scholarly journals Synthesis of Two Novel Homologous Polyphosphoesters Containing Aminophosphonate Units and Cytotoxicity of Some Low-Molecular and Polymeric Aminophosphonate Derivatives

2018 ◽  
Vol 2018 ◽  
pp. 1-8
Author(s):  
Ivanka Kraicheva ◽  
Georgi Momekov ◽  
Rositsa Mihaylova ◽  
Margarita Topashka-Ancheva ◽  
Ivelina Tsacheva ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Leukemic Cell ◽  
The Novel ◽  
Histological Subtype ◽  
New Materials ◽  
Antitumor Effects ◽  
Cytotoxicity Assays ◽  
Leukemic Cell Lines

Two novel polyphosphoesters containing anthracene- and furan-derived aminophosphonate moieties, namely, poly[oxyethylene(aminophosphonate-co-H-phosphonate)]s P-12 and P-13, were synthesized through an addition of poly(oxyethylene H-phosphonate) to 9-anthrylidene-furfurylamine and characterized. The novel polyphosphoester P-12 and a series of previously described anthracene-derived compounds including Schiff bases S-1 and S-2, α-aminophosphonates A-3–A-6, bis-aminophosphonate B-6, two enantiomers A-5a and A-5b, and polyphosphoesters P-8–P-11 containing aminophosphonate units were screened for antitumor activity against a panel of human leukemic cell lines, using cisplatin as a reference cytotoxic agent. As concluded from the cytotoxicity assays, both precursors S-1 and S-2 presented similar cytotoxicity profiles that are cisplatin-like only in the REH cell line. Leader compound of the α-aminophosphonates is A-4 with cell death-inducing properties fully equaling those of the referent drug in all of the screened leukemic cell lines with the only exception being the AML histological subtype HL-60. Some of the polymeric analogues elicited moderate (P-10 and P-12) to low (P-11) cytotoxic activity, whereas the polyphosphoesters P-8 and P-9 produced in vitro antitumor effects largely surpassing cisplatin’s. The compounds P-8, P-9, and A-4 could be potential new materials for anticancer therapeutic purposed.

scholarly journals Greensporone A, a Fungal Secondary Metabolite Suppressed Constitutively Activated AKT via ROS Generation and Induced Apoptosis in Leukemic Cell Lines

Biomolecules ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 126 ◽  
Author(s):  
Kirti Prabhu ◽  
Kodappully Siveen ◽  
Shilpa Kuttikrishnan ◽  
Anh Jochebeth ◽  
Tayyiba Ali ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Leukemic Cell ◽  
Apoptotic Cell Death ◽  
Leukemic Cells ◽  
Leukemic Cell Lines ◽  
Fungal Secondary Metabolite

Greensporone A is a fungal secondary metabolite that has exhibited potential in vitro for anti-proliferative activity in vitro. We studied the anticancer activity of greensporone A in a panel of leukemic cell lines. Greensporone A-mediated inhibition of proliferation is found to be associated with the induction of apoptotic cell death. Greensporone A treatment of leukemic cells causes inactivation of constitutively activated AKT and its downstream targets, including members GSK3 and FOXO1, and causes downregulation of antiapoptotic genes such as Inhibitor of Apoptosis (IAPs) and Bcl-2. Furthermore, Bax, a proapoptotic member of the Bcl-2 family, was found to be upregulated in leukemic cell lines treated with greensporone A. Interestingly, gene silencing of AKT using AKT specific siRNA suppressed the expression of Bcl-2 with enhanced expression of Bax. Greensporone A-mediated increase in Bax/Bcl-2 ratio causes permeabilization of the mitochondrial membrane leading to the accumulation of cytochrome c in the cytoplasm. Greensporone A-induced cytochrome c accumulation causes the activation of caspase cascade and cleavage of its effector, poly(ADP-ribose) polymerase (PARP), leading to apoptosis. Greensporone A-mediated apoptosis in leukemic cells occurs through the generation of reactive oxygen species (ROS) due to depletion of glutathione (GSH) levels. Finally, greensporone A potentiated the anticancer activity of imatinib in leukemic cells. In summary, our study showed that greensporone A suppressed the growth of leukemic cells via induction of apoptotic cell death. The apoptotic cell death occurs by inhibition of AKT signaling and activation of the intrinsic apoptotic/caspase pathways. These results raise the possibility that greensporone A could be developed as a therapeutic agent for the treatment of leukemia and other hematological malignancies.

