scholarly journals Transferrin-Bound Doxorubicin Enhances Apoptosis and DNA Damage through the Generation of Pro-Inflammatory Responses in Human Leukemia Cells

2020 ◽  
Vol 21 (24) ◽  
pp. 9390
Author(s):  
Monika Jedrzejczyk ◽  
Katarzyna Wisniewska ◽  
Katarzyna Dominika Kania ◽  
Agnieszka Marczak ◽  
Marzena Szwed
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Morphological Observation ◽  
Human Leukemia ◽  
Dependent Manner ◽  
Normal Peripheral Blood

Doxorubicin (DOX) is an effective antineoplastic drug against many solid tumors and hematological malignancies. However, the clinical use of DOX is limited, because of its unspecific mode of action. Since leukemia cells overexpress transferrin (Tf) receptors on their surface, we proposed doxorubicin–transferrin (DOX–Tf) conjugate as a new vehicle to increase drug concentration directly in cancer cells. The data obtained after experiments performed on K562 and CCRF-CEM human leukemia cell lines clearly indicate severe cytotoxic and genotoxic properties of the conjugate drug. On the other hand, normal peripheral blood mononuclear cells (PBMCs) were more resistant to DOX–Tf than to DOX. In comparison to free drug, we observed that Tf-bound DOX induced apoptosis in a TRAIL-dependent manner and caused DNA damage typical of programmed cell death. These fatal hallmarks of cell death were confirmed upon morphological observation of cells incubated with DOX or DOX–Tf. Studies of expression of TNF-α, IL-4, and IL-6 at the mRNA and protein levels revealed that the pro-inflammatory response plays an important role in the toxicity of the conjugate. Altogether, the results demonstrated here describe a mechanism of the antitumor activity of the DOX–Tf conjugate.

Deacetylase Inhibitor Cocktails Provide Striking Synergistic Interactions in Human Leukemia Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4404-4404
Author(s):  
Michele Cea ◽  
Antonia Cagnetta ◽  
Floriana Fruscione ◽  
Santina Bruzzone ◽  
Gabriele Zoppoli ◽  
...  
Keyword(s):  
Hydroxamic Acid ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Hdac Inhibitors ◽  
Leukemia Cell ◽  
Lymphocytic Leukemia ◽  
Dominant Negative ◽  
Myelogenous Leukemia ◽  
Leukemia Cells ◽  
Human Leukemia

Abstract Abstract 4404 Cancer cells almost invariably exhibit aberrant histone deacetylase (HDAC) activity leading to changes in chromatine structure, altered gene expression, poor differentiation, impaired apoptosis and increased proliferation. Accordingly, virtually all the HDAC inhibitors currently available show some degree of antitumor activity in preclinical cancer models and several of these compounds are currently under investigation or already approved for the treatment of human malignancies. Such is the case of the hydroxamic acid derivative suberoylanilide hydroxamic acid (Vorinostat, Zolinza), approved for the treatment of cutaneous T cell lymphomas. Sirtuins are a large family of deacetylases characterized by a unique, NAD+-dependent enzymatic mechanism. In addition to their established role in metabolism and longevity, recent evidence points to an emerging role for sirtuins in carcinogenesis. In the attempt to identify drug combinations that would increase the activity of traditional HDAC inhibitors we have explored the combination of valproic acid (VA) and butyrate (BU) with the sirtuin inhibitors cambinol and sirtinol in primary B-cell chronic lymphocytic leukemia (B-CLL) cells (n=35), acute myelogenous leukemia (AML) cells (n=10) and leukemia cell lines. Cell viability was assessed by propidium iodide staining and flow cytometry. Combination indices were determined using the median-effect method. In leukemia cells, exposure to sirtuin inhibitors synergistically increased VA and BU mediated cytotoxicity. Conversely, these drugs were poorly active and failed to show any cooperation in healthy cells, including peripheral blood mononuclear cells and fibroblasts, suggesting a cancer-specific mode of action. Similar results were obtained by combining VA or BU with the Nampt inhibitor APO866, which reduces intracellular NAD+ levels and thereby prevents sirtuin activity. Remarkably, SIRT1 and SIRT6 inhibition per se did not seem to account for cell demise upon HDAC inhibition since expression of a dominant negative SIRT1 isoform or RNA interference-mediated SIRT6 silencing failed to increase VA and BU activity. Our data indicate a specific requirement by leukemia cells for sustained sirtuin activity when classical HDACs are inhibited. This feature is suitable to be therapeutically exploited by combining sirtuin inhibitors or APO866 with classical HDAC inhibitors especially for the treatment of hematological malignancies. Disclosures: No relevant conflicts of interest to declare.

