Received: 1 November 2018 | Accepted: 18 December 2018

DOI: 10.1002/jcp.28072

REVIEW ARTICLE

Curcumin as a therapeutic agent in leukemia

Hamideh Kouhpeikar1 | Alexandra E. Butler2 | Faeze Bamian1 |

George E. Barreto3,4 | Muhammed Majeed5 | Amirhossein Sahebkar6,7,8

1
Department of Hematology and Blood Bank,
Cancer Molecular Pathology Research Center, Abstract
Faculty of Medicine, Mashhad University of Leukemia comprises a group of hematological malignancies responsible for 8% of all
Medical Sciences, Iran
2 cancers and is the most common cancer in children. Despite significant improvements in
Diabetes Research Center, Qatar Biomedical
Research Institute, Doha, Qatar leukemia treatment, the efficacy of conventional chemotherapeutic agents is low and the
3
Departamento de Nutrición y Bioquímica, disease carries a poor prognosis with frequent relapses and high mortality. Curcumin is a
Facultad de Ciencias, Pontificia Universidad
Javeriana, Bogotá, Colombia yellow polyphenol compound with diverse pharmacological actions including anticancer,
4
Instituto de Ciencias Biomédicas, Universidad antioxidant, antidiabetic, anti‐inflammatory, immunomodulatory, hepatoprotective, lipid‐
Autónoma de Chile, Santiago, Chile
regulating, antidepressant, and antiarthritic. Many cellular and experimental studies have
5
Sabinsa Corporation, East Windsor, New
Jersey
reported the benefits of curcumin in treating leukemia. Curcuminʼs anticancer effects are
6
Biotechnology Research Center, exerted via various mechanisms. Here, we review the effects of curcumin on various
Pharmaceutical Technology Institute, types of leukemia whilst considering its mechanisms of action.
Mashhad University of Medical Sciences,
Mashhad, Iran
7
KEYWORDS
Neurogenic Inflammation Research Center,
Mashhad University of Medical Sciences, cancer, chemotherapeutic agents, curcumin, leukemia, Wilmsʼ tumor 1 (WT1)
Mashhad, Iran
8
School of Pharmacy, Mashhad University of
Medical Sciences, Mashhad, Iran

Correspondence
Amirhossein Sahebkar, PharmD, PhD,
Department of Medical Biotechnology, School
of Medicine, Mashhad University of Medical
Sciences, Mashhad, P.O. Box: 91779‐48564,
Iran.
Email: sahebkara@mums.ac.ir;
amir_saheb2000@yahoo.com

1 | INTRODUCTION Leukemia is the most common type of childhood malignancy that

Leukemia is a heterogeneous group of hematological cancers that
predominantly involves the peripheral blood and bone marrow. Leukemia
is responsible for 8% of all cases of cancer, including all age groups and
imposes heavy costs in terms of diagnosis and treatment (Zand et al.,
2010). Leukemia is classified into four types: Acute myeloid leukemia
(AML), Acute lymphoblastic leukemia (ALL), Chronic myeloid leukemia
(CML), and Chronic lymphocytic leukemia (CLL). The different types of
leukemia present with general signs and symptoms such as anemia,
leukopenia, fatigue, weakness, and susceptibility to different infections
(Rafiq et al., 2018). Figure 1.
accounts for about 30% of all cancers in children under the age of 15
(Koohi et al., 2015). Over 350,000 new cases of leukemia were
diagnosed in 2012. There are several options for leukemia treatment
that include chemotherapy, bone marrow transplantation, and radiation
therapy. General treatment approaches used for AML include a
combination of cytarabine and daunorubicin (DNR). Similarly, in ALL,
combinations of four standard drugs are prescribed: vincristine,
corticosteroids, asparaginase, and anthracycline (usually doxorubicin
[DOX] or DNR; Cooper & Brown, 2015). Rituximab is a monoclonal
antibody that is often prescribed for the treatment of non‐Hodgkinʼs
lymphoma, CLL, and autoimmune disorders. The primary options

J Cell Physiol. 2019;1-11. wileyonlinelibrary.com/journal/jcp © 2019 Wiley Periodicals, Inc. | 1

