Flavopiridol Induces Apoptosis in Chronic Lymphocytic Leukemia Cells Via Activation of Caspase-3 Without Evidence of bcl-2 Modulation or Dependence on Functional p53

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3804-3816 ◽  
Author(s):  
John C. Byrd ◽  
Charlotte Shinn ◽  
Jamie K. Waselenko ◽  
Ephraim J. Fuchs ◽  
Teresa A. Lehman ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cell Lines ◽  
Caspase 3 ◽  
Mononuclear Cells ◽  
P53 Protein ◽  
Lymphocytic Leukemia ◽  
Vitro Activity ◽  
Interleukin 4 ◽  
In Vitro Activity

Abstract Flavopiridol has been reported to induce apoptosis in lymphoid cell lines via downregulation of bcl-2. The in vitro activity of flavopiridol against human chronic lymphocytic leukemia (CLL) cells and potential mechanisms of action for inducing cytotoxicity were studied. The in vitro viability of mononuclear cells from CLL patients (n = 11) was reduced by 50% at 4 hours, 24 hours, and 4 days at a flavopiridol concentration of 1.15 μmol/L (95% confidence interval [CI] ±0.31), 0.18 μmol/L (95% CI ±0.04), and 0.16 μmol/L (95% CI ±0.04), respectively. Loss of viability in human CLL cells correlated with early induction of apoptosis. Exposure of CLL cells to 0.18 μmol/L of flavopiridol resulted in both decreased expression of p53 protein and cleavage of the caspase-3 zymogen 32-kD protein with the appearance of its 20-kD subunit. Contrasting observations of others in tumor cell lines, flavopiridol cytotoxicity in CLL cells did not correlate with changes in bcl-2 protein expression alterations. We evaluated flavopiridol’s dependence on intact p53 by exposing splenocytes from wild-type (p53+/+) and p53 null (p53−/−) mice that demonstrated no preferential cytotoxicity as compared with a marked differential with F-ara-a and radiation. Incubation of CLL cells with antiapoptotic cytokine interleukin-4 (IL-4) did not alter the LC50 of flavopiridol, as compared with a marked elevation noted with F-ara-a in the majority of patients tested. These data demonstrate that flavopiridol has significant in vitro activity against human CLL cells through activation of caspase-3, which appears to occur independently of bcl-2 modulation, the presence of IL-4, or p53 status. Such findings strongly support the early introduction of flavopiridol into clinical trials for patients with B-CLL.

Flavopiridol Induces Apoptosis in Chronic Lymphocytic Leukemia Cells Via Activation of Caspase-3 Without Evidence of bcl-2 Modulation or Dependence on Functional p53

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3804-3816 ◽  
Author(s):  
John C. Byrd ◽  
Charlotte Shinn ◽  
Jamie K. Waselenko ◽  
Ephraim J. Fuchs ◽  
Teresa A. Lehman ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cell Lines ◽  
Caspase 3 ◽  
Mononuclear Cells ◽  
P53 Protein ◽  
Lymphocytic Leukemia ◽  
Vitro Activity ◽  
Interleukin 4 ◽  
In Vitro Activity

Flavopiridol has been reported to induce apoptosis in lymphoid cell lines via downregulation of bcl-2. The in vitro activity of flavopiridol against human chronic lymphocytic leukemia (CLL) cells and potential mechanisms of action for inducing cytotoxicity were studied. The in vitro viability of mononuclear cells from CLL patients (n = 11) was reduced by 50% at 4 hours, 24 hours, and 4 days at a flavopiridol concentration of 1.15 μmol/L (95% confidence interval [CI] ±0.31), 0.18 μmol/L (95% CI ±0.04), and 0.16 μmol/L (95% CI ±0.04), respectively. Loss of viability in human CLL cells correlated with early induction of apoptosis. Exposure of CLL cells to 0.18 μmol/L of flavopiridol resulted in both decreased expression of p53 protein and cleavage of the caspase-3 zymogen 32-kD protein with the appearance of its 20-kD subunit. Contrasting observations of others in tumor cell lines, flavopiridol cytotoxicity in CLL cells did not correlate with changes in bcl-2 protein expression alterations. We evaluated flavopiridol’s dependence on intact p53 by exposing splenocytes from wild-type (p53+/+) and p53 null (p53−/−) mice that demonstrated no preferential cytotoxicity as compared with a marked differential with F-ara-a and radiation. Incubation of CLL cells with antiapoptotic cytokine interleukin-4 (IL-4) did not alter the LC50 of flavopiridol, as compared with a marked elevation noted with F-ara-a in the majority of patients tested. These data demonstrate that flavopiridol has significant in vitro activity against human CLL cells through activation of caspase-3, which appears to occur independently of bcl-2 modulation, the presence of IL-4, or p53 status. Such findings strongly support the early introduction of flavopiridol into clinical trials for patients with B-CLL.