scholarly journals PARP Inhibition Sensitize BCR-ABL1 Positive Cel

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3367-3367 ◽  
Author(s):  
Haruka Hiroki ◽  
Masatoshi Takagi ◽  
Yuko Ishi ◽  
Jinhua Piao ◽  
Tomohiro Morio
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Parp Inhibitor ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Parp Inhibition ◽  
Akt Pathway ◽  
Leukemic Cell Lines

Introduction: BCR-ABL1 play a key role in the development of chronic myelogenous leukemia and a part of Ph1 positive acute lymphoblastic leukemia (ALL). BCR-ABL1 functions as a tyrosine kinase. Whereas, BCR-ABL1 induces genomic instability by downregulation of BRCA1. An innate error of BRCA1, a molecule involved in the homologous recombination repair pathway, causes hereditary breast and ovarian cancer. PARP inhibitor (PARPi) induces synthetic lethality in BRCA defective cell. Therefore, PARP inhibitor is expected to induce efficient cell death with BCR-ABL1 positive cell. In addition, in some previous reports, reduction of PARP1 activity leads to the upregulation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway and BCR-ABL1 tyrosine kinase activates PI3K/AKT pathway. These findings suggest activation of the PI3K/AKT pathway leading to PARPi resistance in BCR-ABL1 positive leukemic cells. Here, we demonstrate that PARP inhibition attenuates BCR-ABL1 mediated leukemogenesis and aberration of factors associated with PARP inhibitor resistance induces cell death to fully transformed leukemic cells. Method: Bone marrow-derived mononuclear cells (MNC) from wild type mice and BCR-ABL1 transgenic (Tg) mice were exposed to PARPi in vivo, and cell death was analyzed Annexin-V positivity. PARPi sensitivity to BCR-ABL1 expressed cell was also investigated in vivo bone marrow transplantation model using mouse hematopoietic stem cell (HCS) infected with BCR-ABL1 expressing retrovirus. To evaluate more precisely the results obtained in vitro and in vivo transplantation model, the genetical approach was also performed. The Parp1 knockout (KO) mice were crossed with BCR-ABL1 Tg mice. Then, Leukemia development and subsequent mouse death were observed. In vitro, HR activity was examined using DR-GFP assay. Genomic instability was investigated using the breakage-fusion-bridge (BFB) generation.Maintenance of HSC as a progenitor of the leukemic cell was analyzed by repopulation activity using colony assay. The growth-inhibitory effect was assessed using BCR-ABL positive cell lines with PARPi and PI3K inhibitor. Results: BCR-ABL1 Tg mice derived MNC showed more hypersensitivity to PARPi. Mouse HCS was infected with BCR-ABL1 expressing retrovirus and transplanted lethally Olaparib or vehicle was administrated intraperitoneal injection one day after transplantation. BCR-ABL1 mediated leukemic death was observed 1 month after transplantation in sham-treated mouse, whereas, Olaparib treated mouse did not develop BCR-ABL1 mediated leukemia. Parp1 KO BCR-ABL1 Tg mice attenuated leukemia development and extended their survival compared with BCR-ABL1 Tg mice. In vitro experiment revealed HR activity was down-regulated by BCR-ABL1 expression in DR-GFP assay. The number of BFB generation was increased in BCR-ABL1 Tg with Parp1 KO background. The colony-forming activity of BCR-ABL1 positive HSC was totally abolished by PARP inhibition after 3 times serial replating, whereas sham-treated HSC retained repopulation activity. However, the effect of PARPi on BCR-ABL positive leukemic cell lines was controversial. Therefore, leukemic cell lines were treated with the PARPi and inhibitors toward the molecules associated with PARPi resistance. As a result, a combination of PARPi with PI3K inhibitor effectively induce cell death in PARPi resistant BCR-ABL1 positive leukemic cell lines. Conclusion and discussion: Tyrosine kinase inhibitor (TKI) is the gold standard of the therapeutic option of BCR-ABL1 positive leukemia. However, TKI monotherapy is not sufficient for complete eradication of leukemic cells. It is highly expected that molecules effectively induce cell death to leukemic cells combined with TKI. PARPi would be one of these candidates. However, PARPi could not induces efficient death in all of the cancer cells that carry the mutation of molecules associated with the HR defect. Comprehensive genetic analysis to reveal PARPi resistance is important for HRR defective cancer cells. Combination therapy of PARPi and inhibitorstoward the molecules associated with PARPi resistance would be a good therapeutic option for Ph1 positive leukemia. Disclosures No relevant conflicts of interest to declare.