2 |
recommended for CML treatment include chemotherapy (busulfan or
hydroxyurea), imatinib, interferon-alfa (IFN), and allogeneic bone marrow
transplantation (Kasteng, Sobocki, Svedman, & Lundkvist, 2007; Redaelli
et al., 2004). Despite the advances in treatment options for leukemia,
patients suffer from many problems, such as relapse of the disease, poor
prognosis, and high mortality. Chemotherapy and radiotherapy often
have side effects including hair loss, loss of appetite, mouth ulcers,
diarrhea, vomiting, liver damage, and neurological disorders (Rafiq et al.,
2018). Therefore, identifying new therapeutic approaches with higher
efficacy and fewer side effects for leukemia is crucial. Curcumin
(diferuloylmethane) is an important phytochemical derived from
turmeric and imparts the yellow color of the spice. Various studies have
shown that this phytochemical has diverse pharmacological properties,
including anticancer (Mirzaei et al., 2016; Momtazi et al., 2016;
Ramezani, Hatamipour, & Sahebkar, 2018), antioxidant (Panahi, Alishiri,
Parvin, & Sahebkar, 2016; Sahebkar et al., 2013; Sahebkar, Serban,
Ursoniu, & Banach, 2015), antidiabetic (Sharma, Kulkarni, & Chopra,
2006), anti‐inflammatory (Ghandadi & Sahebkar, 2017; Sahebkar, 2014a;
Sahebkar, Cicero, Simental‐Mendía, Aggarwal, & Gupta, 2016), antiox-
idant (Sahebkar et al., 2015), immunomodulatory (Sahebkar et al., 2016),
hepatoprotective (Panahi et al., 2017), lipid‐regulating (Cicero et al.,
2017; Ganjali et al., 2017; Panahi et al., 2016; Sahebkar, 2014b), and
antidepressant (Esmaily et al., 2015) activities. Curcumin has proven
effective in the treatment of various diseases, for example osteoarthritis
(Panahi et al., 2014), musculoskeletal disorders (Sahebkar & Henrotin,
2015; Sahebkar et al., 2015), metabolic syndrome (Panahi et al., 2015;
KOUHPEIKAR ET AL.
F I G U R E 1 Signaling pathways involved
in leukemia pathogenesis and inhibited by
curcumin. Curcumin triggers apoptosis via
BAX upregulation. Curcumin also inhibits
the proliferation of leukemia cells by
inhibiting BCR‐ABL,FLT3‐ITD, and WT1.
BAX: Bcl‐2‐associated X; Bcl‐2: B‐cell
lymphoma 2; ERK: extracellular
signal‐regulated kinase; FLT3: FMS‐like
tyrosine kinase 3; MTOR: the mammalian
target of rapamycin; NF‐κB: nuclear
factor‐κB; PI3K: phosphatidylinositol‐4,
5‐bisphosphate 3‐kinase; PKB or AKT:
protein kinase B; PKC: protein kinase C;
WT1: Wilmsʼ tumor 1 [Color figure can be
viewed at wileyonlinelibrary.com]
Panahi, Khalili, Hosseini, Abbasinazari, & Sahebkar, 2014), endothelial
dysfunction (S Karimian, Pirro, P Johnston, Majeed, & Sahebkar, 2017),
respiratory disorders (Lelli, Sahebkar, Johnston, & Pedone, 2017; Panahi,
Ghanei, Bashiri, Hajihashemi, & Sahebkar, 2015), autoimmune diseases
(Abdollahi, Momtazi, Johnston, & Sahebkar, 2018), and depression
(Panahi, Badeli, Karami, & Sahebkar, 2015). Recently, an increasing
number of preclinical studies have reported the antineoplastic activity of
curcumin in gastric cancer (Xue et al., 2014), squamous cell carcinoma
(Wu, Lu, & Cui, 2015), colon cancer (Esmatabadi et al., 2015), lung cancer
(Badrzadeh et al., 2014), renal cell carcinoma (Pei et al., 2014), liver
carcinoma (Li et al., 2014), leukemia (Banjerdpongchai & Wilairat, 2005),
and cervical cancer (Basu et al., 2013). Moreover, curcumin decreases
the growth of the breast, cervical, skin, and pancreatic cancer cell lines
(Panahi et al., 2018). Curcuminʼs anticancer attributes are due to its
effects on various cellular pathways, which include suppression of
nuclear factor‐κB (NF‐κB), signal transducer and activator of transcrip-
tion (STAT3), and activation of protein kinase B (AKT or PKB) (Anto,
Mukhopadhyay, Denning, & Aggarwal, 2002; Bush, Cheung, & Li, 2001).
One of the main advantages of curcumin is its safety in comparison with
other natural agents (thymoquinone, celastrol, butein, resveratrol, and
emodin). It does not cause significant complications, even at high dosage
and has no inhibitory effect on healthy cells (Gupta, Patchva, &
Aggarwal, 2013). By contrast, in one study by Lee, Zhang, and Sanderson
(2008) on HL‐60 leukemia cells, resveratrol, a natural antioxidant agent,
was found to not only inhibit proliferation of leukemia cells but also to
negatively affect the cells. Moreover, kidney problems after the
