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Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 278-283
By
From the Departments of Internal Medicine and Biochemsitry, Human
Morphology, and Pathology and Laboratory Medicine, American University
of Beirut, Beirut, Lebanon; UPR 9051 CNRS, (Laboratoire associé
au comité de Paris de la Ligue contre le Cancer), Paris, France;
and CNRS URA 1461 and the Department of Hematology, Necker Hospital,
Paris, France.
Human T-cell lymphotropic virus type I (HTLV-I) is the causative
agent of adult T-cell leukemia/lymphoma (ATL). ATL is an aggressive
proliferation of mature activated T cells associated with a poor
prognosis. The combination of the antiviral agents, zidovudine (AZT)
and
ADULT T-CELL leukemia/lymphoma (ATL) is
an aggressive lymphoproliferative disorder associated with the human
T-cell lymphotropic virus type I (HTLV-I).1 ATL-associated
tumor cells are constitutively-activated CD4+ T cells with
characteristic convoluted nuclei and basophilic cytoplasm.2
ATL remains of very bad prognosis due to severe immunosuppression and
to an intrinsic resistance of leukemia cells to high doses of
chemotherapy. Combination chemotherapy regimens, in particular those
designed for treatment of aggressive non-Hodgkin's lymphoma or acute
lymphoblastic leukemia have little effect in the treatment of ATL
patients, with a median survival around 6 months in the acute
form.3 Important advances in the treatment of ATL were
reported in two independent phase II studies4-6 with the
combination of an antiretroviral agent zidovudine (AZT) and interferon- Arsenic trioxide (As) was shown to be an effective treatment for acute
promyelocytic leukemia (APL). In a phase II study,7 15 of
16 APL patients resistant to all-trans retinoic acid (ATRA) and
conventional chemotherapy achieved complete remission with intravenous
infusion of As. In vitro studies on APL-derived cell line (NB4) showed
that As induced apoptosis at micromolar concentration.7 The
molecular mechanisms of As action in APL are not fully elucidated; however, we have shown that As induces the specific degradation of the
PML/RAR Here we report a synergistic effect of the combination of As and IFN on
cell proliferation, cell cycle phases distribution, and apoptosis in
HTLV-I-infected cells. Our results support the use of As and IFN in
ATL therapy.
Reagents and Drugs
Cell Lines
Preparation of Peripheral Blood Mononuclear Cells (PBMC) PBMC were extracted from diluted venous blood from a patient with acute ATL and from a healthy seronegative individual by Hypaque-Ficoll centrifugation (Lymphoprep, Nyegaard, Norway). Cells were cultured in RPMI 1640 medium supplemented with 10% heat-inactivated FCS, antibiotics, and with 100 U/mL recombinant human IL-2 (rhIL-2). Cells were maintained at 37°C in a 5% CO2 humidified atmosphere.Proliferation Assay Cells were cultured in 96-well, flat-bottom microtiter plates (Nunc, Naperville, IL) in quadruplicates. Test drugs were added at the indicated concentrations at the initiation of culture. At different time points of culture (24 hours, 48 hours, and 72 hours), 3H-thymidine (1 µCi/well; Amersham, Buckinghamshire, UK) was added for the last 4 hours. Cells were harvested on a PHD cell harvester (Cambridge Technology, Watertown, MA), and dried at 50°C overnight. Bio-HP liquid scintillation fluid (Fisher Scientific, Fair Lawn, NJ) was then added. DNA synthesis was quantified by measuring the cellular incorporation of 3H-thymidine using a Wallac 1409 liquid scintillation counter (Pharmacia-LKB, Uppsala, Sweden), and were expressed as counts per minute (CPM). Cell proliferation was expressed as percentage of corresponding control. Each experiment was performed in quadruplicate and repeated a minimum of three times.DNA Content Analysis Cells were obtained at different times after treatment, washed twice with cold phosphate-buffered saline (PBS), and fixed in cold ( 20°C) 100% ethanol and kept overnight at 4°C.
Subsequently, cells were rinsed with PBS, treated with Tris-HCl buffer
(pH 7.4) containing 1% RNase, and stained with propidium iodide (PI)
100 µg/mL (final concentration). Distribution of cell cycle phases with different DNA contents was determined using a FACScan flow cytometer (Becton Dickinson, San Jose, CA). In each sample, 10,000 ungated events were acquired. Analysis of cell cycle distribution (including apoptosis) was performed using Modfit software (Becton Dickinson).