Repositioning of Difluorinated Propanediones as Inhibitors of Histone Methyltransferases and their Biological Evaluation in Human Leukemic Cell Lines

2019 ◽  
Vol 18 (13) ◽  
pp. 1892-1899 ◽  
Author(s):  
Tanushree Pal ◽  
Asmita Sharda ◽  
Bharat Khade ◽  
C. Sinha Ramaa ◽  
Sanjay Gupta
Keyword(s):  
Cell Lines ◽  
Physiological Role ◽  
Leukemic Cell ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Leukemic Cell Lines ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Subsequent Decrease

Background: At present, ‘pharmaco-epigenomics’ constitutes the hope in cancer treatment owing to epigenetic deregulation- a reversible process and playing a role in malignancy. Objective: Chemotherapy has many limitations like host-tissue toxicity, drug resistance. Hence, it is imperative to unearth targets to better treat cancer. Here, we intend to repurpose a set of our previously synthesized difluorinated Propanediones (PR) as Histone lysine Methyltransferase inhibitors (HMTi). Methods: The cell lines of leukemic origin viz. histiocytic lymphoma (U937) and acute T-cell leukemia (JURKAT) were treated with PR-1 to 7 after docking studies with active pocket of HMT. The cell cycle analysis, in vitro methylation and cell proliferation assays were carried out to delineate their physiological role. Results: A small molecule PR-4, at 1 and 10µM, has shown to alter the methylation of histone H3 and H4 in both cell lines. Also, treatment shows an increase in G2/M population and a subsequent decrease in the G0/G1 population in U937. In JURKAT, an increase in both G2/M and S phase population was observed. The sub-G1 population showed a steady rise with increase in dose and prolonged time intervals in U937 and JURKAT cell lines. In SRB assay, the PR showed a cell growth of 42.6 and 53.4% comparable to adriamycin; 44.5 and 53.2% in U937 and JURKAT, respectively. The study suggests that PR-4 could emerge as a potential HMT inhibitor. Conclusion: The molecule PR-4 could be a lead in developing more histone lysine methyltransferases inhibitors with potential to be pro-apoptotic agents.

Differential expression of a novel proline-rich homeobox gene (Prh) in human hematolymphopoietic cells

Blood ◽  
1995 ◽  
Vol 85 (5) ◽  
pp. 1237-1245 ◽  
Author(s):  
G Manfioletti ◽  
V Gattei ◽  
E Buratti ◽  
A Rustighi ◽  
A De Iuliis ◽  
...  
Keyword(s):  
Cell Lines ◽  
Constitutive Expression ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Maturation Stage ◽  
Lymphoid Tissues ◽  
Specific Cell ◽  
B Cell Differentiation ◽  
Leukemic Cell Lines

Proline-rich homeobox (Prh) is a novel human homeobox-containing gene recently isolated from the CD34+ cell line KG-1A, and whose expression appears mainly restricted to hematopoietic tissues. To define the pattern of Prh expression within the human hematopoietic system, we have analyzed its constitutive expression in purified cells obtained from normal hematopoietic tissues, its levels of transcription in a number of leukemia/lymphoma cell lines representing different lineages and stages of hematolymphopoietic differentiation, and its regulation during in vitro maturation of human leukemic cell lines. Prh transcripts were not detected in leukemic cells of T-lymphoid lineage, irrespective of their maturation stage, and in resting or activated normal T cells from peripheral blood and lymphoid tissues. In contrast, high levels of Prh expression were shown in cells representing early stages of B lymphoid maturation, being maintained up to the level of circulating and tissue mature B cells. Terminal B-cell differentiation appeared to be conversely associated with the deactivation of the gene, since preplasmacytic and plasmocytoma cell lines were found not to express Prh mRNA. Prh transcripts were also shown in human cell lines of early myelomonocytic, erythromegakaryocytic, and preosteoclast phenotypes. Prh expression was lost upon in vitro differentiation of leukemic cell lines into mature monocyte-macrophages and megakaryocytes, whereas it was maintained or upregulated after induction of maturation to granulocytes and osteoclasts. Accordingly, circulating normal monocytes did not display Prh mRNA, which was conversely detected at high levels in purified normal granulocytes. Our data, which show that the acquisition of the differentiated phenotype is associated to Prh downregulation in certain hematopoietic cells but not in others, also suggest that a dysregulated expression of this gene might contribute to the process of leukemogenesis within specific cell lineages.