KOUHPEIKAR ET AL.
administration of Emodin have been reported in several studies (Wang
et al., 2007). In this review, we summarize the cellular, experimental, and
clinical investigations related to curcuminʼs effectiveness in different
types of leukemia and discuss its potential mechanisms of action.
2 | ANTICANCER EFF ECTS O F C URCUMIN
ON DIFFERENT TYPES O F LE UKE MIA
2.1 | Chronic myeloid leukemia
CML is characterized by the breakpoint cluster region‐Abelson (BCR‐
ABL) fusion gene, which is responsible for the pathogenesis of CML
(Jabbour & Kantarjian, 2016). BCR‐ABL has three breakpoint cluster
regions, major (M‐bcr), minor, and micro (µ‐bcr). M‐bcr is the major
breakpoint that encodes a 210 kDa protein, also produces a 190 kDa
protein, whereas μ‐bcr encodes a 230 kDa protein (Nandagopalan et al.,
2016). The P210 BCR‐ABL protein is essential in the pathogenesis of
CML. This cytoplasmic protein induces the proliferation of progenitor
cells of the hematopoietic system via initiation of various pathways,
including the Ras/Raf/mitogen‐activated protein kinase (MAPK) pathway
and protects CML cells from apoptosis (Williams et al., 2013; Wu, Xu, Wu,
& Chen, 2003). Therefore, targeting this oncoprotein is an appealing
therapeutic strategy. Previously, Wu, Xu, Wu, and Chen (2003) studied
the effects of curcumin on K562 cells and determined that curcumin
caused inhibition of proliferation of K562 cells via downregulation of
p210 BCR‐ABL, thus leading to inhibition of the Ras signal transduction
pathway. Indeed, Mukherjee, Sarkar, Mukherjee, Biswas, and Roy (2016)
showed that curcumin enhances the efficacy of imatinib mesylate (IM) in
CML cells. K562 cells were treated with varying concentrations of IM
either alone or with curcumin (30 μM). The MTT assay indicated that
curcumin significantly increased the toxicity of IM. Western blotting
revealed that both IM alone and the combination treatment of IM plus
curcumin downregulated the expression of NF‐κB subunits p50 and p65,
survivin, heat shock protein 90 (Hsp90), and p210 BCR‐ABL. Further-
more, they showed that the combination treatment of IM and curcumin
increased the activity of caspases 3, 8, and 9 (Mukherjee et al., 2016).
Similarly, Zhang et al. (2007) found that a combination of phosphor-
othioate antisense oligonucleotides and curcumin resulted in synergistic
inhibitory effects on K562 cell proliferation through downregulation of
P210 BCR‐ABL, NF‐κB, and Hsp90.
CML blast phase cells often express the multidrug transporter and P‐
glycoprotein (p‐gp). Overexpression of p‐gp interacts with chemother-
apeutic drugs like IM, which causes resistance to chemotherapeutic
agents, thus hindering their efficacy. For example, in CML, p‐gp
overexpression is associated with a limited distribution of IM to the
brain (Peng, Tiwari, Wu, & Chen, 2012). As p‐gp is a main cellular
mechanism of resistance in myeloid leukemia, it seems to be an attractive
therapeutic approach. Multiple studies have demonstrated that curcumin
modulates the expression of p‐gp in leukemia and other cancerous cells
(Anuchapreeda et al., 2006). Dash and Konkimalla (2017) reported that a
prepared liposomal combination of DOX and curcumin inhibited p‐gp and
reversed DOX resistance in K562 cells. Misra and Sahoo confirmed that
curcumin and DOX act synergistically to induce cell death in leukemia
| 3
cells. These authors found that curcumin contributes to the accumulation
of DOX inside the nucleus and the combinatorial treatment inhibited
multidrug resistance and downregulated the expression of B‐cell
lymphoma 2 protein (BCL‐2). Moreover, results of RT‐PCR indicated
downregulation of the BCR‐ABL gene (Misra & Sahoo, 2011, 2013).
Another well‐recognized factor in resistance to chemotherapeutic
agents is glutathione s‐transferase p1‐1 (GSTP1‐1). In many cancers
including prostate cancer, squamous cell carcinoma, ALL, and CLL,
overexpression of GSTP1‐1 has been reported (Cookson, Reuter,
Linkov, & Fair, 1997; Sauerbrey, Zintl, & Volm, 1994; Schisselbauer
et al., 1990). Curcuminʼs effect on GSTP1‐1 in CML cells was
investigated by Duvoix et al. (2003); curcumin reduced the expression
of GSTP1‐1 and, because tumor necrosis factor alpha (TNF‐α),
activator protein 1, and NF‐kB are positioned on the GSTP1‐1 gene
