Col-6, a Compound Found in Edible Plants, Induces Apoptosis of Human Leukemia Cells and Down-Regulate Bcl-2 Expression.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4380-4380
Author(s):  
Xudong Ma ◽  
A. Beklemisheva ◽  
Delong Liu ◽  
J.W. Chiao
Keyword(s):  
Mononuclear Cells ◽  
Leukemic Cell ◽  
G1 Arrest ◽  
Human Leukemia ◽  
Edible Plants ◽  
Proliferating Cells ◽  
Normal Peripheral Blood ◽  
High Concentrations ◽  
Induced Apoptosis

Abstract Col-6 is a compound found in certain edible plants. Col-6 has been synthesized, and structurely-characterized. This study investigated its effects on the growth of human promyelocytic leukemic cell line, HL-60. Exposure of HL-60 cells to Col-6 at high concentrations (≥40 μM) resulted in cytolysis in 90% cells within 72 hours. At lower concentrations (<20 μM) the cell density and viability were reduced as compared to untreated cells. A 30% reduction in cell growth rate was seen at 10 μM within 48 hours. A reduction of the proliferating cells in S and G2M phases along with an increase of G1 were detected, indicating a G1 arrest. Multiple assays were used to characterize apoptosis, including DNA strand breaks by TUNEL assay, and the presence of sub-G1 peak by flow cytometry. Col-6 induced apoptosis of HL-60 cells regularly at a concentration as low as 0.1 μM. The degree of apoptosis was proportional to the concentrations and the length of exposure. Mononuclear cells isolated from normal peripheral blood (PBMC) and bone marrow (BMMC) were similarly exposed to Col-6. At a concentration as high as 40 μM, Col-6 did not cause apoptosis of PBMC nor BMMC, suggesting that Col-6 does not have the apoptotic effects on normal non-dividing cells. Apoptosis was further correlated with the increase of caspase 9, and the cleavage of PARP (substrate of caspases), as defined by Western blot analyses. The expression of bcl-2 was markedly decreased in the treated cells. Conclusion: Col-6, a compound found in edible plants, induced apoptosis of HL-60 cells and down-regulation of bcl-2. Col-6 may be a potential novel anti-leukemia agent. Further in vivo study is indicated.

scholarly journals Discovery of vanoxerine dihydrochloride as a CDK2/4/6 triple-inhibitor for the treatment of human hepatocellular carcinoma

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Ying Zhu ◽  
Kun-Bin Ke ◽  
Zhong-Kun Xia ◽  
Hong-Jian Li ◽  
Rong Su ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle Progression ◽  
G1 Arrest ◽  
Huh7 Cells ◽  
Synergistic Cytotoxicity ◽  
Combination Study ◽  
Experimental Approaches ◽  
Induced Apoptosis

Abstract Background Cyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC). Methods We used the combination of computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC. Results We identified vanoxerine dihydrochloride as a new CDK2/4/6 inhibitor, and a strong cytotoxicdrugin human HCC QGY7703 and Huh7 cells (IC50: 3.79 μM for QGY7703and 4.04 μM for Huh7 cells). In QGY7703 and Huh7 cells, vanoxerine dihydrochloride treatment caused G1-arrest, induced apoptosis, and reduced the expressions of CDK2/4/6, cyclin D/E, retinoblastoma protein (Rb), as well as the phosphorylation of CDK2/4/6 and Rb. Drug combination study indicated that vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in vitro in Huh7 cells. Finally, in vivo study in BALB/C nude mice subcutaneously xenografted with Huh7 cells, vanoxerine dihydrochloride (40 mg/kg, i.p.) injection for 21 days produced significant anti-tumor activity (p < 0.05), which was comparable to that achieved by 5-Fu (10 mg/kg, i.p.), with the combination treatment resulted in synergistic effect. Immunohistochemistry staining of the tumor tissues also revealed significantly reduced expressions of Rb and CDK2/4/6in vanoxerinedihydrochloride treatment group. Conclusions The present study isthe first report identifying a new CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrated that this drug represents a novel therapeutic strategy for HCC treatment.