Effects of Berberine on Arylamine N-acetyltransferase Activity and 2-Aminofluorene-DNA Adduct Formation in Human Leukemia Cells

2000 ◽  
Vol 28 (02) ◽  
pp. 227-238 ◽  
Author(s):  
J. G. Chung ◽  
G. W. Chen ◽  
C. F. Hung ◽  
J. H. Lee ◽  
C. C. Ho ◽  
...  
Keyword(s):  
High Performance ◽  
Leukemia Cell ◽  
Adduct Formation ◽  
Dna Adduct ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Dependent Manner ◽  
Aminobenzoic Acid ◽  
Intact Cells ◽  
Human Leukemia Cells

Berberine is an alkaloid occuring in the plant genera Berberis and Coptis. Although berberine had been demonstrated to have antineoplastic function by inhibiting DNA-synthesis in activated lymphocytes, there is no available information to address berberine affects on human leukemia cell N-acetyltransferase (NAT) activity and 2-aminofluorene (AF)-DNA adduct formation. Thus, berberine was tested for inhibition of arylamine NAT activity and AF-DNA adduct formation in human leukemia cells. The NAT activity was measured by a high performance liquid chromatography assaying for the amounts of N-acetyl-2-aminofluorene (AAF) and N-acetyl-p-aminobenzoic acid (N-Ac-PABA) and the remaining AF and p-aminobenzoic acid (PABA). The NAT activity and AF-DNA adduct formation in human leukemia cells were inhibited by berberine in a dose-dependent manner, i.e. the higher the concentration of berberine, the higher the inhibition of NAT activity and AF-DNA adduct. The data also indicate that berberine decreased the apparent values of Km and Vmax from human leukemia cells in both cytosol and intact cells.

scholarly journals Endoplasmic Reticulum Stress Signaling Comprises a G9a Inhibitor Tolerance Pathway and PERK Inhibition Increases Anti-Leukemia Activity of G9a Inhibitor in Leukemia Cells and Leukemia Stem-like Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1360-1360
Author(s):  
Jieun Jang ◽  
Ju-In Eom ◽  
Hoi-kyung Jeung ◽  
So-Young Seol ◽  
Haerim Chung ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Leukemia Cell ◽  
Apoptotic Cell Death ◽  
Leukemia Cells ◽  
Dependent Manner ◽  
Eif2α Phosphorylation ◽  
Kg1 Cells