promoter, curcumin also inhibited these factors. Furthermore, they
reported that the pro‐caspases 8 and 9 are induced by curcumin.
Curcuminʼs synergistic effects with other chemotherapy drugs
have been shown in various studies. Iqbal et al. (2016) reported that
combinatorial treatment of KCl‐22 cells (a CML cell line) with
curcumin plus TRAIL (TNF‐related apoptosis‐inducing ligand) induced
apoptosis and arrested cell cycle in the G2/M phase Iqbal et al. (2016).
In agreement with this result, Martinez‐Castillo et al. (2016) also
published that curcumin‐induced cell cycle arrest in G2/M. Curcumin
decreased the levels of antiapoptotic markers like BCL‐2 and X‐linked
inhibitor of apoptosis protein. Moreover, curcumin increased the
expression of p73, a tumor suppressor protein that induces apoptosis
in k562 cells. NF‐κB, a transcription factor, affects biological processes
such as cell survival and cell cycle progression. NF‐κB is important in
the pathogenesis of leukemia. Reuter et al. (2009) evaluated
the curcuminʼs effect on 84 TNF‐α‐activated genes of NF‐κB pathways
in K562 cells. Of the genes evaluated, the expression of 10 messenger
RNAs (mRNAs) is increased and 29 are decreased by curcumin.
2.2 | Acute myeloid leukemia
According to the French American British classification system, AML is
classified into myeloblastic (M0), M0 without maturation (M1), M0
with maturation (M2), promyelocytic (M3), myelomonocytic (M4),
monocytic (M5), erythroleukemia (M6), and megakaryocytic (M7)
(Deschler & Lübbert, 2006; Pesakhov et al., 2016). The primary
difficulty in the treatment of AML is the chemoresistance, and CD34+
AML cells indicate poor prognosis and resistance to spontaneous
apoptosis. Rao et al. (2011) investigated the cytotoxic effects of
curcumin in DNR‐insensitive CD34+ AML cell lines (KG1a, Kasumi‐1).
Curcumin synergistically increased DNRʼs cytotoxic effects and
inhibited cell proliferation through cell cycle arrest in G1/the S phase.
The expression of both Bcl‐2 mRNA and protein were reduced by
curcumin and it induced activation of caspase‐3. DNA methyltransfer-
ase 1 (DNMT1) is a mediator of DNA methylation that catalyzes
methyl group transfer to DNA. Aberrant DNA methylation leads to
tumor suppressor genes silencing, has been reported in many tumors
and is linked to the pathogenesis of cancer. Therefore, development of
novel DNA methylation inhibitors with less toxicity is needed. In this
4 |
regard, Yu et al. (2013) studied the effects of curcumin on the activity
of DNMT in AML cells in vitro and in vivo. Curcumin reduced the
DNMT activity through downregulation of Transcription Factor1 (Sp1)
and NF‐kB component, p65 (two positive regulators of DNMT1), which
results in reactivation of p15INK4B as a tumor suppressor. Further-
more, in mice, administration of curcumin significantly reduced AML
tumor growth (Toyota et al., 2001).
FMS‐like tyrosine kinase 3 (FLT3) is an important diagnostic
marker in patients with AML. Overexpression of this marker has
been reported in different hematologic cancers, including 70–100%
of AML, ALL, and blast crisis of CML, and has a poor prognosis.
Curcumin dose‐dependently decreases levels of FLT3 and STAT5A in
AML cells (Tima, Ichikawa, Ampasavate, Okonogi, & Anuchapreeda,
2014). At the molecular level, curcumin acts through various
mechanisms. Zhu et al. (2016) found that curcumin inhibitory effects
on human M5 leukemia cells (SHI‐1 cell line) were associated with
suppression of MAPK and matrix metalloproteinase (MMP) signaling.
Moreover, curcumin deregulates factors such as Forkhead box
protein M1 (FoxM1) transcription factor and JNK/ERK pathways
(Yang et al., 2012; Zhang et al., 2014; Zhu et al., 2016).
2.3 | Acute lymphoblastic leukemia
Poly (ADP‐ribose) polymerase‐1 (PARP1) is a nuclear protein that
plays a role in repairing DNA damage. PARP1 participates in
numerous pathological processes including inflammation, cell survi-
val, angiogenesis, and cell death. Overexpression of PARP1 in present
in various primary human cancer cell lines (Chaitanya, Alexander, &
Babu, 2010; Green et al., 2015). Mishra, Singh, and Narayan et al.
(2016) reported that curcumin inhibits the proliferation of REH and
RS4;11 cells (an ALL cell line) via cleavage of PARP1 pathways