Apoptosis Studies Nuclear staining. Cells under study were treated with test drugs, which were added at the indicated concentrations at the initiation of culture. Nuclei were then labeled by Hoechst 33342 (Polysciences, Warrington, PA) for 2 minutes at room temperature. Cells were then observed under fluorescence microscopy using ultraviolet (UV) filter pack. The total number of nuclei and the percentage of apoptotic nuclei was noted. TUNEL assay. The terminal deoxy-transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL) assay was used to monitor the extent of DNA fragmentation due to apoptosis. The assay was performed according to the recommendations of the manufacturer (Boehringer, Mannheim, Germany). Fluorescein-conjugated dUTP incorporated in nucleotide polymers was detected and quantified using flow cytometry. Approximately 10,000 cells per sample were acquired and analyzed using Cell-Quest software (Becton Dickinson). Annexin-V staining.
Cells under study were incubated with various test agents and apoptosis
was assessed by Annexin-V binding. Briefly, cells were incubated with
fluorescein isothiocyanate (FITC)-conjugated Annexin-V according to the
recommendations of the manufacturer (Boehringer), in the presence of 1 mmol/L CaCl2. Nuclei of cells were counterstained with PI
and cells were either screened by flow cytometry (approximately 10,000 events) or by fluorescence microscopy. Apoptosis was estimated by the
relative amount of FITC+-PI Western Blot Analysis Approximately 107 cells from various treatments were solubilized at 4°C in lysis buffer (0.01 mol/L Tris-Cl (pH 7.4), 0.5% sodium deoxycholate, 0.5% Triton X-100, 0.05% sodium dodecyl sulfate [SDS]). The samples were loaded onto a 12% SDS-polyacrylamide gel, subjected to electrophoresis, and transferred to nitrocellulose membrane that was subsequently stained with 0.2% Ponceau red to assure equal protein loading and transfer. After blocking of the membrane in 1% bovine serum albumin (BSA), the blots were reacted with 1:100 dilution of HTLV-I seropositive patients sera for 2 hours at 37°C. After washing, the blots were incubated with antihuman IgG (Fc-specific) conjugated to peroxidase. Binding of antibodies was detected by staining by chemoluminescence using the ECL detection kit (Amersham, Buckinghamshire, UK).
Effects of IFN, As, and Their Combination on Cell Proliferation Cell proliferation was assessed by the ability of cells to incorporate 3H-thymidine into their DNA. Results are expressed as percent of control and represent the mean of at least four independent experiments. Figure 1 represents the most striking differences between the HTLV-I+ cell line (HUT-102) and the HTLV-I cell line (CEM) at 48 hours
of treatment. The results observed with MT-2 and Jurkatt cells (data
not shown) were similar to those obtained with HUT-102 and CEM cells,
respectively. No major difference was observed for the basal
incorporation in the different cell lines at the different time points
(24, 48, and 72 hours). Several conclusions emerge from this study.
First, HTLV-I-transformed cells appear to be much more sensitive to
the effect of IFN than control cells in which growth suppression is
minimal and only occurs at 3 days (data not shown). This is interesting
in view of the fact that these patients clinically respond to IFN.
Secondly, HTLV-I HUT-102 cells are considerably more sensitive to As
than control cells (CEM) or MT2 cells at 3 days of treatment
(incorporation rates as percent of control are: 26 ± 5; 83 ± 16; and 107 ± 9, respectively for HUT-102, CEM, and MT-2). Finally,
a very strong synergy is found between IFN and As at any time and any
dose of IFN used, in both HTLV-I-infected cells HUT-102 (Fig 1) and
MT-2 (data not shown), contrasting with control cells CEM (Fig 1) and Jurkatt (data not shown). In control cells, a modest synergy was found