A Novel Peptide Derived from Ginger Induces Apoptosis through the Modulation of p53, BAX, and BCL2 Expression in Leukemic Cell Lines

Planta Medica ◽  
2021 ◽  
Author(s):  
Chawalit Chatupheeraphat ◽  
Sittiruk Roytrakul ◽  
Narumon Phaonakrop ◽  
Kamolchanok Deesrisak ◽  
Sucheewin Krobthong ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cell Lines ◽  
Mononuclear Cells ◽  
Raji Cell ◽  
Leukemic Cell ◽  
B Cell Lymphoma ◽  
Leukemic Cells ◽  
Peripheral Blood Mononuclear ◽  
Normal Peripheral Blood ◽  
Peptide Fraction

AbstractDespite the efficacy of chemotherapy, the adverse effects of chemotherapeutic drugs are considered a limitation of leukemia treatment. Therefore, a chemotherapy drug with minimal side effects is currently needed. One interesting molecule for this purpose is a bioactive peptide isolated from plants since it has less toxicity to normal cells. In this study, we extracted protein from the Zingiber officinale rhizome and performed purification to acquire the peptide fraction with the highest cytotoxicity using ultrafiltration, reverse-phase chromatography, and off-gel fractionation to get the peptide fraction that contained the highest cytotoxicity. Finally, a novel antileukemic peptide, P2 (sequence: RALGWSCL), was identified from the highest cytotoxicity fraction. The P2 peptide reduced the cell viability of NB4, MOLT4, and Raji cell lines without an effect on the normal peripheral blood mononuclear cells. The combination of P2 and daunorubicin significantly decreased leukemic cell viability when compared to treatment with either P2 or daunorubicin alone. In addition, leukemic cells treated with P2 demonstrated increased apoptosis and upregulation of caspase 3, 8, and 9 gene expression. Moreover, we also examined the effects of P2 on p53, which is the key regulator of apoptosis. Our results showed that treatment of leukemic cells with P2 led to the upregulation of p53 and Bcl-2-associated X protein, and the downregulation of B-cell lymphoma 2, indicating that p53 is involved in apoptosis induction by P2. The results of this study are anticipated to be useful for the development of P2 as an alternative drug for the treatment of leukemia.

scholarly journals Molecular profiling of LGL leukemia reveals role of sphingolipid signaling in survival of cytotoxic lymphocytes

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 770-781 ◽  
Author(s):  
Mithun Vinod Shah ◽  
Ranran Zhang ◽  
Rosalyn Irby ◽  
Ravi Kothapalli ◽  
Xin Liu ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Gene Expression Signature ◽  
Effector Memory ◽  
Cytotoxic Lymphocytes ◽  
Peripheral Blood Mononuclear ◽  
Term Survival ◽  
Memory Cytotoxic T Lymphocytes ◽  
Induced Apoptosis ◽  
Lgl Leukemia

Abstract T-cell large granular lymphocyte (LGL) leukemia is characterized by clonal expansion of CD3+CD8+ cells. Leukemic LGLs correspond to terminally differentiated effector-memory cytotoxic T lymphocytes (CTLs) that escape Fas-mediated activation-induced cell death (AICD) in vivo. The gene expression signature of peripheral blood mononuclear cells from 30 LGL leukemia patients showed profound dysregulation of expression of apoptotic genes and suggested uncoupling of activation and apoptotic pathways as a mechanism for failure of AICD in leukemic LGLs. Pathway-based microarray analysis indicated that balance of proapoptotic and antiapoptotic sphingolipid-mediated signaling was deregulated in leukemic LGLs. We further investigated sphingolipid pathways and found that acid ceramidase was constitutively overexpressed in leukemic LGLs and that its inhibition induced apoptosis of leukemic LGLs. We also showed that S1P5 is the predominant S1P receptor in leukemic LGLs, whereas S1P1 is down-regulated. FTY720, a functional antagonist of S1P-mediated signaling, induced apoptosis in leukemic LGLs and also sensitized leukemic LGLs to Fas-mediated death. Collectively, these results show a role for sphingolipid-mediated signaling as a mechanism for long-term survival of CTLs. Therapeutic targeting of this pathway, such as use of FTY720, may have efficacy in LGL leukemia.

Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 3138-3147 ◽  
Author(s):  
Thomas Strömberg ◽  
Anna Dimberg ◽  
Anna Hammarberg ◽  
Kristina Carlson ◽  
Anders Österborg ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Intracellular Signaling ◽  
Kinase Inhibitor ◽  
Mammalian Target Of Rapamycin ◽  
G1 Arrest ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Induced Apoptosis ◽  
Molecular Mode

Abstract Circumvention of chemoresistance in the B-cell neoplasm multiple myeloma (MM) might be achieved by targeting certain intracellular signaling pathways crucial for survival of the malignant clone. The use of the macrolide rapamycin, selectively inhibiting the phosphoprotein mammalian target of rapamycin (mTOR) downstream of, for example, insulin-like growth factor-I receptor (IGF-IR), possibly represents such a molecular mode of therapy. By using a panel of MM cell lines we showed that rapamycin induced G0/G1 arrest, an effect being associated with an increase of the cyclin-dependent kinase inhibitor p27 and a decrease of cyclins D2 and D3. Interestingly, in primary, mainly noncycling MM cells, rapamycin, at clinically achievable concentrations, induced apoptosis. More important, rapamycin sensitized both MM cell lines and primary MM cells to dexamethasone-induced apoptosis. This effect was associated with a decreased expression of cyclin D2 and survivin. The phosphorylation of the serine/threonine kinase p70S6K at Thr389 and Thr421/Ser424 was down-regulated by rapamycin and/or dexamethasone. Strikingly, the combinatorial treatment with rapamycin and dexamethasone suppressed the antiapoptotic effects of exogenously added IGF-I and interleukin 6 (IL-6) as well as their stimulation of p70S6K phosphorylation. The induction of apoptosis by rapamycin and dexamethasone despite the presence of survival factors was also demonstrated in primary MM cells, thus suggesting this drug combination to be active also in vivo. (Blood. 2004;103:3138-3147)