(Mishra, Singh, & Narayan, 2016). Curcumin modulates DNA
methylation in AML cells, downregulating the expression of DNMT1,
which leads to upregulation of p15, a tumor suppressor gene, and
causes apoptosis of ALL cells (Sharma et al., 2015).
The Philadelphia chromosome that encodes BCR‐ABL fusion is a
common genetic abnormality in patients with AML, particularly
adults. This fusion carries a poor prognosis of the disease and
interacts with various signaling pathways, including AKT/MTOR
(mammalian target of rapamycin), STAT5, and RAF/MEK/ERK, which
affect apoptosis of lymphoid cells. Imatinib is a TKI prescribed for
these patients. Conversely, Ph+ ALL cells have a poor response to
imatinib and resistance to this agent is observed in these patients
(Druker et al., 2001; Ottmann et al., 2002). Imatinib treatment
enhances the activity of the AKT/MTOR pathway that appears to
interfere with the efficacy of imatinib. Therefore, inhibition of this
pathway may improve the response to imatinib. Curcumin is an
antitumor agent that inhibits various signaling pathways especially
mTOR. Curcuminʼs inhibitory effects, both alone and in combination
with imatinib, on ALL cells in vitro and in vivo was studied. Curcumin
reduced the activation of AKT/mTOR and ABL/STAT5. Moreover,
curcumin downregulated the expression of BCR/ABL and reduced
the ratio of BCL‐2 to BAX. In this study, curcumin not only exhibited
KOUHPEIKAR ET AL.
synergistic antitumor effects with imatinib in the SUP‐B15 cell line
but also inhibited cell growth in samples from both recently
diagnosed and imatinib‐resistant patients (Guo et al., 2015).
2.4 | Chronic lymphocytic leukemia
CLL is the most common type of hematological malignancy in the
Western world (22–30%; Hallek, 2013; Stephens, Gramegna, Laskin,
Botteman, & Pashos, 2005). CLL‐B cells interact with their micro-
environment and survival of B cells is improved by contact with the
bone marrow stromal cells. Therefore, the lifespan of B cells increases,
causing abnormal accumulation of these cells (Golombick, Diamond,
Manoharan, & Ramakrishna, 2017). Ghosh et al. (2009) studied
curcuminʼs inhibitory effects on cells from patients with CLL; curcumin
inhibited NF‐kB, STAT3, and AKT signaling pathways. Studying the
protection of stromal cells on CLL‐B cells, curcumin and epigalloca-
techin‐3 gallate (EGCG) combination showed a reversal of stromal
mediated protection. Moreover, curcumin induced apoptosis via PARP
cleavage, exerting an independent effect on the caspase pathway
(Ghosh, Kay, Secreto, & Shanafelt, 2009).
3 | CURCUMIN ʼS EFF ECT O N THE WILMS ʼ
TUMOR 1 GENE EXPRESSION
The Wilmsʼ tumor 1 (WT1) gene is located at chromosome 11p13,
encoding a transcription factor essential for embryonal progression
(Gao et al., 2012). Overexpression of WT1 (1,000–10,000 folds) has
been shown in AML, ALL, and CML cells, particularly in blast crisis, and
this upregulation carries a poor prognosis (Miwa, Beran, & Saunders,
1992; Miyagi et al., 1993). Gao et al. (2012) investigated the curcuminʼs
effect on WT1 gene expression in leukemic cells (K562 and HL‐60).
Curcumin reduced WT1 gene expression through upregulation of miR‐
15a/16‐1 expression, whereas downregulation of WT1 stimulates
apoptosis whilst inhibiting proliferation of tumor cells. In line with this
study, it has been reported that miR‐15a/16‐1 targets WT1 and
decreases WT1 expression, inhibiting leukemia cell growth (Semsri, Krig,
Kotelawala, Sweeney, & Anuchapreeda, 2011). Protein kinase C (PKC) is
a large family of proteins which are involved in cellular processes such
as proliferation, differentiation, and apoptosis (Battaini & Mochly‐Rosen,
2007). Curcumin has been reported to regulate various cellular
pathways including PKC (Kunnumakkara, Anand, & Aggarwal, 2008).
Semsri et al. (2011) published that curcumin downregulated WT1 via
downregulation of the PKC signaling pathway.
4 | EF FECTS O F C URCUMIN I N CL IN I CAL
TRIALS
Increased nitric oxide (NO) concentrations are associated with the
proliferation of tumor cells and stimulate angiogenesis. NO is also
involved in the p53 mutation in cancer cells such as colon, lung, and
oropharynx cancer (Lala & Orucevic, 1998). Ghalaut et al. (2012)
T A B L E 1 The effects of curcumin on different types of leukemia as reported in in vitro studies