Abstract Background: Histone methyltransferase (HMTase) G9a regulates the transcription of multiple genes by primarily catalyzing dimethylation of histone H3 lysine 9 (H3K9me2), as well as several non-histone lysine sites. Recently, pharmacological and genetic targeting of the G9a was shown to be efficient in slowing down acute myeloid leukemia (AML) cell proliferation in a mouse model and human AML cell lines thus making this HMTase potential target for epigenetic therapy of AML. Activation of adaptive mechanisms to drug plays a crucial role in drug resistance and relapse by allowing cell survival under stressful conditions. Therefore, inhibition of the adaptive response is considered as a prospective therapeutic strategy. The tolerance mechanism to HMTase regulation in leukemia cell is unclear yet. The PERK-eIF2α phosphorylation pathway is an important arm of the unfolded protein response (UPR), which is induced under conditions of endoplasmic reticulum (ER) stress. Recent previous studies showed that pro-survival ER stress is induced in cancer cells and contributes to development of drug resistance. Methods: We investigated the levels of apoptosis and ER stress by G9a inhibitor BIX-01294 in leukemia cell lines. U937, cytarabine-resistant U937 (U937/AR) and KG1 were used. U937/AR cell line was established in our laboratory by exposing parental U937 cells to stepwise increasing concentrations of cytarabine. Results: We initially examined the expression of G9a in leukemia cell lines and the primary AML cells obtained from a patient at the different time point. In U937/AR cells and primary AML cells obtained at relapse, G9a expression was increased compare to that in U937 cells and primary AML cells obtained at diagnosis, respectively. G9a expression was also increased in KG1 cells. In both of U937 and U937/AR, apoptotic cell death was induced by BIX-01294 in a dose-dependent manner. In contrast, apoptotic cell death was minimal in KG1 cells which are enriched in cells expressing a leukemia stem cell phenotype (CD34+CD38-). To address the activation of ER stress response by BIX-01294 in leukemia cells, we examined the effect of BIX-01294 treatment on PERK and eIF2α protein expression and phosphorylation levels. We found that treatment of U937, U937/AR, KG1 cells with 3μM of BIX-01294 for 24h caused an upregulation of phosphorylated PERK and eIF2α. The upregulation of PERK phosphorylation was associated with a decrease in PERK protein levels after treatment. To further address the role of the PERK-eIF2α phosphorylation in BIX-01294 sensitivity, we examined whether PERK inhibition using small interfering RNA (siRNA) or specific inhibitor could sensitize cells to BIX-01294-mediated death. The siRNA against PERK effectively inhibited BIX-01294-mediated phosphorylation of PERK and eIF2α in U937 and U937/AR cells. The addition of PERK siRNA led to a significant increase in the extent of BIX-01294-induced apoptotic cell death in U937 (P = 0.0003) and U937/AR (P < 0.0001) as compared with that of BIX-01294 treatment alone. PERK inhibitor GSK260641 significantly increased BIX-01294-induced apoptotic cell death in U937 (P < 0.0001) and U937/AR (P = 0.006) cells. To our surprise, addition of PERK siRNA or GSK260641 increased the sensitivity of KG1 cells to BIX-01294-mediated death in a dose-dependent manner (P = 0.0003 for siRNA, P = 0.0053 for GSK260641). Conclusion: These data demonstrated that PERK-eIF2α activation has a pro-survival function to G9a inhibitor in leukemia cells and mediates resistance of AML stem cells to G9a inhibitor treatment. The PERK-eIF2α phosphorylation arm may represent a suitable target for combating resistance to G9a inhibitor in AML. The mechanisms underlying the increased sensitivity of AML cells with PERK inhibition to G9a inhibitor are unclear at present and are needed to define in further studies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Apoptosis induced by erythroid differentiation of human leukemia cell lines is inhibited by Bcl-XL

Blood ◽  
1996 ◽  
Vol 87 (9) ◽  
pp. 3837-3843 ◽  
Author(s):  
A Benito ◽  
M Silva ◽  
D Grillot ◽  
G Nunez ◽  
JL Fernandez-Luna
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Leukemia Cell ◽  
K562 Cells ◽  
Erythroid Differentiation ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Human Leukemia Cells ◽  
Leukemia Cell Lines ◽  
Wide Range

The induction of tumor cell differentiation represents an attractive strategy for the treatment of a wide range of malignancies. Differentiation of HL-60 promyelocytic leukemia cells towards neutrophils or monocytes has been shown to induce apoptotic cell death, which is inhibited by bcl-2 over-expression. However, the role of the bcl-2 gene family during erythroid differentiation of human leukemia cells remains unknown. We found that human erythroleukemia (HEL) and K562, two leukemia cell lines that undergo erythroid differentiation do not express Bcl-2, but express Bcl-XL, a related protein that functions as an inhibitor of apoptosis. Differentiation of HEL or K562 cells with inducers of erythroid differentiation (hemin, retinoic acid, or transforming growth factor-beta) was accompanied by progressive cell death and degradation of genomic DNA into oligonucleosomal fragments. The loss of cellular viability was associated with downregulation of bcl-xL mRNA and protein. In contrast, the levels of Bax, another Bcl-2 family member implicated in apoptosis remained unaltered. Constitutive expression of Bcl-XL by gene transfer inhibited apoptosis triggered by erythroid differentiation of HEL K562 cells. Yet, Bcl-XL did not alter the expression of epsilon-globin, which is induced during erythoid differentiation of HEL and K562 cells, arguing that apoptosis and differentiation can be uncoupled by Bcl-XL. These results indicate that Bcl-XL acts as an antiapoptosis protein in leukemia cells that undergo erythroid differentiation and that downregulation of bcl-x is a component of the apoptotic response that is coupled to differentiation in human leukemia cells.