The Hsp90 Inhibitor SNX7081 Restores the Fludarabine Sensitivity of Chronic Lymphocytic Leukemia (CLL) Cells Harbouring Mutations of ATM or TP53

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2473-2473
Author(s):  
O. Giles Best ◽  
Stephen P Mulligan
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cell Lines ◽  
Caspase 3 ◽  
Mononuclear Cells ◽  
Single Agent ◽  
Treatment Strategies ◽  
Lymphocytic Leukemia ◽  
Functional Assay ◽  
Simultaneous Exposure

Abstract Abstract 2473 Introduction: Resistance to fludarabine-based treatment represents a challenge in the clinical management of Chronic Lymphocytic Leukemia (CLL). Despite the unprecedented response rates seen with the fludarabine (F), cyclophosphamide (C), Rituximab (R) regimen novel treatment strategies are required that do not rely on an intact p53 signaling pathway. We recently described the activity of a novel, synthetic inhibitor of the molecular chaperone, heat-shock protein 90 (Hsp90) named SNX7081 (Serenex, now Pfizer) against CLL cells in vitro (Best et al., 2010 BJH). Here we explored the effect of this inhibitor on the fludarabine sensitivity of 3 haematological cell lines and 12 patient samples with mutations of ATM or TP53. Methods: Mononuclear cells were isolated by density centrifugation from CLL patients following informed consent. The 13 patient samples selected for study were determined to have mutations of either ATM or TP53 using a functional assay described in detail elsewhere (Best et al., 2008). The Mec1 (CLL), Mec2 (CLL) and U266 (B-ALL) cell lines were maintained under standard conditions in RPMI-1640 with 2mM L-glut and 1% pen/strep. Sensitivity to fludarabine, with and without SNX7081, was assessed using the MTT (3–4, 5-dimethylthiazol-2,5-diphenyl tetrazolium bromide) assay. Synergy between the agents, activation of caspase-3 and the induction of double stranded DNA (dsDNA) breaks following treatment were all assessed by flow cytometry using the mitochondrial membrane potential dye DilC1 (5) and propidium iodide (PI) or appropriate antibodies. Results: The IC50 for fludarabine was significantly higher in the 3 cell lines and 13 patient samples with ATM/TP53 lesions than in 4 cell lines or 10 patient samples defined as ATM/TP53 wild-type. Simultaneous exposure to a combination of fludarabine and SNX7081 at a ratio based on the IC50 of the compounds as single agent significantly reduced the IC50 for fludarabine (P<0.01); in 11 patient samples the IC50 for fludarabine was reduced to within a clinically achievable range (<5μM). Synergy between fludarabine and SNX7081 was evident as an effect on the distribution of the cell lines in the cell cycle and as a marked effect on the proportion of apoptotic cells (DilC (1)5 negative/PI negative) in cultures of both the cell lines and patient samples. Furthermore, we show that the combination of the compounds has a greater than additive effect on the activation of caspase-3 and on the formation of dsDNA breaks, as evidenced by the phosphorylation of g-H2Ax. Conclusions: Our studies suggest that inhibition of Hsp90 may overcome fludarabine resistance conferred by mutations of ATM or TP53. The mechanism of the synergy between these compounds appears to be via augmentation of fludarabine-induced dsDNA breaks and is concomitant with an increase in caspase-3 signaling. The data suggest that this combination may represent a promising regimen in the treatment of fludarabine-refractory CLL. Disclosures: Mulligan: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Schering, now Genzyme: Honoraria.