scholarly journals Akacid Medical Formulation Induces Apoptosis in Myeloid and Lymphatic Leukemic Cell Lines In Vitro and In Vivo

PLoS ONE ◽  
2015 ◽  
Vol 10 (2) ◽  
pp. e0117806 ◽  
Author(s):  
Hannes Neuwirt ◽  
Elisabeth Wabnig ◽  
Clemens Feistritzer ◽  
Iris E. Eder ◽  
Christina Salvador ◽  
...  
Keyword(s):  
Cell Lines ◽  
Leukemic Cell ◽  
Leukemic Cell Lines

Bioproduct obtained from probiotic microorganisms consortia-studies regarding the effects generated in vitro on two types of leukemic cell lines

2017 ◽  
Vol 655 (1) ◽  
pp. 275-286
Author(s):  
Nicoleta Radu ◽  
Viviana Roman ◽  
Marinela Bostan ◽  
Mariana Voicescu ◽  
Ciprian Tanasescu
Keyword(s):  
Cell Lines ◽  
Leukemic Cell ◽  
Leukemic Cell Lines

Cannabis-induced cytotoxicity in leukemic cell lines: the role of the cannabinoid receptors and the MAPK pathway

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1214-1221 ◽  
Author(s):  
Thomas Powles ◽  
Robert te Poele ◽  
Jonathan Shamash ◽  
Tracy Chaplin ◽  
David Propper ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cell Death ◽  
Cell Lines ◽  
Leukemic Cell ◽  
Cytotoxic Agents ◽  
Complex Signal ◽  
Signal Transduction Pathways ◽  
Potent Inducer ◽  
Leukemic Cell Lines

Abstract Δ9-Tetrahydrocannabinol (THC) is the active metabolite of cannabis. THC causes cell death in vitro through the activation of complex signal transduction pathways. However, the role that the cannabinoid 1 and 2 receptors (CB1-R and CB2-R) play in this process is less clear. We therefore investigated the role of the CB-Rs in mediating apoptosis in 3 leukemic cell lines and performed microarray and immunoblot analyses to establish further the mechanism of cell death. We developed a novel flow cytometric technique of measuring the expression of functional receptors and used combinations of selective CB1-R and CB2-R antagonists and agonists to determine their individual roles in this process. We have shown that THC is a potent inducer of apoptosis, even at 1 × IC50 (inhibitory concentration 50%) concentrations and as early as 6 hours after exposure to the drug. These effects were seen in leukemic cell lines (CEM, HEL-92, and HL60) as well as in peripheral blood mononuclear cells. Additionally, THC did not appear to act synergistically with cytotoxic agents such as cisplatin. One of the most intriguing findings was that THC-induced cell death was preceded by significant changes in the expression of genes involved in the mitogen-activated protein kinase (MAPK) signal transduction pathways. Both apoptosis and gene expression changes were altered independent of p53 and the CB-Rs.

Induction of apoptotic cell death by direct-current treatment in human leukemic cell lines

1997 ◽  
Vol 123 (7) ◽  
pp. 370-376 ◽  
Author(s):  
Masatsugu Kurokawa ◽  
Hiroshi Sakagami ◽  
Fumio Kokubu ◽  
Hiromichi Noda ◽  
Minoru Takeda ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Direct Current ◽  
Apoptotic Cell ◽  
Leukemic Cell ◽  
Current Treatment ◽  
Apoptotic Cell Death ◽  
Human Leukemic Cell ◽  
Leukemic Cell Lines

Pioglitazone Inhibits the Growth of Human Leukemic Cell Lines and Primary Leukemic Cells in Vitro.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4493-4493 ◽  
Author(s):  
Yoshihiro Hatta ◽  
Minoru Saiki ◽  
Yuko Enomoto ◽  
Shin Aizawa ◽  
Umihiko Sawada ◽  
...  
Keyword(s):  
Cell Lines ◽  
Colony Formation ◽  
Mononuclear Cells ◽  
Hematopoietic Cells ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Peroxisome Proliferator ◽  
Leukemic Cell Lines ◽  
Ppar Γ