scholarly journals Dynamin inhibition causes context-dependent cell death of leukemia and lymphoma cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0256708
Author(s):  
Christopher von Beek ◽  
Linnéa Alriksson ◽  
Josefine Palle ◽  
Ann-Marie Gustafson ◽  
Mirjana Grujic ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Acute Leukemia ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Tumor Formation ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Bone Marrow Biopsies

Current chemotherapy for treatment of pediatric acute leukemia, although generally successful, is still a matter of concern due to treatment resistance, relapses and life-long side effects for a subset of patients. Inhibition of dynamin, a GTPase involved in clathrin-mediated endocytosis and regulation of the cell cycle, has been proposed as a potential anti-cancer regimen, but the effects of dynamin inhibition on leukemia cells has not been extensively addressed. Here we adopted single cell and whole-population analysis by flow cytometry and live imaging, to assess the effect of dynamin inhibition (Dynasore, Dyngo-4a, MitMAB) on pediatric acute leukemia cell lines (CCRF-CEM and THP-1), human bone marrow biopsies from patients diagnosed with acute lymphoblastic leukemia (ALL), as well as in a model of lymphoma (EL4)-induced tumor growth in mice. All inhibitors suppressed proliferation and induced pronounced caspase-dependent apoptotic cell death in CCRF-CEM and THP-1 cell lines. However, the inhibitors showed no effect on bone marrow biopsies, and did not prevent EL4-induced tumor formation in mice. We conclude that dynamin inhibition affects highly proliferating human leukemia cells. These findings form a basis for evaluation of the potential, and constraints, of employing dynamin inhibition in treatment strategies against leukemia and other malignancies.

Cytokine-regulated expression of survivinin myeloid leukemia

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2784-2790 ◽  
Author(s):  
Bing Z. Carter ◽  
Michele Milella ◽  
Dario C. Altieri ◽  
Michael Andreeff
Keyword(s):  
Cell Lines ◽  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
Leukemia Cell ◽  
Survivin Expression ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Normal Peripheral Blood ◽  
Gm Csf ◽  
Cytokine Stimulation

Abstract Survivin, a member of the inhibitors-of-apoptosis gene family, is expressed in a cell-cycle–dependent manner in all the most common cancers but not in normal differentiated adult tissues.Survivin expression and regulation were examined in acute myeloid leukemia (AML). Survivin was detected by Western blot analysis in all myeloid leukemia cell lines and in 16 of 18 primary AML samples tested. In contrast, normal CD34+ cells and normal peripheral blood mononuclear cells expressed no or very low levels of survivin. Cytokine stimulation increasedsurvivin expression in leukemic cell lines and in primary AML samples. In cultured primary samples, single-cytokine stimulation substantially increased survivin expression in comparison with control cells, and the combination of G-CSF, GM-CSF, and SCF increased survivin levels even further. Conversely, all-trans retinoic acid significantly decreased survivinprotein levels in HL-60, OCI-AML3, and NB-4 cells within 96 hours, parallel to the induction of myelomonocytic differentiation. Using selective pharmacologic inhibitors, the differential involvement of mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol-3 kinase (PI3K) pathways were demonstrated in the regulation of survivin expression. The MEK inhibitor PD98059 down-regulated survivin expression in both resting and GM-CSF–stimulated OCI-AML3 cells, whereas the PI3K inhibitor LY294002 inhibited survivin expression only on GM-CSF stimulation. In conclusion, these results demonstrate thatsurvivin is highly expressed and cytokine-regulated in myeloid leukemias and suggest that hematopoietic cytokines exert their antiapoptotic and mitogenic effects, at least in part, by increasing survivin levels.