KRN5500: a novel therapeutic agent with in vitro activity against human B-cell chronic lymphocytic leukemia cells mediates cytotoxicity via the intrinsic pathway of apoptosis

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4547-4550 ◽  
Author(s):  
John C. Byrd ◽  
David M. Lucas ◽  
Andrew P. Mone ◽  
Joshua B. Kitner ◽  
Joseph J. Drabick ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mononuclear Cells ◽  
Lymphocytic Leukemia ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Effector Caspase ◽  
Sensitivity Pattern ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Therapy of B-cell chronic lymphocytic leukemia (CLL) is currently palliative, emphasizing the need for identification of new therapies for this disease. KRN5500 is a novel agent that has a unique sensitivity pattern in the National Cancer Institute cell line screening panel, suggesting a unique mechanism of action. To assess its in vitro activity in CLL, we exposed peripheral mononuclear cells from CLL patients (n = 11) to varying concentrations of this agent. Viability of the CLL cells was reduced by 50% (LC50) at 4 hours, 24 hours, and 4 days at KRN5500 concentrations of 2.50 μM, 0.276 μM, and 0.139 μM, respectively. KRN5500 induced cellular injury via caspase-dependent apoptosis involving the intrinsic mitochondrial (caspase-9) initiating caspase and caspase-3 effector caspase; however, expression of the antiapoptotic mitochondrial membrane protein Bcl-2 was unaffected. These data demonstrate KRN5500 has significant in vitro activity against human CLL cells, thus providing support for introduction of this agent into clinical trials for patients with CLL.

Depsipeptide (FR901228): A Novel Therapeutic Agent With Selective, In Vitro Activity Against Human B-Cell Chronic Lymphocytic Leukemia Cells

Blood ◽  
1999 ◽  
Vol 94 (4) ◽  
pp. 1401-1408 ◽  
Author(s):  
John C. Byrd ◽  
Charlotte Shinn ◽  
Rajani Ravi ◽  
Carl R. Willis ◽  
Jamie K. Waselenko ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Clinical Trials ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mononuclear Cells ◽  
Lymphocytic Leukemia ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Therapy of B-cell chronic lymphocytic leukemia (CLL) has been limited by both the nonselectivity of therapeutic agents toward normal residual immune cells and inherent drug resistance. Identification of agents that spare normal immune effector cells, thus facilitating addition of immune-based therapies, and that modulate factors associated with drug resistance in CLL might represent a major therapeutic advance. Depsipeptide (FR901228) is a novel agent entering clinical trials that has selective in vitro activity against resistant leukemia cell lines. To assess its in vitro activity in CLL, we exposed peripheral mononuclear cells from CLL patients (n = 10) to varying concentrations of this agent. Viability of the CLL cells was reduced by 50% (LC50) at 4 hours, 24 hours, and 4 days at depsipeptide concentrations of 0.038, 0.024, and 0.015 μmol/L, respectively. Depsipeptide had marked selective cytotoxicity when compared with normal blood mononuclear cells, in which the LC50 was 3.44 μmol/L at 4 hours (P = .03), 0.965 μmol/L at 24 hours (P = .01), and 0.0318 μmol/L at 96 hours (P = .04). Inhibition of bone marrow progenitor cell growth was also minimal after incubation with 0.015 μmol/L (19% inhibition of colony forming unit-granulocyte-macrophage [CFU-GM]; 17% inhibition burst forming unit-erythroid [BFU-E]) and 3.44 μmol/L (24% inhibition of CFU-GM; 57% inhibition BFU-E) of depsipeptide for 4 hours, followed by a 14-day incubation period. Expression of apoptotic proteins after depsipeptide exposure (0.015 μmol/L) included no change in bcl-2, elevation of bax, and decreased expression of p27. These data demonstrate that depsipeptide has significant selective in vitro activity against human CLL cells concurrent with favorable alterations of the bcl-2:bax protein ratio and decrease in p27 expression. Such findings strongly support the early introduction of depsipeptide into clinical trials for patients with CLL.

Depsipeptide (FR901228): A Novel Therapeutic Agent With Selective, In Vitro Activity Against Human B-Cell Chronic Lymphocytic Leukemia Cells

Blood ◽  
1999 ◽  
Vol 94 (4) ◽  
pp. 1401-1408 ◽  
Author(s):  
John C. Byrd ◽  
Charlotte Shinn ◽  
Rajani Ravi ◽  
Carl R. Willis ◽  
Jamie K. Waselenko ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Clinical Trials ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mononuclear Cells ◽  
Lymphocytic Leukemia ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Cell Chronic Lymphocytic Leukemia