at day 3 as in most cell lines.11a Indeed, a 50% reduction
in 3H-thymidine incorporation into CEM cells was only
observed at 72 hours of treatment for IFN doses over 100 U/mL in the
presence of As (data not shown). Finally, note that in
HTLV-I+ cells HUT-102 (Fig 1) and MT-2 (data not shown), As
addition leads to an almost complete growth arrest for IFN doses over
100 U/mL (the therapeutic dose in patients).
Effects of IFN, As, and Their Combination on Cell Cycle To investigate whether the inhibition of cell proliferation was due to cell cycle arrest or/and apoptosis, cell cycle analyses were performed under the same culture conditions as previously described. We first examined cellular DNA contents distribution by flow cytometry for the presence of a pre-G1 region phase. No major variation was observed between HUT-102 and CEM cells at different time points. Hence, Table 1 illustrates data collected at 72 hours of treatment. As, but not IFN alone, induced a significant increase in apoptosis in HUT-102 cells, but not in CEM cells. A clear synergy between the two agents was observed in either HTLV-I+ or HTLV-I cells, consistent with
our previous data in other cells.11a Note, however, that
the synergy was much stronger in HUT-102 cells reaching 48% with
modest doses of each agent.
Apoptosis Studies The cell-cycle distribution studies suggested that As induced apoptosis in HTLV-I-derived cell lines, a process enhanced by IFN treatment. Three established criteria were subsequently used to assess apoptosis in our system. First, HUT-102 cells were stained with Hoechst 33342. Figure 2 shows that the nuclei of HUT-102 cells treated with As and IFN underwent apoptosis, as shown by their characteristically condensed, fragmented, and intensely fluorescent nuclei (Fig 2C; arrowheads). Control cells displayed the typical morphology of normal nuclei (Fig 2A), as HUT-102 cells treated with As only (data not shown). Under light microscopy, cells treated with both As and IFN (Fig 2D) were less numerous and exhibited membrane blebbing when compared with control cells (Fig 2B). Second, the TUNEL assay shows DNA cleavage by labeling free 3 -OH ends. At 48 hours
of culture, the percentage of TUNEL+ HUT-102, representing
apoptotic cells, was 3% for the control cells, 7% with As, 3% with
1,000 U/mL, 16% with the combination of As and 1,000 U/mL of IFN. At
72 hours of culture (Fig 3), the percentage
of TUNEL+ HUT-102, was 2% for the control cells, 9% with
As, 3% with 1,000 U/mL of IFN, 35% with the combination of As and
1,000 U/mL of IFN. For the control cell line CEM, at 72 hours of
culture (Fig 3), the percentage of TUNEL+ CEM cells was 1%
for the control cells and 14% with the combination of As and 1,000 U/mL of IFN. Finally, cell death was also determined in the HUT-102
cell line using FITC-conjugated Annexin-V membrane staining and PI
nuclear counterstaining. The fluorescence microscopy analysis of
HUT-102 cells treated with the combination of As and IFN showed the
presence of apoptotic cells (FITC+, PI)
with some necrotic or postapoptotic ones (FITC+,
PI+) (Fig 4 [see page 281]). These different cell
populations were quantified by flow cytometry analysis at different
times of culture (48 hours and 72 hours). In Fig 4, the percentage of
dead cells is relative to the total cell population, while the
percentage of apoptotic cells is presented with regard to the
PI, ie, nondead cells. Again, As lead to a
significant increase in both apoptotic or postapoptotic cells, and this
was enhanced by IFN cotreatment at either 24 or 48 hours.
Ex Vivo Studies The effect of the combination of As and IFN in vitro was substantiated by ex vivo experiments. PBMC from a patient with acute ATL and one healthy seronegative control were cultured ex vivo and immediately treated with As, IFN, and their combination. At 72 hours of culture, the percentage of ATL cells in the pre-G1 phase was 18% for the untreated cells, 42% with As, 42% with 100 U/mL IFN, and 62% with the combination of As and 100 U/mL of IFN. By contrast, in the control normal lymphocytes, at 72 hours of culture, the percentage of cells in the pre-G1 phase was 9% for the untreated cells, 17% with As, 7% with 100 U/mL, and 18% with the combination of As and 100 U/mL of IFN. Moreover, at 3 days in ATL cells treated with the combination of As and IFN had almost completely withdrawn from the cell cycle with (S + G2 + M) phases at 23% for the untreated cells, 12% with As, 30% with 100 U/mL of IFN, and 5% with the combination of As and 100 U/mL of IFN. By contrast, the cell-cycle distribution of normal lymphocytes was unaffected by this treatment.Analysis of HTLV-I Protein Expression Western blot analysis of HUT-102 proteins using anti-HTLV-I+ sera showed the typical profile of HTLV-I proteins as described previously.12 No quantitative or qualitative modification of the profile pattern was observed in cells treated with IFN, As, or their combination (data not shown).
