Critical Reviews in Oncology/Hematology 112 (2017) 2130

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Critical Reviews in Oncology/Hematology

journal homepage: www.elsevier.com/locate/critrevonc

The roles of reactive oxygen species (ROS) and autophagy in the

survival and death of leukemia cells
Yong-Feng Chen a,b, , Hao Liu c , Xin-Jing Luo a,b , Zhiqiang Zhao a,b , Zhen-You Zou a,b,d ,
Jing Li e , Xiao-Jing Lin f , Yong Liang b,
a
Department of Basic Medical Sciences, School of Medicine of Taizhou University, Taizhou 318000, Zhejiang, China
b
Institute of Tumor, School of Medicine of Taizhou University, Taizhou 318000, Zhejiang, China
c
School of Pharmacy, Shanghai Jiaotong University, Shanghai 200240, China
d
Biochemistry Department of Purdue University, West Lafayette, IN 47906, USA
e
Department of Histology and Embryology, North SiChuan Medical College, Nanchong 637000, Sichuan, China
f
Department of Hematology, the Afliated Hospital of Guiyang Medical College, Guiyang 550004, China

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2. The role of ROS in hematopoiesis and the pathogenesis of leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
3. The role of autophagy in hematopoiesis and the pathogenesis of leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
4. ROS autophagy interaction implicated in the evolution of MDS to AML . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
5. Exploiting ROS for overcoming drug resistance in leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
6. Targeting autophagy to overcome drug resistance in leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
7. ROS-induced autophagy as a therapeutic strategy for treatment of leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
8. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Conict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

a r t i c l e i n f o a b s t r a c t

Article history: As a clonal disease of hematopoietic stem cells (HSCs), the etiology and pathogenesis of leukemia is not
Received 17 November 2015 fully understood. Recent studies suggest that cellular homeostasis plays an essential role in maintaining
Received in revised form the function of HSCs because dysregulation of cellular homeostasis is one of the major factors underlying
27 November 2016
the malignant transformation of HSCs. Reactive oxygen species (ROS) and autophagy, key factors regu-
Accepted 6 February 2017
lating cellular homeostasis, are commonly observed in the human body. Autophagy can be induced by
ROS through a variety of signaling pathways, and conversely inhibits ROS-induced damage to cells and
Keywords:
tissues. ROS and autophagy coordinate to maintain cellular homeostasis. Previous studies have demon-
Reactive oxygen species (ROS)
Autophagy
strated that both of ROS and autophagy play important roles in the development of leukemia and are
Leukemia closely involved in drug resistance in leukemia. Interference with cellular homeostasis by promoting pro-
Hematopoiesis grammed leukemia cell death via ROS and autophagy has been veried to be an efcient technique in the
Homeostasis treatment of leukemia. However, the critical roles of ROS and autophagy in the development of leukemia
Programmed cell death are largely unknown. In this review, we summarize the roles of ROS and autophagy in the pathogenesis
Drug resistance of leukemia, which may allow the identication of novel targets and drugs for the treatment of leukemia
based on the regulation of HSCs homeostasis through ROS and autophagy.
2017 Elsevier B.V. All rights reserved.

1. Introduction

Corresponding author at: School of Medicine of Taizhou University, Taizhou, Reactive oxygen species (ROS) are a class of oxygen metabo-
318000, Zhejiang, China. lites and oxygen-containing materials that are derived from oxygen
Corresponding author. metabolites, and they include all peroxide and oxygen-free radi-
E-mail addresses: cyfeng@tzc.edu.cn (Y.-F. Chen), liangytzc@163.com (Y. Liang).