Therapy of B-cell chronic lymphocytic leukemia (CLL) has been limited by both the nonselectivity of therapeutic agents toward normal residual immune cells and inherent drug resistance. Identification of agents that spare normal immune effector cells, thus facilitating addition of immune-based therapies, and that modulate factors associated with drug resistance in CLL might represent a major therapeutic advance. Depsipeptide (FR901228) is a novel agent entering clinical trials that has selective in vitro activity against resistant leukemia cell lines. To assess its in vitro activity in CLL, we exposed peripheral mononuclear cells from CLL patients (n = 10) to varying concentrations of this agent. Viability of the CLL cells was reduced by 50% (LC50) at 4 hours, 24 hours, and 4 days at depsipeptide concentrations of 0.038, 0.024, and 0.015 μmol/L, respectively. Depsipeptide had marked selective cytotoxicity when compared with normal blood mononuclear cells, in which the LC50 was 3.44 μmol/L at 4 hours (P = .03), 0.965 μmol/L at 24 hours (P = .01), and 0.0318 μmol/L at 96 hours (P = .04). Inhibition of bone marrow progenitor cell growth was also minimal after incubation with 0.015 μmol/L (19% inhibition of colony forming unit-granulocyte-macrophage [CFU-GM]; 17% inhibition burst forming unit-erythroid [BFU-E]) and 3.44 μmol/L (24% inhibition of CFU-GM; 57% inhibition BFU-E) of depsipeptide for 4 hours, followed by a 14-day incubation period. Expression of apoptotic proteins after depsipeptide exposure (0.015 μmol/L) included no change in bcl-2, elevation of bax, and decreased expression of p27. These data demonstrate that depsipeptide has significant selective in vitro activity against human CLL cells concurrent with favorable alterations of the bcl-2:bax protein ratio and decrease in p27 expression. Such findings strongly support the early introduction of depsipeptide into clinical trials for patients with CLL.

Cyclin-Dependent Kinase Inhibitor Seliciclib Shows In Vitro Activity in Diffuse Large B Cell Lymphomas.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4738-4738
Author(s):  
Francesco Bertoni ◽  
Katia Lacrima ◽  
Andrea Rinaldi ◽  
Sara Vignati ◽  
Vittoria Martin ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Active Agent ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Large B Cell

Abstract Background. Despite recent improvements in treatment, a significant fraction of patients with diffuse large B cell lymphoma (DLBCL) still fail therapy. Therefore, new therapeutic modalities are needed to advance the cure rate. Seliciclib (CYC202, R-roscovitine) is a purine analogue developed as an inhibitor of CDK2/cyclin E CDK7/cyclin H and CDK9/cyclin T. Seliciclib has been shown to be active in B cell neoplasms, such as mantle cell lymphoma, chronic lymphocytic leukemia and in multiple myeloma in vitro. The aim of this study was to assess the in vitro activity of seliciclib in DLBCL. Materials and methods. The anti-proliferative activity of seliciclib was tested in nine human DLBCL cell lines and six DLBCL primary cell cultures. The effects of seliciclib on the cell cycle and on apoptosis, as well as on transcription-related proteins were assessed. Results. The cell viability of all DLBCL cell lines and primary cells was reduced by seliciclib treatment. The IC50 for the cell lines ranged from 13 to 36 μM. The effect of seliciclib was independent of the genetic aberrations characterizing the cell lines. After seliciclib exposure cells accumulated in G2/M or in G1 phase, with most of the cells showing signs of apoptosis. Despite the clear cytotoxic effect and induction of apoptosis, we could not identify a unique mechanism of action. Conclusions. Our in vitro data suggest that seliciclib is an active agent in DLBCL. Its efficacy is apparently independent of the underlying chromosomal translocations characteristic of DLBCL. The drug might represent a new therapeutic agent in this lymphoma subtype.

scholarly journals Potent Inhibition of the Growth and Induction of Apoptosis in Lymphoma By the Anthelminthic Drug Niclosamide: In Vitro Data

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5131-5131
Author(s):  
Junaid Ansari ◽  
Paula Polk ◽  
Jeffrey Aufman ◽  
Guillermo A Herrera ◽  
James Cardelli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Lines ◽  
Mononuclear Cells ◽  
Lymphocytic Leukemia ◽  
Lymphoma Cell ◽  
B Lymphoma

