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Mortality rates for leukemia are high
despite considerable improvements in treatment. Since polyphenols exert
pro-apoptotic effects in solid tumors, our study investigated the effects of
polyphenols in haematological malignancies. The effect of eight polyphenols
(quercetin, chrysin, apigenin, emodin, aloe-emodin, rhein, cis-stilbene and
trans-stilbene) were studied on cell proliferation, cell cycle and apoptosis
in four lymphoid and four myeloid leukemic cells lines, together with normal
haematopoietic control cells.
Methods: Cellular proliferation was measured by
CellTiter-Glo® luminescent assay; and cell cycle arrest was assessed using
flow cytometry of propidium iodide stained cells. Apoptosis was investigated
by caspase-3 activity assay using flow cytometry and apoptotic morphology was
confirmed by Hoescht 33342 staining.
Results: Emodin, quercetin, and
cis-stilbene were the most effective polyphenols at decreasing cell viability
(IC50 values of 5-22 µM, 8-33 µM, and 25-85 µM respectively) and inducing
apoptosis (AP50 values (the concentration which 50% of cells undergo
apoptosis) of 2-27 µM, 19-50 µM, and 8-50 µM respectively). Generally,
lymphoid cell lines were more sensitive to polyphenol treatment compared to
myeloid cell lines, however the most resistant myeloid (KG-1a and K562) cell
lines were still found to respond to emodin and quercetin treatment at low
micromolar levels. Non-tumor cells were less sensitive to all polyphenols
compared to the leukemia cells.
Conclusions: These findings suggest that
polyphenols have anti-tumor activity against leukemia cells with differential
effects. Importantly, the differential sensitivity of emodin, quercetin, and
cis-stilbene between leukemia and normal cells suggests that polyphenols are
potential therapeutic agents for leukemia.
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موجز عن المشاركة: 1
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The mortality
of leukaemia is still high despite the considerable improvements in
chemotherapeutic agents. Our previous work has shown that polyphenols and
polyacetylenes have potential in the treatment of leukaemia (Dahlawi et al
2012; Zaini et al 2011). Furthermore, in a comparative study of the
effect eight polyphenols in cell eight leukaemia cell lines and one
non-tumour control cell, quercetin and emodin were shown to be the most
effective at induction of apoptosis, cell cycle arrest and inhibiting ATP
levels (as a marker of proliferation), in leukaemia compared to non-tumour
cells. Using IC10 and IC25 treatment doses (the concentration which inhibits
10% and 25% of cell ATP levels respectively) an investigation was made of the
effects of the quercetin and emodin on five standard chemotherapy treatments
(doxorubicin, etoposide, cisplatin, cyclophosphamide and chlorambucil), on
cell proliferation, cell cycle and apoptosis 24hrs post-treatment in two
human myeloid (KG1a and THP-1) and two human lymphoid (Jurkat and CCRF-CEM)
leukaemia cell lines.
Methods: The
combination effects of polyphenols and chemotherapies on cell ATP levels was
measured by CellTiter-Glo® luminescent assay, cell cycle was assessed using
propidium iodide (PI) staining and flow cytometry and induction of apoptosis
was investigated by caspase-3 activity assay using flow cytometry and by
morphological assessment following Hoechst 33342 staining.
Results:
Quercetin synergistically inhibited ATP levels, and induced apoptosis and
cell cycle accumulation when combined with etoposide, cisplatin and
cyclophosphamide in both lymphoid cell lines, whilst having an additive
effect in the myeloid cell lines. Quercetin also had an additive effect when
used in combination with doxorubicin and chlorambucil, in all leukaemia cell
lines. Similarly emodin produces a synergistic effect when combined with
etoposide and doxorubicin, and an additive affect with cisplatin,
cyclophosphamide and chlorambucil) in both lymphoid cell lines.
Conclusion:
This study show that quercetin and emodin have a potential role at enhancing
the action of chemotherapy in the treatment of leukaemia, however the levels
of action depend on the polyphenol and cell lineage. This suggests that there
is a different mechanism of action of these polyphenol-chemotherapy
combinations in the treatment in lymphoid and myeloid leukaemia.
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موجز عن المشاركة: 2
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Background: The mortality
of leukaemia is still high despite the considerable improvements in
chemotherapeutic agents. For this reason, our study aimed to investigate the polyphenols as
alternative agents for leukaemia treatment in which the most recent studies
have been focused only on solid
tumours. Here, we specifically selected eight compounds from the major
classes of polyphenols (quercetin , chrysin, apigenin, emodin, aloe-emodin, rhein, cis-stilbene
and trans-stilbene) and their effects were investigated on cell
proliferation, cell cycle and apoptosis on a panel of human myeloid (KG1a,
HL60 THP-1,and K562) and lymphoid (JURKAT, CCRF-CEM, MOLT-3, and U937) leukaemia cell lines.
Methods: The effect of
polyphenols on cell proliferation was measured by CellTiter-Glo® Luminescent
Assay and cell cycle was assessed using propidium iodide (PI) staining and
flow cytometry. Induction of apoptosis was investigated by caspase 3 activity assay using flow
cytometry and Hoescht stain using fluorescence microscopy.
Results and
Conclusions: our study showed that emodin, quercetin, and
cis-stilbene were the most effective polyphenols at inhibiting cell
proliferation (with IC50 values ranged between 5-22μM, 8-33μM, 30-85μM,
respectively) and inducing the apoptosis (with AP50 values ranged between
2-27μM, 19-50μM, 8-50μM, respectively), following 24hr for all the leukemic types. All
myeloid cell lines have been more sensitive to apigenin comparing to other
compounds in inducing apoptosis while at higher concentrations between
84-235μM. Meanwhile, all lymphoid cell lines showed greatest sensitivity to
the all polyphenols
comparing to the myeloid cell line. Our data showed that all eight
polyphenols where significantly found to inhibit cell proliferation and arrest the cell cycle for all
leukemic cell lines with varied responses in inducing the early and late
apoptosis, this variety of action between cell
lines suggesting that there is a different mechanism of the action of each of
these molecules. In conclusion, our findings suggest that polyphenols could be used as new
chemotherapeutic agents in the treatment of leukaemia.
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