http://dx.doi.org/10.1016/j.critrevonc.2017.02.004
1040-8428/ 2017 Elsevier B.V. All rights reserved.
22 Y.-F. Chen et al. / Critical Reviews in Oncology/Hematology 112 (2017) 2130
cals. ROS are chemically more active than oxygen, tightly associated
with cellular homeostasis, and can signicantly affect cellular
homeostasis and metabolism (Nogueira and Hay, 2013a). In normal
concentrations, ROS serve as important second messengers that
are involved in a variety of signal transduction events that regu-
late the growth, proliferation, and differentiation of cells (Landry
and Cotter, 2014; Kobashigawa et al., 2015). Redox dysregulation
causes an excessive generation and accumulation of ROS, leading
to oxidative damage to cells and tissues, which is involved in the
development of cancers and many other human diseases (Montero
and Jassem, 2011; Nogueira and Hay, 2013b).
Autophagy, which involves lysosomal-dependent degradation
of macromolecules and organelles in cells, plays an essential role in
maintaining cellular homeostasis and is involved in the pathogen-
esis of numerous diseases (Chen et al., 2014a). A number of signal
transduction pathways are related to the function and coordination
between ROS and autophagy in cells in response to cellular stress.
ROS and autophagy interact to maintain cellular homeostasis. ROS
can induce autophagy, but autophagy serves as a buffer system to
control the level of ROS in cells and reduce their toxic effects (Li
et al., 2015). Redox imbalances and/or autophagy dysregulations
affect the proliferation and differentiation of hematopoietic stem
cells (HSCs), leading to the development of hematological malig-
nancies in some degree (Naka et al., 2008; Evangelisti et al., 2015).
Recent progress in leukemia has revealed that ROS and autophagy
are strongly associated with the development of this disease. In
addition, they are also potentially involved in the mechanism of
drug resistance of leukemia cells. It has been reported that the
disruption of cellular homeostasis through ROS and autophagy
is an effective approach to circumvent the development of drug
resistance in leukemia cells (Evangelisti et al., 2015; Udensi and
Tchounwou, 2014; She et al., 2007; Ekiz et al., 2012; Torgersen
and Simonsen, 2013). However, the roles of ROS and autophagy
in the development and treatment of leukemia remain unclear.
In particular, the signal transduction pathways involving ROS and
autophagy in the maintenance of cellular homeostasis are largely
unknown. Elucidation of the molecular mechanisms underlying
ROS and autophagy in the pathogenesis of leukemia may provide
novel targets and drugs for the treatment of this disease.
2. The role of ROS in hematopoiesis and the pathogenesis
of leukemia
ROS can be classied as exogenous or endogenous ROS accord-
ing to their origins. Exogenous ROS are generated in the body by
external sources such as radiation and drugs, and endogenous ROS
are mainly the products of aerobic metabolism in cells (Lee et al.,
2013). ROS can be generated by a number of approaches, including
mitochondria, the NADPH oxidase system (NOXs), and the xanthine
oxidase system, among which NOXs are the most important source
of ROS (Libik-Konieczny et al., 2015). NOXs are located in the cyto-
plasmic membrane and can be quickly activated by bacterial lipid
polysaccharides, TNF-, or IL-1 to produce ROS, a second messen-
ger molecule that is involved in a variety of signal transduction
pathways (Dickinson and Chang, 2011).
Normal levels of ROS are essential for maintaining the phys-
iological functions of cells by regulating their proliferation and
differentiation, and for controlling immune responses and cellu-
lar inammation (Owusu-Ansah and Banerjee, 2009; Kwak et al.,
2015). Excess ROS can cause oxidative stress, leading to oxidative
damage to organelles, proteins, lipids, and DNA, disruption of cellu-
lar structures and functions, or cell death (Yorimitsu and Klionsky,
2007). ROS regulate the function of HSCs in a concentration-
dependent manner. At normal levels, ROS serve as a signaling
molecule to control the proliferation, differentiation, and mobi-
lization of HSCs (Ludin et al., 2014; Juntilla et al., 2010); however,
higher levels of ROS have toxic effects on HSCs (Shao et al., 2011).
HSCs reside mainly in the bone marrow in the quiescent state. Com-
pared with other types of cells, HSCs are more susceptible to ROS