Abstract Background and Purpose: Niclosamide is an anthelminthic drug which has been used for the treatment of human parasitic infections for many years. Niclosamide interacts with lysosomes and induces autophagy. In recent years, it has demonstrated anti-cancer potential in leukemia, breast cancer, colon cancer, myeloma, ovarian, prostate and lung cancer models. Multiple pathways like Wnt/β-catenin, mTORC1, STAT3, NF-κB and notch signaling were reported to be involved. Only limited studies were done in lymphoma models. We hypothesized that niclosamide may also have in vitro and in vivo activities in lymphomas. Non-Hodgkin lymphomas generally respond well to chemotherapy and/ or immunotherapy, however many patients relapse and ultimately become refractory. Relapses are often caused by tumor stem cells not eliminated by cytostatic drugs. Therefore new treatment approaches and new targets are desirable. Materials and Methods: Established B lymphoma cell lines were exposed to different concentrations of niclosamide (0.1-4µM) and IC50 was calculated at 24, 48 and 72 hours. The cell concentration, viability and proliferation were assessed by CellTiter-Blue viability and trypan blue exclusion assays. Apoptosis was assessed by a combined annexin-V/ propidium iodide stain. Gene expression changes were studied using GeneChip Human Transcriptome Array 2.0 (Affymetrix) with 44 699 annotated genes. Colony forming assays were performed in methylcellulose. Ultrastructural changes were studied using a Hitachi electron microscope. As normal controls, peripheral blood mononuclear cells from individuals without active cancer were incubated with niclosamide for up to 72 hours. Samples from patients with chronic lymphocytic leukemia were also treated under the same conditions. Results: Treatment with niclosamide at doses as low as 0.1 μM resulted in time-and dose- dependent apoptosis, cytotoxicity and inhibition of proliferation in aggressive lymphoma cell lines. The 50% inhibitory concentration in a proliferation assay (mean of data at 24, 48 and 72 hours) is shown in the Table below. Niclosamide also inhibited clonal growth in semi-solid media. Electron microscopy showed that filopodia increased and lipid vacuoles developed whereas mitochondria were less numerous and had fewer cristae (when KOPN-8 was treated with 0.5 μM for 48 hours). The viability of mononuclear cells from 8 individuals without lymphoma was unchanged (or minimally decreased) when incubated with niclosamide. As far as cells from two patients with untreated chronic lymphocytic leukemia are concerned, no cytotoxicity was observed at doses between 0.5 and 5 μM. Gene expression changes were studied the cell lines Daudi and KOPN-8 treated with 2.5 μM for 3 and 6 h. 96 genes were consistently overexpressed , 59 down-regulated. Ten out of the 96 overexpressed genes involved the TNF pathway and immunoregulation including CD95. Thirteen out of the 59 down-regulated genes are involved in mitochondrial function. Table.Cell lineDescription of Cell TypeIC 50STDDaudiBurkitt lymphoma cell line0.37 μM± 0.12HBL-2Diffuse large B cell lymphoma cell line0.68 μM± 0.15KOPN-8B precursor ALL cell line0.6 μM± 0.08RamosBurkitt lymphoma cell line0.58 μM± 0.04RajiBurkitt lymphoma cell line0.65 μM± 0.10SU-DHL4-VRVincristine resistant lymphoma cell line0.5 μM± 0.02 Conclusion: Niclosamide effectively inhibits the proliferation of B lymphoma cell lines and induces apoptosis. Preliminary data show that Niclosamide targets genes involved in the TNF pathway and interferes with mitochondrial function. Normal lymphocytes are not sensitive to niclosamide. The in-vitro activity of niclosamide is at least comparable or superior to the activity seen in other malignancies. Niclosamide may target drug-resistant lymphoma stem cells and has clinical potential. We plan to study combination treatments and perform in vivo studies. Acknowledgments: The authors thank Drs. Borje Andersson, Shile Huang, Nakle Saba, Ben Valdez and Ellen Vitetta for their kind gift of cell lines. Disclosures No relevant conflicts of interest to declare.

Gemcitabine demonstrates in vitro activity against human B-cell chronic lymphocytic leukemia

2001 ◽  
Vol 25 (6) ◽  
pp. 435-440 ◽  
Author(s):  
Jamie K Waselenko ◽  
Michael R Grever ◽  
Charlotte A Shinn ◽  
Ian W Flinn ◽  
John C Byrd
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Cell Chronic Lymphocytic Leukemia ◽  
Human B Cell

scholarly journals Fucoxanthin, A Carotenoid Derived from Phaeodactylum tricornutum Exerts Antiproliferative and Antioxidant Activities In Vitro