scholarly journals OX40 Expressed on Fresh Leukemic Cells From Adult T-Cell Leukemia Patients Mediates Cell Adhesion to Vascular Endothelial Cells: Implication for the Possible Involvement of OX40 in Leukemic Cell Infiltration

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2951-2958 ◽  
Author(s):  
Akihiro Imura ◽  
Toshiyuki Hori ◽  
Kazunori Imada ◽  
Shin Kawamata ◽  
Yuetsu Tanaka ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
Mononuclear Cells ◽  
Vascular Endothelial Cells ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia

Abstract We demonstrated previously that OX40 and its ligand, gp34, directly mediate adhesion of activated normal CD4+ T cells, as well as human T-cell leukemia virus type I (HTLV-I)–transformed T cells to vascular endothelial cells. In the present study, we examined expression of OX40 on fresh leukemic cells from patients with adult T-cell leukemia (ATL) and its possible involvement in cell adhesion. Flow cytometric analysis showed that peripheral blood mononuclear cells (PBMC) or lymph node tumor cells from 15 of 17 cases expressed significant levels of OX40 without stimulation. On the other hand, gp34 was not expressed on these cells, although its expression is also known to be associated with HTLV-I-infection. In Western blot analysis, a 50-kD protein band was detected by anti-OX40 monoclonal antibody (MoAb) in two ATL cases examined, as well as phytohemagglutinin (PHA) blasts and Hut102, an HTLV-I–infected T-cell line, but not in resting PBMC or Jurkat. Expression of OX40 mRNA was shown by reverse transcriptase-polymerase chain reaction in all ATL cases tested, PHA-blasts, and Hut102, but not in resting PBMC or Jurkat. We could not detect expression of HTLV-I viral mRNA in any of the cases tested. Cell adhesion assay was performed and in at least three cases, fresh ATL cells exhibited adhesion to human umbilical vein endothelial cells that could be considerably inhibited by either anti-OX40 MoAb or anti-gp34 MoAb. Immunohistochemical staining of skin biopsy specimens indicated that infiltrating mononuclear cells express OX40 in vivo. Taken together, these data indicate that leukemic cells from most, but not all, ATL patients constitutively express OX40, which may play a role in leukemic cell infiltration in addition to cell adhesion in vivo.

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.

MTOR Inhibitors Activate the AKT Kinase in Multiple Myeloma Cells by Upregulating the IGF-1/IRS-1/PI-3 Kinase Cascade.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3350-3350 ◽  
Author(s):  
Yijiang Shi ◽  
HuaJun Yan ◽  
Patrick Frost ◽  
Bao Hoang ◽  
Joseph Gera ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Xenograft Model ◽  
Mtor Inhibitors ◽  
Pi3 Kinase ◽  
Serine Phosphorylation ◽  
G1 Arrest ◽  
Akt Activation ◽  
Induced Apoptosis

Abstract MTOR inhibitors, such as rapamycin and CCI-779, have shown pre-clinical potential as therapy for multiple myeloma (MM). By inhibiting expression of cell cycle proteins, these agents induce G1 arrest. However, by also inhibiting an mTOR-dependent phosphorylation of insulin receptor substrate-1 (IRS-1), they may alter its subcellular localization and/or prevent its degradation which could enhance IGF-1 signaling and downstream PI3-kinase/AKT activation. This may be a particular problem in MM where IGF-1-induced activation of AKT is an important anti-apoptotic cascade. We, thus, studied PI3-kinase/AKT activation in MM cells treated with mTOR inhibitors. Rapamycin enhanced basal AKT activity, AKT phosphorylation and PI3-kinase activity in MM cell lines. Both PTEN-null as well as PTEN-wild type myeloma lines were similarly affected. Rapamycin also significantly prolonged activation of AKT induced by exogenous IGF-1. CCI-779, used in a xenograft model, also resulted in MM cell AKT activation in vivo. Blockade of IGF-1 receptor function prevented rapamycin’s activation of AKT. Furthermore, rapamycin prevented serine phosphorylation of IRS-1 and IRS-1 degradation. Though similarly blocking IRS-1 degradation, proteasome inhibitors did not activate MM cell AKT. Although rapamycin sensitized MM cells for dexamethasone-induced apoptosis, it protected against PS-341-induced apoptosis. Thus, mTOR inhibitors activate PI3-K/AKT in MM cells and activation depends on basal IGF-1/IGF-R signaling. As activated AKT may protect against apoptosis, future use of mTOR inhibitors in myeloma patients will have to carefully consider the types of anti-myeloma agents used in combination.