(Jang and Sharkis, 2007; Richardson et al., 2015). Increased levels
of ROS can result in DNA damage in HSCs, leading to dysfunctions
such as abnormal proliferation and differentiation (Yahata et al.,
2011). In the bone marrow microenvironment, many cells, such as
-smooth muscle actin (SMA)+ macrophages and mesenchymal
stromal cells (MSCs), are involved in maintaining the balance of ROS
in stem cells (Fig. 1) (Ludin et al., 2014). In addition, the deletion of
a number of genes such as FoxO3 or Atm can increase ROS levels
and inhibit HSCs self-renewal and hematopoiesis, suggesting that
these genes are involved in ROS production and the regulation of
hematopoiesis (Zhou et al., 2013).
Under normal physiological conditions, the generation and
degradation of ROS in the body maintain in a state of equilibrium.
An imbalance between oxidant and antioxidant systems results
in the over-production and accumulation of ROS. Previous studies
have shown that ROS over-production due to redox dysregulation
plays an important role in the proliferation, survival, differentia-
tion, immune escape, and epigenetic changes observed in leukemia
cells (Lewandowski et al., 2010). Devi et al. observed increased
levels of superoxide anion and hydrogen peroxide generated by
polymorphonuclear leukocytes in the peripheral blood of untreated
leukemia patients (Devi et al., 2000). Interestingly, the changes in
superoxide anion and hydrogen peroxide levels in the peripheral
blood were not associated with the leukemia types, suggesting that
increased ROS is a common feature of all leukemia types (Devi
et al., 2000). It has been reported that high levels of ROS can lead
to genomic instability and are associated with the development
and progression of leukemia (Popp and Bohlander, 2010). Rassool
et al. reported that DNA damage and error-prone repair of damaged
DNA were consistent with the increased levels of ROS detected in a
myeloid leukemic disease progression model (Rassool et al., 2007).
Zhou et al. found that the serum level of 8-oxo-2 -deoxyguanosine
(8-oxo-dG), a biomarker of oxidative damage to DNA, was signif-
icantly higher in acute myeloid leukemia (AML) patients than in
normal controls (Zhou et al., 2010). In addition, Collado et al. found
that the levels of 8-oxo-dG were signicantly higher in the lympho-
cytes of patients with CLL compared with normal controls (Collado
et al., 2012). Taken together, these results suggest that oxidative
DNA damage caused by ROS is closely associated with the develop-
ment of leukemia.
To date, the precise mechanisms underlying ROS overproduc-
tion remain largely unknown. Recent studies suggest that increased
production of ROS in AML, chronic myelogenous leukemia (CML),
and promyelocytic leukemia (PL) is mainly attributed to the consti-
tutive activation of NOXs (Hole et al., 2013; Singh et al., 2012; Dong
et al., 2004). Hole et al. also found that elevated ROS in AML cells
was associated with reduced levels of glutathione (GSH) and deple-
tion of antioxidant defense proteins (Hole et al., 2013). In addition,
reduced antioxidant levels were also identied in other types of
leukemia (Battisti et al., 2008; Oltra et al., 2001; Silber et al., 1992),
suggesting that the imbalance between oxidant and antioxidant
systems is a major cause of the overproduction of ROS. However,
improved antioxidant responses have also been observed in differ-
ent types of leukemia and may represent adaptive responses that
protect cells against oxidative stress damage (Devi et al., 2000).
These inconsistent results may be explained by the heterogeneous
nature of leukemia, for which the oxidant and antioxidant levels
detected in different type of leukemia or the same type at differ-
ent disease stages are distinct. However, this hypothesis requires
further investigation.
As the major source of ROS, NOXs improve both the survival
and proliferation of leukemia cells by increasing the production of
 Y.-F. Chen et al. / Critical Reviews in Oncology/Hematology 112 (2017) 2130
Fig. 1. Environmental factors maintain the balance of ROS in stem cells. Mesenchymal stromal cells (MSCs) and -smooth muscle actin (SMA)+ macrophages cooperate to
maintain low levels of ROS in HSCs. The SMA+ macrophages contain cyclooxygenase-2 (COX-2), which produces prostaglandin E2 (PGE2) to reduce intracellular ROS levels