Here we show that As and IFN induce apoptosis and cell-cycle arrest in
HTLV-I-infected cells. The dramatic synergy between these two agents
and the modest effect on HTLV-I
The authors thank Drs F. Homaidan and G. Dbaibo for their critical reading of the report. The excellent technical assistance of the American University of Beirut Core Laboratory Facilities personnel is greatly appreciated.
Submitted April 23, 1998;
accepted August 26, 1998.
Address reprint requests to Ali Bazarbachi, MD, PhD, Department of Internal Medicine, American University of Beirut, PO Box 113-6044, Beirut, Lebanon; email: bazarbac{at}aub.edu.lb.
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M. E. El-Sabban, R. Nasr, G. Dbaibo, O. Hermine, N. Abboushi, F. Quignon, J. C. Ameisen, F. Bex, H. de The, and A. Bazarbachi Arsenic-interferon-alpha -triggered apoptosis in HTLV-I transformed cells is associated with Tax down-regulation and reversal of NF-kappa B activation Blood, October 15, 2000; 96(8): 2849 - 2855. [Abstract] [Full Text] [PDF]
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G. J. Roboz, S. Dias, G. Lam, W. J. Lane, S. L. Soignet, R. P. Warrell Jr, and S. Rafii Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis Blood, August 15, 2000; 96(4): 1525 - 1530. [Abstract] [Full Text] [PDF]
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 P. Costantini, E. Jacotot, D. Decaudin, and G. Kroemer Mitochondrion as a Novel Target of Anticancer Chemotherapy J Natl Cancer Inst, July 5, 2000; 92(13): 1042 - 1053. [Abstract] [Full Text] [PDF]
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C. Nicot, R. Mahieux, S. Takemoto, and G. Franchini Bcl-XL is up-regulated by HTLV-I and HTLV-II in vitro and in ex vivo ATLL samples Blood, July 1, 2000; 96(1): 275 - 281. [Abstract] [Full Text] [PDF]
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C. Perkins, C. N. Kim, G. Fang, and K. N. Bhalla Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-xL Blood, February 1, 2000; 95(3): 1014 - 1022. [Abstract] [Full Text] [PDF]
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G. Kroemer and H. de The Arsenic Trioxide, a Novel Mitochondriotoxic Anticancer Agent? J Natl Cancer Inst, May 5, 1999; 91(9): 743 - 745. [Full Text] [PDF]
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E. M. Rego, L.-Z. He, R. P. Warrell Jr., Z.-G. Wang, and P. P. Pandolfi Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RARalpha and PLZF-RARalpha oncoproteins PNAS, August 29, 2000; 97(18): 10173 - 10178. [Abstract] [Full Text] [PDF]
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| Copyright © 1999 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Synergize to Induce Cell Cycle
Arrest and Apoptosis in Human T-Cell Lymphotropic Virus Type
I-Transformed Cells
Top
Abstract
Introduction
interferon (IFN), is a potent treatment of ATL. Recently,
arsenic trioxide (As) was shown to be an effective treatment of acute
promyelocytic leukemia (APL). We have tested the effects of the
combination of As and IFN on cell proliferation, cell cycle phases
distribution, and apoptosis in ATL-derived or control T-cell lines. A
high synergistic effect between IFN and As was observed in ATL-derived
cell lines in comparison to the control cell lines, with a dramatic
inhibition of cell proliferation, G1 arrest, and induction of
apoptosis. Similar results were obtained with fresh leukemia cells
derived from an ATL patient. Although the mechanisms involved are
unclear, these results could provide a rational basis for combined As
and IFN treatments in ATL.
) and HUT-102 (
). Incorporation rates that reflected
both the number of cells and the individual DNA synthesis are expressed
as percentage (±SD) of control and represent the mean of the results
obtained in at least four independent experiments.
), dead. Fluorescence microscopy analysis showed the presence of
apoptotic cells (small arrows) and dead cells (large arrows).