Inhibition of Bortezomib-Induced Apoptosis in Chronic Lymphocytic Leukemia by Red Blood Cell Uptake.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5027-5027
Author(s):  
Luise M.C. Wheat ◽  
Susan L. Kohlhaas ◽  
Johan Monbaliu ◽  
Roland De Coster ◽  
Aneela Majid ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Whole Blood ◽  
Mononuclear Cells ◽  
Lymphocytic Leukemia ◽  
Cell Uptake ◽  
Reversible Inhibitor ◽  
Apoptotic Pathway ◽  
Mutational Status ◽  
Induced Apoptosis

Abstract Bortezomib (PS-341/Velcade™) is a reversible inhibitor of the proteasome that has shown promising activity in clinical trials in several malignancies including multiple myeloma, mantle cell lymphoma and follicular lymphoma, including those with refractory disease. However, results have been less encouraging in chronic lymphocytic leukemia (CLL) and we have, therefore, sought to determine the barriers to effective therapy with bortezomib in this disease. Patients with CLL were eligible but were required to have received no therapy in the six months prior to the study. In a panel of 26 patients with CLL, both purified mononuclear cells and whole blood were tested for their apoptotic response to bortezomib (1–100 nM) up to 24 h by flow cytometry and western blotting. In all cases, purified CLL cells were sensitive to bortezomib-induced apoptosis in a concentration and time-dependent fashion, irrespective of stage of disease, resistance to prior therapy, IGHV mutational status or the presence of TP53 mutations. Apoptosis was induced at low (&gt;10 nM) nanomolar concentrations of bortezomib by activation of the intrinsic apoptotic pathway. Bortezomib-induced apoptosis correlated with levels of ubiquitination, Bax activation, and caspase cleavage. Apoptosis of CLL cells was obtained at drug levels readily obtained in vivo using currently-used dosing protocols. However, in vitro, it was necessary to maintain these concentrations for 16–24 hours to obtain maximal apoptosis. Apoptosis measured in a whole blood apoptosis assay was markedly less than in isolated lymphocytes at comparable time points and concentrations. Activity of bortezomib in purified cells was not diminished by addition of exogenous plasma but was abrogated by addition of autologous red blood cells (RBC), suggesting preferential active uptake of the drug by these cells. These data were confirmed in animal models showing preferential distribution of bortezomib to the RBC fraction. RBC uptake may therefore account for the low serum levels of bortezomib attained in vivo during terminal half-life and thus the lack of activity against cells in the peripheral blood. Together with pharmacokinetic and in vivo data, these studies suggest that different dosing schedules of bortezomib other than bolus injections may be more effective in patients with CLL.

scholarly journals Preclinical Antileukemia Activity of Tramesan: A Newly Identified Bioactive Fungal Metabolite

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
M. R. Ricciardi ◽  
R. Licchetta ◽  
S. Mirabilii ◽  
M. Scarpari ◽  
A. Parroni ◽  
...  
Keyword(s):  
Cell Lines ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Leukemic Cell ◽  
Bioactive Compound ◽  
Primary Cells ◽  
Peripheral Blood Mononuclear ◽  
Normal Peripheral Blood ◽  
Leukemic Cell Lines

Despite improvements that occurred in the last decades in the acute myeloid leukemia (AML) treatment, clinical results are still unsatisfactory. More effective therapies are required, and innovative approaches are ongoing, including the discovery of novel antileukemia natural compounds. Several studies have described the activity of extracts from mushrooms which produce compounds that exhibited immunological and antitumor activities. The latter has been demonstrated to be promoted in vitro by mushroom polysaccharides via induction of apoptosis. However, the antileukemia activity of these compounds on primary cells is still not reported. In the present study, we examined the in vitro effects of Tramesan (TR), a bioactive compound extracted from Trametes versicolor, on leukemic cell lines and primary cells. Our results demonstrated that TR induced a marked growth inhibition of leukemic cell lines and primary cells from AML patients. The antiproliferative effects of TR were associated in primary AML cells with a significant increase of apoptosis. No significant cytotoxic effects were observed in normal peripheral blood mononuclear cells (MNC) from healthy donors. Our data demonstrated a cytotoxic activity of TR on leukemia cells prompting further translational applications. Ongoing studies are elucidating the molecular mechanisms underlying its antileukemic activity.

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