as S-100 beta +T cell leukemia. We discussed clinicopathological features of S-100 beta +T cell leukemia/lymphoma by assessing similar cases reported so far. S-100 beta +T cell leukemia/lymphoma is a new type of s/c T lymphocytic leukemia/lymphoma with aggressive features.

scholarly journals Fluorouracil Selectively Enriches Stem-like Leukemic Cells in a Leukemic Cell Line

2010 ◽  
pp. 419-427 ◽  
Author(s):  
Ling Zhang ◽  
Song Yang ◽  
Yu-Juan He ◽  
Hui-Yuan Shao ◽  
Li Wang ◽  
...  
Keyword(s):  
Cell Line ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Leukemic Cell Line

Aberrant expression of B-lymphocyte stimulator by B chronic lymphocytic leukemia cells: a mechanism for survival

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2973-2979 ◽  
Author(s):  
Anne J. Novak ◽  
Richard J. Bram ◽  
Neil E. Kay ◽  
Diane F. Jelinek
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
B Lymphocyte ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Aberrant Expression ◽  
B Lymphocyte Stimulator

B-cell chronic lymphocytic leukemia (B-CLL) is defined by the accumulation of CD5+ B cells in the periphery and bone marrow. This disease is not characterized by highly proliferative cells but rather by the presence of leukemic cells with significant resistance to apoptosis and, therefore, prolonged survival. B-lymphocyte stimulator (BLyS) is a newly identified tumor necrosis factor (TNF) family member shown to be critical for maintenance of normal B-cell development and homeostasis and it shares significant homology with another TNF superfamily member, APRIL. The striking effects of BLyS on normal B-cell maintenance and survival raises the possibility that it may be involved in pathogenesis and maintenance of hematologic malignancies, including B-CLL. In this study, we investigated the status of APRIL and BLyS expression, as well as their receptors, in this disease. All B-CLL patient cells studied expressed one or more of 3 known receptors for BLyS; however, the pattern of expression was variable. In addition, we demonstrate for the first time that B-CLL cells from a subset of patients aberrantly express BLyS and APRIL mRNA, whereas these molecules were not detectable in normal B cells. Furthermore, we provide in vitro evidence that BLyS protects B-CLL cells from apoptosis and enhances cell survival. Because these molecules are key regulators of B-cell homeostasis and tumor progression, leukemic cell autocrine expression of BLyS and APRIL may be playing an important role in the pathogenesis of this disease.

scholarly journals S-100 beta positive T cell leukemia

Blood ◽  
1988 ◽  
Vol 71 (5) ◽  
pp. 1299-1303 ◽  
Author(s):  
K Takahashi ◽  
Y Ohtsuki ◽  
H Sonobe ◽  
K Hayashi ◽  
S Nakamura ◽  
...  
Keyword(s):  
T Cell ◽  
Human Peripheral Blood ◽  
Leukemic Cell ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
S 100 ◽  
T Cell Phenotypes

Abstract We reported a peculiar case with T cell leukemia. The patient was a 34- year-old woman showing extensive splenomegaly and marked leukemic cell proliferation and running a rapid fatal clinical course. The leukemic cells were morphologically ordinary lymphocytes showing suppressor/cytotoxic(s/c) T cell phenotypes and containing S-100b protein. Southern blot analysis revealed rearrangement of the beta chain genes of the T cell receptor (TcR) of the leukemic cells. Because these phenotypic and morphologic features were identical with those of S-100 beta+T lymphocytes (S-100 beta +TL) in normal human peripheral blood, we regarded this case as S-100 beta +T cell leukemia. We discussed clinicopathological features of S-100 beta +T cell leukemia/lymphoma by assessing similar cases reported so far. S-100 beta +T cell leukemia/lymphoma is a new type of s/c T lymphocytic leukemia/lymphoma with aggressive features.

A Novel Multiparameter Flow Cytometric Cytotoxicity Assay Detects p53 Deletion as the Major Cause of In Vitro Resistance to Fludarabine in B-Cell Chronic Lymphocytic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4470-4470
Author(s):  
James Z. Huang ◽  
Antony C. Bakke ◽  
Guang Fan ◽  
Rita Braziel ◽  
Ken M. Gatter ◽  
...  
Keyword(s):  
Drug Sensitivity ◽  
Drug Exposure ◽  
Leukemic Cell ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Multiparameter Flow Cytometry ◽  
Diagnostic Strategy ◽  
Significant Difference

