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Page 29
allied
academies
August 23-24, 2018 | London, UK
Hematology and Oncology
2
nd
International Conference on
Journal of Hematology and Blood Disorder | Volume 2
The Anti-Cancer Potential of Polyphenols in the Treatment of Leukemia
Mahbub AA
1
, Le Maitre CL
2
and
Haywood-Small SL
2
1
Umm Al Qura University, Saudi Arabia
2
Sheffield Hallam University, UK
L
eukaemia is a complex disease affecting all blood cell
lineages. It affects millions of people worldwide each
year and mortality rates are high, despite considerable
improvements in treatment. Thus, new therapies for leukemia
are urgently needed to improve leukemia patients’ health and
survival. Since polyphenols exert pro-apoptotic effects in solid
tumours, our study investigated the effects of polyphenols in
Hematological malignancies. Methods: The effects of eight
polyphenols (quercetin, chrysin, apigenin, emodin, aloe-
emodin, rhein, cis-stilbene, and trans-stilbene) was studied on
cellular proliferation, the induction of apoptosis and cell cycle
progression in four lymphoid (JURKAT, MOLT-3, CCRF-CEM
and U937) and four myeloid (HL-60, THP-1, K562 and KG-1a)
leukaemia cells lines, together with normal haematopoietic
control cells (CD34+ HSC and CD133+ HSC) from cord blood.
Further to this, an investigation was made of the effects of the
most promising polyphenols used in combination with five
standard chemotherapeutic agents (etoposide, doxorubicin,
methotrexate, 6mercaptopurine, and 5-fluorouracil). For
this polyphenol and chemotherapy combination work, four
leukemia cells lines were used: the two most sensitive (JURKAT
and CCRFM-CEM) and two most resistant (KG1a and THP-
1) to polyphenol treatment. Subsequently, an investigation
was undertaken to identify potential mechanisms of action
of these polyphenols when used alone and in combination
with chemotherapeutics. The extrinsic and intrinsic apoptotic
pathwayswere investigated togetherwitheffectsonglutathione
levels and DNA damage. Results: Emodin, quercetin, and cis-
stilbene were the most effective polyphenols at decreasing
cell viability and inducing apoptosis. Lymphoid cell lines were
normally more sensitive to polyphenol treatment compared
to myeloid cell lines; however, those myeloid (KG-1a and
K562) cell lines which were most polyphenol resistant; were
however affected by emodin and quercetin at micromolar
treatment doses. Non-tumour cells were less sensitive to all
polyphenols compared to the leukemia cells. Mechanistically,
most polyphenols alone depleted glutathione (GSH) levels
associated with a direct activation in caspase 8 and caspase 9
in leukemia cell lines at 24 h. Polyphenols also had differential
capacities to induce DNA damage in the leukemia cell lines.
Polyphenols acted synergistically in lymphoid cell lines and
differently in myeloid cell lines producing either synergistic,
additive, competitive antagonistic or antagonistic effects;
when they were combined with topoisomerase inhibitor
agents (etoposide and doxorubicin). In contrast, they worked
antagonisticallywithanti-metabolites agents (methotrexateand
6-mercaptopurine) in both lymphoid and myeloid leukaemia
cell lines. Mechanistically the synergistic induction of apoptosis
observed following the combination of polyphenols with
chemotherapeutic agents was caused by the direct activation
of intrinsic or/ and extrinsic apoptotic pathway through the
up-regulation of caspase 8 or caspase 9 within the lymphoid
and myeloid leukaemia cell line. Furthermore, it has been
shown the synergistic effects observed when polyphenols and
chemotherapyagentswerecombinedwascorrelatedwithdown
regulation of GSH levels and an induction of DNA damagewhich
drove apoptosis. Alternatively, where there was an antagonist
effect, there was an upregulation of GSH levels, a reduction in
DNA damage and the level of apoptosis. Conclusions: These
findings demonstrate that polyphenols induce apoptosis and
arrest cell cycle in leukemia cell lines which could translate to
anti-cancer activities in leukemia, although the effects were
dependant on polyphenol type and origin of the cell line
investigated. Importantly, the differential sensitivity of emodin,
quercetin, and cis-stilbene between leukemia and normal cells
suggests that polyphenols are potential therapeutic agents
for leukemia. Furthermore, this study concluded that the
efficacy of standard chemotherapeutic agents was differentially
modulated by polyphenols, producing either synergistic,
additive or competitive antagonistic/antagonistic effects, which
was dependent on the type of polyphenol, chemotherapy agent
and cell line. Interestingly the study showed that synergistic
or antagonistic effects observed following the combination
treatments were strongly dependent on the modulation
of glutathione levels in association with the formation of
γ-H2AX nuclear foci and DNA damage in leukemia cell lines.
e:
a.mahbub@hotmail.com