Type of leukemia Dose of curcumin Type of cell line Mechanism of action of curcumin Finding Ref
ALL 15 µM SUP‐B15 Inhibition of AKT/MTOR, Increased the anti‐leukemia Guo et al. (2015)
KOUHPEIKAR

BCR/ABL effects of imatinib

ET AL.

ALL Dependent manner CEM, HSB2, Jurkat, and Inhibition of PI3‐kinase/AKT Stimulated caspase‐dependent Hussain et al. (2006)
MOLT‐4 pathway apoptosis
ALL Dependent manner RS4; 11, Reh, and Jurkat Suppression of AKT pathway Increased the antitumor Wang, Geng, Wang, &
effects of L‐asparaginase Lu (2012)
ALL 8.14 µM CCRF‐CEM Pro‐oxidant activity G2/M phase arrest (Kong et al., 2009)
ALL 30 µM B6p210, B6T315I Reduction of NF‐kB levels and Induced apoptosis William, Goodrich,
upregulation of p53 Peng, & Li (2008)
AML 10 µM THP‐1 cells Blocked potassium channel Inhibited proliferation of AML Banderali et al. (2011)
Kv11.1 cells
AML Dependent manner KG‐1 Upregulation of folate receptor b Increased cytotoxicity effects Zand (2013)
and FRb protein of Methotrexate
AML 10 µM MV4‐11 Downregulated DNMT1 Suppressed proliferation of Yu et al. (2013)
expression AML cells
AML 40 µM THP‐1 cells Suppression of Akt and ERK Induced cell apoptosis Shi et al. (2015)
pathways, and upregulation of
p53 and JNK pathways
AML 4 μM EoL‐1 Reduction of FLT3 and STAT5A Arrested cell cycle at the G0/ Tima et al. (2014)
levels G1 phase
AML‐M3 9.8 μM HL‐60 Suppression of telomerase activity Induced cell apoptosis Mukherjee et al. (2007)
AML‐M3 10–30 μM HL‐60/VCR Suppression of SMS and GCS/ Stimulated apoptosis of Shakor et al. (2014)
accumulation of ceramide multidrug‐resistant cells
AML‐M3 40 μM HL‐60 Increased γH2AX levels Synergistic cytogenotoxic Papież and
effect with epicatechin Krzyściak (2017)
AML‐M3 (0, 0.5, 1, 5 HL‐60 Downregulation of MMP and Bcl‐ Induced cell apoptosis Tan et al. (2006)
and 10 μM 2/upregulation of Bax/release of
cytochrome c
AML‐M3 2 μM HL‐60 Upregulation of BAX and Sp1 Increased the anti‐leukemia Chen, Wang, Wang,
binding at the BAX promoter/ effects of valproic acid Kang, and
activation of p38 MAPK Wang (2010)
AML‐M3 20 μM HL‐60 Increasing the oxidative Increased the antileukemic Papież et al. (2016)
stress (ROS) effect of etoposide
(Continues)
|
5
 6
|