Antioxidants ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 183 ◽  
Author(s):  
Ulrike Neumann ◽  
Felix Derwenskus ◽  
Verena Flaiz Flister ◽  
Ulrike Schmid-Staiger ◽  
Thomas Hirth ◽  
...  
Keyword(s):  
Health Effects ◽  
Cell Lines ◽  
Metabolic Activity ◽  
Phaeodactylum Tricornutum ◽  
Caspase 3 ◽  
Mononuclear Cells ◽  
Antioxidant Activities ◽  
Fold Increase ◽  
Anti Inflammatory

Microalgae contain a multitude of nutrients and can be grown sustainably. Fucoxanthin, a carotenoid from Phaeodactylum tricornutum, could have beneficial health effects. Therefore, we investigated the anti-inflammatory, antioxidative and antiproliferative effects of fucoxanthin derived from this diatom in vitro. The effects of purified fucoxanthin on metabolic activity were assessed in blood mononuclear cells and different cell lines. In cell lines, caspase 3/7 activity was also analyzed. Nitrogen monoxide release and mRNA-expression of proinflammatory cytokines were measured. For antioxidant assays, cell free assays were conducted. Additionally, the antioxidant effect in neutrophils was quantified and glutathione was determined in HeLa cells. The results show that neither did fucoxanthin have anti-inflammatory properties nor did it exert cytotoxic effects on mononuclear cells. However, the metabolic activity of cell lines was decreased up to 58% and fucoxanthin increased the caspase 3/7 activity up to 4.6-fold. Additionally, dose-dependent antioxidant effects were detected, resulting in a 63% decrease in chemiluminescence in blood neutrophils and a 3.3-fold increase in the ratio of reduced to oxidized glutathione. Our studies show that fucoxanthin possesses antiproliferative and antioxidant activities in vitro. Hence, this carotenoid or the whole microalgae P. tricornutum could be considered as a food or nutraceutical in human nutrition, showcasing beneficial health effects.

scholarly journals Cytokine influence on killing of fresh chronic lymphocytic leukemia cells by human leukocytes

Blood ◽  
1991 ◽  
Vol 77 (12) ◽  
pp. 2707-2715 ◽  
Author(s):  
D Cemerlic ◽  
B Dadey ◽  
T Han ◽  
L Vaickus
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mononuclear Cells ◽  
Protein A ◽  
Human Leukocyte ◽  
Lymphocytic Leukemia ◽  
Target Antigen ◽  
Peripheral Blood Mononuclear ◽  
Ifn Gamma ◽  
Hla Dr

Abstract The feasibility of combining the Lym-1 monoclonal antibody (MoAb) with interferon-gamma (IFN-gamma) in the treatment of chronic lymphocytic leukemia (CLL) was evaluated. We used an in vitro tumor lysis model that incorporated fresh CLL cells from 21 different patients as targets for two distinct normal human leukocyte effector subsets, neutrophils, and peripheral blood mononuclear cells (PBMCs). Lym-1 antigen (Lym-1- Ag) expression varied greatly and did not correlate with the expression of other CLL-associated antigens such as CD5, CD19, or HLA-DR. CLL cells were not lysed by neutrophils alone or with IFN-gamma in the absence of Lym-1. Neutrophil Lym-1-dependent cytotoxicity (ADCC) in the absence of IFN-gamma was weak and inconsistent. IFN-gamma exposure induced MoAb-dependent lysis of 80% of 21 CLL targets and resulted in an eightfold augmentation of neutrophil ADCC against the remainder. Cytotoxicity correlated directly and positively with Lym-1-Ag expression. Confirmation of the need for interaction between neutrophil IgG Fc receptors (Fc gamma Rs) and the Fc portion of the Lym-1 MoAb was obtained by demonstrating that purified Staphylococcus aureus Protein A (SpA) inhibited ADCC. IFN-gamma exposure caused no consistent alternations in Lym-1-Ag expression on CLL cells so that target antigen upregulation was unlikely to account for augmentation of neutrophil ADCC. PBMCs alone, exposed to interkeukin-2 (IL-2) or IFN-gamma, or with Lym-1 in the presence or absence of IL-2 or IFN-gamma were unable to lyse CLL targets. PBMCs were able to kill Raji Burkitt lymphoma cells in conjunction with Lym-1, so their ability to interact with Lym- 1-coated targets and their lytic functions appeared intact. These results emphasize the importance of examining fresh tumor cells with different leukocyte effector subsets before designing a clinical trial that combines a therapeutic MoAb with a cytokine.

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