Abstract Individual patients with B-CLL demonstrate variable responses to standard induction and salvage therapeutic regimens. It would be highly desirable to develop a predictable and reproducible laboratory diagnostic strategy that guides the selection of appropriate drugs and/or regimens based on the drug sensitivity and resistance profiles of leukemic cells for individual patients. As a first step towards this goal, a study was designed to investigate the differences of in vitro drug sensitivity profiles of leukemic cells with different cytogenetic abnormalities from CLL patients. CLL cells from 43 patients were incubated in vitro with four commonly used chemotherapeutic agents (fludarabine, chlorambucil, cladribine or prednisolone) individually or in combination. Multiparameter flow cytometry was utilized to determine the decrease in leukemic cell viability after drug exposure. Both fresh and cryopreserved samples were assessed and were found to be equivalent for assay, regardless of the percentage of B-CLL cells or the degree of spontaneous apoptosis. The highest in vitro resistance to fludarabine, was seen in all seven cases of B-CLL cells with deletions of p53, a cytogenetic abnormality associated with poor clinical outcome. Interestingly, in vitro response to chlorambucil and prednisolone was seen some CLL cases with p53 deletion and correlated with clinical response to these drugs. In CLL cases without p53 deletion, a marked variability in vitro drug sensitivity CLL cells was observed but no significant difference was detected among cases with normal cytogenetics (n=13), ATM deletion (n=4), trisomy 12 (n=3), or 13q deletion (n=7). Our findings provide direct evidence of cellular resistance to fludarabine in CLL associated with p53 deletion, confirming prior clinical observations. In vitro drug sensitivity assay may prove useful in guiding choices for therapy for CLL patients based on the drug sensitivity profile of leukemic cells in individuals.

Introduction of Constitutivelly Active Akt in Primary CLL B-Cells Results in Upregulation of Mcl-1, Bcl-XL and Cyclin D3 and Promotes Leukemic Cell Survival.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2805-2805
Author(s):  
Pablo Longo ◽  
Stefania Gobessi ◽  
Luca Laurenti ◽  
Simona Sica ◽  
Giuseppe Leone ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Survival ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Cyclin D3 ◽  
Leukemic Cells ◽  
Interleukin 4 ◽  
Antiapoptotic Proteins ◽  
Sustained Activation ◽  
Constitutively Active

Abstract The PI3K/Akt and Raf/MEK/ERK pathways are key regulators of various cellular responses, including proliferation, survival, differentiation, migration and malignant transformation. These pathways are activated in chronic lymphocytic leukemia B-cells by a number of survival or growth stimulatory signals, such as immobilized anti-IgM antibodies, interleukin-4, phorbol-ester, CXCL12, or stimulatory CpG oligonucleotides. Moreover, enhanced activation of Akt has been implicated in the pathogenesis of the CLL-like disorder that develops in mice transgenic for the TCL1 oncogene. To further delineate the relative contribution of the PI3K/Akt and Raf/MEK/ERK pathways in regulating leukemic cell growth and survival, we introduced constitutively active Akt or constitutively active MEK2 in primary CLL B-cells by nucleofection. Expression of constitutively active Akt consistently promoted survival, as evidenced by a higher percentage of Annexin V/PI negative cells after 48 hours in culture (median 52%) compared to samples transfected with control vector (median 31%). Immunoblot analysis of several important antiapoptotic proteins revealed that enforced activation of Akt upregulates Mcl-1 and Bcl-xL, whereas no changes were observed in the levels of Bcl-2. Expression of constitutively active Akt also induced an increase in size and granularity of the leukemic cells, indicating increased metabolic activity. These changes were associated with significant induction of cyclin D3, indicating that activation of Akt is required for both leukemic cell survival and cell cycle progression. In contrast, introduction of constitutively active MEK2 induced sustained activation of ERK, but showed only a modest increase in the percentage of viable CLL B-cells (median 36%) and no significant changes in the levels of any of the investigated antiapoptotic proteins. These experiments provide direct evidence that sustained activation of Akt promotes leukemic cell survival and upregulates Mcl-1, an antiapoptotic protein that has been associated with resistance to chemotherapy in patients with CLL.

Acidic Leucine-Rich Nuclear Phosphoprotein 32 Family Member B (ANP32B), a Novel Caspase-3 Substrate, Exerts Anti-Apoptotic Effects on Acute Myeloid Leukemic Cells.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1337-1337
Author(s):  
Yun Yu ◽  
Shao-Ming Shen ◽  
Li-Shun Wang ◽  
Qian Zhao ◽  
Guo-Qiang Chen
Keyword(s):  
Cell Line ◽  
Nuclear Export ◽  
Caspase 3 ◽  
Expression Profiles ◽  
Leukemic Cell ◽  
Site Directed Mutagenesis ◽  
Leukemic Cells ◽  
Leukemic Cell Line ◽  
Nuclear Phosphoprotein ◽  
Acute Myeloid