TABLE 1 (Continued)

Type of leukemia Dose of curcumin Type of cell line Mechanism of action of curcumin Finding Ref
AML‐M3 Dependent manner HL‐60 Increasing the oxidative Regulated the oxidative burst Derochette
stress (ROS) et al. (2013)
AML‐M3 10, 15, 20, HL‐60 Activation of caspase‐3 Induced cell apoptosis Dikmen, Canturk,
and 40 μM Ozturk, and
Tunali (2010)
AML‐M3 10, 25, and 50 μM HL‐60 Downregulation of ornithine Induced cell apoptosis Liao et al. (2008)
decarboxylase
AML‐M3 20 μM HL‐60 Development of endoplasmic Induced cell apoptosis Pae et al. (2007)
reticulum
CML 20 μM K562 Activation of autophagy Inhibited cell proliferation Jia, Li, Qin, &
Liang (2009)
CML 70 µM K562 Stimulated topoisomerase I and II Prevented cell growth López-Lázaro
et al. (2007)
CML 5 to 30 µM K562 Caspase‐independent apoptosis Induced G2/M phase arrest Martínez-Castillo
et al. (2018)
CML 40 µM K562 and LAMA84 Downregulation of miR‐21/ Downregulation of BCR‐ABL Taverna et al. (2015)
induction of PTEN expression expression
CML 48 µM or 35 µM K562 Upregulation of HSP protein Inhibited proliferation Teiten, Reuter,
expression/downregulation of Schmucker, Dicato, &
Bag‐1 expression Diederich (2009)
Note. ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; BCR‐ABL: breakpoint cluster region‐Abelson; CML: chronic myeloid leukemia; MTOR: the mammalian target of rapamycin
KOUHPEIKAR
ET AL.
KOUHPEIKAR ET AL.
T A B L E 2 The effects of curcumin on different types of leukemia as reported in in vivo studies
Type of Dose of Duration of
leukemia curcumin treatment Type of administering
ALL 25 mg/kg 14‐day Injected intraperitoneally
ALL 40 mg/kg 14‐day Injected intraperitoneally
AML 200 mg/kg 23‐day Oral gavage
AML 100 mg/kg 28‐day Injected intraperitoneally
AML‐M3 100 mg/kg 23‐day Oral gavage
CML 2 mg/kg 14‐day Oral gavage
Note. ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; BCR‐ABL: breakpoint cluster region‐Abelson; BM: bone marrow; CML: chronic
myeloid leukemia; DNMT1: DNA methyltransferase 1; WBC: white blood cell
evaluated the efficacy of turmeric powder on patients with CML. Fifty
patients were enrolled and assigned to either imatinib alone or 15 g/
day turmeric with imatinib for six weeks, and NO levels were
measured before and after receiving therapy. Patients receiving
turmeric together with imatinib showed a greater decrease in NO
levels compared with those receiving imatinib alone. In addition, the
hematological response with combination therapy was better than
with imatinib alone. This study suggests that curcumin can be
prescribed as an adjuvant to imatinib in patients with CML. Natural
killer (NK) cells are effectors of innate immunity which target infected
cells and tumor cells and lyse these cells via production of cytokines.
Studies have reported NK cell deficiency in CLL and other
malignancies. Thus, focusing on methods to increase populations of
NK cells in cancer therapy is necessary (Lowry & Zehring, 2017;
Ziegler, Kay, & Zarling, 1981). In CLL, increased T cell and NK cell
populations can delay progression of the disease (Gonzalez‐
Rodriguez et al., 2010). The effect of phytosomal curcumin (a form
of curcumin complexed with phospholipids to enhance the absorption
[Mirzaei et al., 2017]) on absolute lymphocyte count (ALC), T cell, and
NK cell populations in patients with early Stage CLL were investigated.
A total of 21 patients with lymphocytosis were enrolled in the study
and prescribed 2 gm oral curcumin daily for 2 months. Curcumin
increased T cell (both CD4 and CD8) and NK cell populations, as cell
types that are involved in tumor cell eradication, via immunomodula-
tion. Curcumin also decreased the ALC by immune response induction
via increasing CD4, CD8, and NK cell numbers. This study suggests
curcuminʼs usefulness for a small number of patients with CLL
(Golombick, Diamond, Manoharan, & Ramakrishna, 2015; Huergo‐
Zapico et al., 2014). Similarly, Golombick, Diamond, Manoharan, and
Ramakrishna (2016) investigated curcuminʼs efficacy together with