JAZ “Targeting” Compounds Induce G1 Cell Cycle Arrest Followed by Cell Death in Human Leukemia Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2658-2658
Author(s):  
Mingli Yang ◽  
George Q. Yang ◽  
Jinghua Jia ◽  
David Ostrov ◽  
W. Stratford May
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

Abstract JAZ (just another zinc finger protein) was previously identified in our laboratory as a unique ZFP that preferentially binds to double-stranded (ds) RNA rather than dsDNA. We found that interleukin-3 growth factor withdrawal upregulates JAZ expression in factor-dependent hematopoietic cells in association with p53 activation and induction of apoptotic cell death. We recently discovered JAZ as a novel direct, positive regulator of p53 transcriptional activity. The mechanism involves direct binding to p53’s C-terminal (negative) regulatory domain to activate “latent” p53 in response to non-genotoxic stress signals. Our preliminary data indicate that JAZ is differentially expressed in murine and human bone marrow cells and in normal and malignant hematopoietic tissues and cell lines. Thus, we have explored JAZ as a potentially novel molecular target in human leukemia by identifying small molecules that bind and activate JAZ. Using a high-throughput, “molecular docking” strategy, we have screened approximately 240,000 small molecules for their ability to interact with JAZ. Based on the Lipinski Rules for Drug Likeness (molecular characteristics favorable for absorption and permeability), we identified ~70 putative “drug-like” binding molecules with high scores and obtained ~40 of them from the NCI Developmental Therapeutics Program. We first tested their cytotoxic effect on various human leukemia cell lines including wt p53 expressing Reh pre-B lymphoblastic leukemia and Molt-3 T-cell lymphoblastic leukemia cells, and p53-deficient U937 leukemic monocyte lymphoma and KU812 and K562 chronic myelogenous leukemia cells. We have selected four “candidate” JAZ-targeting (J1-J4) compounds for further investigation because they are potent (IC50 = &lt;1 to ~50 μM) in killing leukemia cells in association with upregulation of JAZ protein expression and p53 activation. Since we previously demonstrated that JAZ can induce G1 cell cycle arrest prior to apoptosis in NIH3T3 mouse fibrablast cells in association with upregulation of p21, dephosphorylation of Rb and repression of cyclin A, we have tested these J-compounds for their potential effect on cell cycle progression. Drug treatment followed by flow cytometry analysis was carried out in human leukemia cell lines. Results reveal that the J2, J3 and J4 but not J1 compounds induce significant G1 cell cycle arrest followed by cell death in a dose- and time-dependent manner (e.g. an increase in the G1 population by up to 35 % at 24 hr following the treatment at doses of 0.1 to 50 μM). These data indicate that the J2-J4 compounds can not only induce leukemia cell killing but also mediate growth arrest. Interestingly, J3 and J4 are FDA-approved drugs (for the treatment of non-cancer diseases), suggesting a potentially novel role for these clinically available drugs as therapy for hematologic malignancies. Therefore, while further in vitro and in vivo characterization remains to be carried out, the JAZ-“targeting” compound(s) points the way to develop a potentially novel therapeutic strategy targeting JAZ to treat human leukemia.

scholarly journals Cytotoxicity of Bacterial Metabolic Products, including Listeriolysin O, on Leukocyte Targets

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
R. Stachowiak ◽  
M. Lyzniak ◽  
B. K. Budziszewska ◽  
K. Roeske ◽  
J. Bielecki ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Leukemia Cell ◽  
Jurkat Cells ◽  
Human Leukemia ◽  
Dependent Manner ◽  
Listeriolysin O ◽  
Peripheral Blood Mononuclear

Bacterial toxins can exhibit anticancer activities. Here we investigated the anticancer effects of the listeriolysin O toxin produced byListeria monocytogenes. We found that supernatants ofListeria monocytogenesstrains (wild type, 1189, and 1190) were cytotoxic to the Jurkat cell line and human peripheral blood mononuclear cells (PBMC) in a concentration-dependent manner. The supernatant of strain 1044, not producing listeriolysin O, was inactive. The supernatants ofListeriastrains were also cytotoxic toward B cells of chronic leukemia patients, with no significant differences in activities between strains. We also tested supernatants ofBacillus subtilisstrains BR1-90, BR1-S, and BR1-89 producing listeriolysin O. BR1-S and BR1-89 were cytotoxic to PBMC and to Jurkat cells, the latter being more sensitive to the supernatants. BR1-90 was not hemolytic or cytotoxic to PBMC, but was cytotoxic to Jurkat cells in the concentration range of 10–30%, suggesting that listeriolysin O is selectively effective against T cells. Overall, the response of human peripheral blood mononuclear and human leukemia cell lines to bacteria supernatants containing listeriolysin O depended on the bacteria strain, target cell type, and supernatant concentration.