Abstract The acidic leucine-rich nuclear phosphoprotein 32B (ANP32B, also called APRIL) is a member of a conserved superfamily of nuclear proteins that includes ANP32A/pp32, a factor that binds histones and inhibits their acetylation and regulates cell growth and differentiation in a tissue-specific manner. Recently, ANP32B was identified as a novel histone chaperone, and it can interact with the transcription factor KLF5, leading to transcriptional repression of a KLF5-downstream gene through stimulation of promoter region-specific histone incorporation and inhibition of histone acetylation. Additionally, ANP32B and/or ANP32A also serve as adaptor molecules linking the HuR nucleocytoplasmic shuttle protein and the nuclear export receptor CRM1 to regulate the cytoplasmic accumulation of some transcripts such as c-fos and CD83. However, its biological activity is still poorly understood. By the two-dimensional electrophoresis plus MALDI-TOF/TOF tandem mass spectrometry-based analysis of subcellular protein expression profiles, we identified ANP32B protein to become a small fragment in the cytosols of apoptotic leukemic cell line induced by NSC606985, a camptothecin analog. The ongoing immunoblot analyses confirmed that ANP32B protein was cleaved during cellular context-independent and caspase-3 activation-dependent apoptosis induced by etoposide, doxorubin and arsenic trioxide besides NSC606985. Further in vitro proteolytic experiments supported that ANP32B is a direct substrate of caspase-3, and the site-directed mutagenesis analysis identified the unclassical aspartate (AEVD163) of ANP32B sequence to be the caspase-3 targeted sites. Thus, we investigated the potential role of ANP32B in apoptosis induction. Our results showed that the suppression of ANP32B expression by siRNA in acute myeloid leukemic cell line U937 cells strongly enhances NSC606985 and etoposide-induced apoptosis. Based on these findings, this work also analyzed molecular mechanism of anti-apoptotic effect of ANP32B, and some interesting findings were confirmed.

Chronic Lymphocytic Leukemia-Exosomes Switch Endothelial and Mesenchymal Stromal Cells into Cancer-Associated Fibroblasts to Sustain Leukemic Cell Survival

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2927-2927 ◽  
Author(s):  
Jerome Paggetti ◽  
Franziska Haderk ◽  
Martina Seiffert ◽  
Bassam Janji ◽  
Yeoun Jin Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Survival ◽  
B Lymphocytes ◽  
Stromal Cells ◽  
Leukemic Cell ◽  
Lymphoid Organs ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells

Abstract Chronic lymphocytic leukemia (CLL), the most common hematologic malignancy in Western countries, is mostly affecting the elderly over 65 year-old. CLL is characterized by the accumulation of mature but non-functional B lymphocytes of clonal origin in the blood and the primary lymphoid organs. CLL was previously considered as a relatively static disease resulting from the accumulation of apoptosis-resistant but quiescent B lymphocytes. However, recent studies using heavy water labeling indicated that CLL is in fact a very dynamic disease with alternation of proliferation phases and peripheral circulation. A focus on the trafficking of CLL cells in vivo has shown that leukemic cells circulate between the blood and the lymphoid organs but have a preference for the bone marrow. Recent next-generation sequencing of CLL cells indicated the presence of different genetic subclones. This intraclonal heterogeneity observed in CLL subpopulations may be in part determined by the interactions that leukemic cells entertain with their microenvironment when B cells migrate into the lymph nodes and the bone marrow. Indeed, tumor-stroma interactions are not only providing signals necessary for leukemic cells survival but may also influence the clonal architecture and evolution. One of these interactions involves CLL-derived exosomes. Here, we show that CLL-exosomes efficiently transfer nucleic acids, including functional microRNAs, and proteins, including MHC-Class II molecules and B-cell specific proteins, to bone marrow mesenchymal stem cells and endothelial cells. CLL-exosomes also activate signaling pathways, including PI3K and NF-κB pathways, in these stromal cells. As a consequence, gene expression is strongly modified indicating a switch towards a cancer-associated fibroblast phenotype. Functionally, exosome-stimulated stromal cells show a striking actin cytoskeleton remodeling characterized by the formation of stress fibers, and enhanced proliferation, motility and angiogenic properties. We also identified several proteins synthesized and secreted by stromal cells that promote leukemic cell adhesion and survival ex vivo. To confirm the involvement of CLL-exosomes in CLL pathology in vivo, MEC-1-eGFP cells were subcutaneously injected into immunocompromised NSG mice together with CLL-exosomes. We observed a significant increase in tumor size and a reduction in survival of exosome-treated animals. Flow cytometry analysis of selected organs indicated an enrichment in leukemic cells in the kidney, providing a potential explanation to the renal failures observed in CLL patients. In conclusion, the communication between CLL cells and stromal cells may be a critical factor influencing CLL progression by promoting leukemic cell survival. This study demonstrates the crucial role of exosomes as mediators of the communication between leukemic cells and their microenvironment. Exosomes could thus represent a suitable target for therapeutic intervention in CLL. Disclosures No relevant conflicts of interest to declare.

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