arabinoxylan in 10 patients with CLL at Stage 0/1. Arabinoxylan has
anti‐inflammatory and proapoptotic effects and can induce an immune
response. Patients with Stage 0/1 CLL received curcumin (6 g) and
Ribraxx (2 g) daily for 6 months. The combination of curcumin and
arabinoxylan reduced ALC (20%) in 22% of patients whilst CD4 and
CD8 T cells increased (Golombick, Diamond, Manoharan, & Ramak-
| 7
Result Ref
Decreased BCR/ABL expression in bone marrow Guo et al. (2015)
(BM)/Decreased infiltration of leukemic cells in spleen
Increased white blood cell (WBC) counts/ Improved William et al. (2008)
survival of mice
Increased normal granulocyte count/Decreased Papież and
percentage of promyelocytes in BM Krzyściak (2014)
Decreased levels of DNMT1/Inhibited Yu et al. (2013)
tumor growth and decreased tumor weight
Decreased the spleen weight/Increased proapoptotic Papież et al. (2016)
effects of etoposide
Downregulation of miR‐21/Decreased tumor growth Taverna et al. (2015)
rishna, 2016). Moreover, a Phase II clinical trial evaluating the effects
of curcumin and cholecalciferol combination in treating patients with
previously untreated Stage 0‐II CLL is ongoing. In this study, patients
(n = 30) receive a combination of curcumin and cholecalciferol orally
for 28 days, repeated for up to six courses (NCT02100423).
5 | CO NCL USIONS
Leukemia was diagnosed in 2.3 million people in 2015. Despite
improvements in treatment, leukemia appears to be largely incurable
with conventional chemotherapy and caused 353,500 deaths in 2015
(Vos et al., 2016; Wang et al., 2016). Conventional chemotherapy
agents have many side effects, and in most cases, patients suffer from
relapse. Curcumin is a natural product that is readily available and is
safe even at high doses. As discussed here, curcumin has a wide range
of anticancer, antioxidant, and anti‐inflammatory properties and its
efficacy in leukemia has been reported in many in vitro (Table 1) and
in vivo (Table 2) studies. In keeping with the evidence presented
here, curcumin can be considered as a therapeutic approach for the
treatment of leukemia alone and in combination with chemotherapy
agents. One limitation of curcumin is that most studies have only
confirmed the anti‐leukemia properties of curcumin in animal and
cellular models. Although there is evidence supporting the efficacy of
curcumin in patients with leukemia, the number of these clinical trials
is limited. Therefore, it is necessary to perform long‐term clinical
trials to confirm the efficacy of curcumin in leukemia patients with
leukemia. Finally, it would be informative to assess if the potential
efficacy of curcumin against leukemia are dose‐dependent, and could
be enhanced using tailored formulations of curcumin with improved
bioavailability and/or reduced metabolism.
CON F LI CTS OF I NTERE ST
Muhammed Majeed is the founder of Sabinsa Corporation and Sami
Labs Ltd. Other authors have no direct competing interests to declare.
8 |
A UT HO R C ONT RI BU TIO NS
H. K. and A. S. conceived the presented idea. H. K., A. S., and F. B.
designed the review and prepared the first draft. A. E. B., G. E. B., and M.
M. critically revised the review. All authors read and approved the final
version.
A C K N O W L E D GM E N T S
This project has been conduct by a grant from cancer research center
of cancer institute of Iran, Sohrabi cancer charity (37312-202-01-97),
this project was also financially supported by the Biotechnology
Development Council of the Islamic Republic of Iran (960206).
OR CID
Alexandra E. Butler http://orcid.org/0000-0002-5762-3917
George E. Barreto http://orcid.org/0000-0002-6644-1971
Amirhossein Sahebkar http://orcid.org/0000-0002-8656-1444
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How to cite this article: Kouhpeikar H, Butler AE, Bamian F,
Barreto GE, Majeed M, Sahebkar A. Curcumin as a
therapeutic agent in leukemia. J Cell Physiol. 2019;1–11.
https://doi.org/10.1002/jcp.28072