scholarly journals COL-3-Induced Molecular and Ultrastructural Alterations in K562 Cells

2022 ◽  
Vol 12 (1) ◽  
pp. 42
Author(s):  
Mona Fares ◽  
Sandra Oerther ◽  
Kjell Hultenby ◽  
Danica Gubrianska ◽  
Ying Zhao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Ultrastructural Changes ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Concentration Dependent Manner ◽  
Transmission Electron Microscopy Analysis

Tetracycline-3 (4-dedimethylamino sancycline, COL-3) is a non-antibiotic tetracycline derivative. COL-3 exerts potent anti-metalloproteinase activity and its antitumor effects have been reported both in vitro and in vivo. In this study, we investigated the mechanisms of COL-3-induced cytotoxicity in a chronic myeloid leukemia cell line, K562, characterized by the BCR–ABL fusion protein. COL-3 induced K562 cell death in a concentration-dependent manner with an IC50 of 10.8 µg/mL and exhibited features of both apoptosis and necrosis. However, flow cytometry analysis revealed that necrotic cells dominated over the early and late apoptotic cells upon treatment with COL-3. Transmission electron microscopy analysis in combination with Western blotting (WB) analysis revealed early mitochondrial swelling accompanied by the early release of cytochrome c and truncated apoptosis inducing factor (tAIF). In addition, ultrastructural changes were detected in the endoplasmic reticulum (ER). COL-3 affected the levels of glucose-regulated protein-94 (GRP94) and resulted in m-calpain activation. DNA double strand breaks as a signature for DNA damage was also confirmed using an antibody against γH2AX. WB analyses did not demonstrate caspase activation, while Bcl-xL protein remained unaffected. In conclusion, COL-3-induced cell death involves DNA damage as well as mitochondrial and ER perturbation with features of paraptosis and programmed necrosis.

scholarly journals IL-17 Biological Effects and Signaling Mechanisms in Human Leukemia U937 Cells

2021 ◽  
Author(s):  
Samuel Evans Adunyah ◽  
Richard Akomeah ◽  
Fareed K.N. Arthur ◽  
Roland S. Cooper ◽  
Joshua C.M. Williams
Keyword(s):  
T Cells ◽  
Inflammatory Responses ◽  
Biological Effects ◽  
Leukemia Cell ◽  
Cytokine Receptors ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Limited Information ◽  
Growth And Survival ◽  
Leukemia Cell Lines

Human Interlekin-17 is produced by memory activated CD4+ T cells and other cells. It was initially considered unique in that its specific receptor is distinct from other cytokine receptors. IL-17 receptor is ubiquitously expressed by different cells including T cells. IL-17 plays a role in regulating growth, immune response and pro-inflammatory responses. It regulates differentiation of a subset of Th0 cells into Th-17 cells, which produce IL-17-induced cytokines. The IL-17R belongs to type 1 cytokine receptors. IL-17 belongs to a superfamily of its own, which includes IL-17A, IL-17B, IL-17C, IL-17E and IL-17F. These members of IL-17 superfamily have some sequence homology but bind to different receptors. Prior to this investigation, limited information existed on the effects of IL-17A in human leukemia cell lines. Our results show that IL-17A promotes growth, anti-apoptotic effects, chemotaxis, cytokine expression and transcriptional factor activation in leukemia cells. IL-17A activates multiple signaling pathways including PI-3 K, Jak–STAT, Raf-ERK1/2 and SRC kinase pathways, which mediate different biological effects of IL-17A in leukemia cells. Our findings implicate IL-17A in leukemia cell growth and survival, supporting potential leukemia therapy via development of anti-IL-17A drugs. This chapter focuses on IL-17A, herein referred to as IL-17.

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