Abstract Troglitazone and pioglitazone are one of thiazolidinediones that are high affinity ligand for the nuclear receptor called peroxisome proliferator-activated receptor gamma (PPAR-γ). Troglitazone is a potent inhibitor of clonogenic growth of acute myeloid leukemia cells when combined with a retinoid. However, the effect of pioglitazone to neoplastic cells and normal hematopoietic cells has not been studied yet. Adult T-cell leukemia (ATL), prevalent in western Japan, is a highly aggressive malignancy of mature T lymphocyte. Therefore, we studied antitumor effect of pioglitazone against leukemic cells including ATL as well as normal hematopoietic cells. With 300 μM of pioglitazone, colony formation of ATL cell lines (MT1, MT2, F6T, OKM3T, and Su9T01) was completely inhibited. Colony formation of HUT102, another ATL cell line, was 12 % compared to untreated control. Clonogenic cells of other leukemic cell lines (K562, HL60, U937, HEL, CEM, and NALM1) was also inhibited to 0–30% of control. Colony formation of primary leukemic cells from 5 AML patients was decreased to 15 %. However, normal hematopoietic cells were weakly inhibited with 300 μM pioglitazone; 77 % of CFU-GM, 70 % of CFU-E, and 33 % of BFU-E survived. Cell cycle analysis showed that pioglitazone decreased the ratio of G2/M phase in HL60 cells, suggesting the inhibition of cell division. By Western blotting, PPAR-γ protein level was similar in all leukemic cells and normal bone marrow mononuclear cells. Taken together, pioglitazone effectively eliminate leukemic cells and could be used as an antitumor agent in vivo.

ARRY-429520, a Novel KSP Inhibitor with Potent Anti-Proliferative Activity in Leukemic Cell Lines.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4401-4401 ◽  
Author(s):  
Christine Lemieux ◽  
Walt DeWolf ◽  
Walt Voegtli ◽  
Eli Wallace ◽  
Rich Woessner ◽  
...  
Keyword(s):  
Cell Lines ◽  
Human Tumor ◽  
Leukemic Cell ◽  
Proliferating Cells ◽  
Single Digit ◽  
Leukemic Cell Lines ◽  
Microtubule Disruption ◽  
In Vitro Characterization ◽  
Ksp Inhibitor

Abstract Kinesins are eukaryotic microtubule-associated motor proteins. There are over 40 known kinesins, approximately 15 of which are closely associated with mitosis. Kinesin Spindle Protein (KSP), also known as Eg5, is a mitotic kinesin that is a required enzyme in mitosis (prophase / prometaphase). This protein plays a key role in the formation of the bipolar spindle, particularly related to its role in centrosome maturation/separation. Because KSP is expressed predominately in proliferating cells and is absent from postmitotic neurons, its inhibition should not produce the peripheral neuropathy associated with traditional microtubule disruption agents (taxanes and vinca alkaloids). We report here the in vitro characterization of a potent KSP inhibitor, ARRY-429520, a member of a series of KSP inhibitors discovered and optimized by structure-based design. ARRY-429520 inhibits human KSP, with an IC50 of 6 nM, by a mechanism which was demonstrated to be uncompetitive with respect to ATP and noncompetitive with respect to tubulin. It was shown to arrest cells in mitosis as measured by FACs analysis as well as the accumulation of phospho- histone H3, with an EC50 of 1.5 nM. Furthermore, this compound was demonstrated to be antiproliferative, with EC50s between 0.3 nM and 6.5 nM against a panel of human tumor cell lines, including various leukemia lines (K-562, KU-812, HL-60, KG-1, MOLT3, MOLT4). In addition, ARRY-429520’s potency in MDR-overexpressing cell lines was minimally impacted as compared to paclitaxel. Cellular imaging studies demonstrate that the normal mitotic spindle configuration was disrupted, with the formation of monopolar spindles, a hallmark feature of KSP inhibition, at single digit nanomolar concentrations of ARRY-429520. Markers of mitotic arrest and apoptosis were demonstrated in tumor xenografts from animals treated with ARRY-429520.

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