in stem cells. PGE2 also promotes CXCL12 production from MSCs. In addition, stem cells are connected to the MSCs via connexin gap junctions that transfer ROS to reduce
ROS levels in stem cells. This gure was adapted from (Ludin et al., 2014).
ROS. However, the underlying mechanism is not fully understood.
Singh et al. found that heme oxygenase 1 (HO-1), a cytoprotective
protein that plays a critical role against oxidative stress, was up-
regulated in CML cells by the NOXs components Rac1 and p47phox
(Singh et al., 2012). Our previous study also showed that HO-1 was
aberrantly overexpressed in a majority of AML patients, especially
patients with acute monocytic leukemia (M5) and leukocytosis (Lin
et al., 2015). Our results further demonstrated that HO-1 inhibited
AML cell apoptosis by activating the JNK/c-JUN signaling path-
way (Lin et al., 2015). Aurelius et al. recently found that the ROS
generated from NOXs in leukemia cells promoted NK and T cell
apoptosis, allowing leukemia cells to escape from antileukemic
lymphocytes (Aurelius et al., 2012). These results suggest that the
NOXs-ROS pathway is a potentially powerful target for the treat-
ment of leukemia.
3. The role of autophagy in hematopoiesis and the
pathogenesis of leukemia
Under normal physiological conditions, autophagy is main-
tained at a low level; however, autophagy can be activated by
exogenous stimuli such as oxidative stress, hypoxia, nutritional
deciencies, and infection. Intracellular soluble proteins, long-lived
proteins, and damaged organelles are transported to the lysosome
for degradation. The degraded products, including free fatty acids,
amino acids, and nucleotides, will be reused by cells. Excessive acti-
vation of autophagy may induces autophagic cell death (Clarke and
Puyal, 2012).
Although the mechanism underlying autophagy has been exten-
sively studied in recent years, the role and regulation of autophagy
in hematopoiesis remains unknown. Recently, Mortensen et al.
reported that conditional knockout of the autophagy-related genes,
Atg7 or FIP200, in the hematopoietic system of mice led to a
functional deciency of HSCs, signicant decrease in hematopoi-
23
etic stem/progenitor cells, ROS accumulation in mitochondria,
DNA damage, and myeloproliferation (Mortensen et al., 2011). In
vitro experiments had shown that Atg7 knockout caused a seri-
ous decline in the colony-forming ability of HSCs (Mortensen
et al., 2011). Similarly, the autophagy inhibitor 3-methyladenine
(3-MA) or Atg5 siRNA suppressed colony formation in HSCs (Salemi
et al., 2012). Taken together, these results suggest that autophagy
plays an important role in maintaining homeostasis, self-renewal,
and differentiation in HSCs; however, the underlying mecha-
nisms require further investigation. The autophagy-related genes
involved in hematopoiesis are shown in Table 1.
It is recently identied that autophagy is associated with
hematopoietic dysplasia and involved in the occurrence and devel-
opment of certain types of leukemia. Robust evidence exists that
autophagy involved in the development of BCR-ABL-mediated
leukemia. The BCR/ABL rearrangement t(9;22)(q34;q11) (Ph chro-
mosome) represents the hallmark of CML and can also be detected
in ALL (Chiaretti et al., 2014). The BCR-ABL protein has been shown
to induce ROS production and DNA damage in CML cells (Sattler
et al., 2000; Benhar et al., 2001). In addition, the BCR-ABL protein,
which possesses extremely high levels of tyrosine kinase activity,
Table 1
Potential roles of autophagy in hematopoiesis.
Hematopoiesis process Autophagy-related
genes involved in
hematopoiesis
HSCs self-renewal ATG7, IRGM, MTOR
HSCs quiescence ATG7, IRGM,
RB1CC1/FIP200
HSCs progenitor ATG7, RB1CC1/FIP200
differentiation/remodeling
Lineage-restricted progenitor ATG3, ATG5, ATG7,
maintenance ULK1, BNIP3L/NIX,
PIK3C3/VPS34
24 Y.-F. Chen et al. / Critical Reviews in Oncology/Hematology 112 (2017) 2130
can phosphorylate itself and many other substrates, activating the
RAS/MAPK, PI3K/AKT, and JAK/STAT signaling pathways. Activation
of these pathways has extensive effects on the growth, differenti-
ation, and survival of hematopoietic cells, including an increase in
proliferation and inhibition of apoptosis, thus promoting the devel-
opment of CML (Samanta et al., 2011; Stella et al., 2013). Altman
et al. reported that autophagy was the primary determinant of the
survival of cells expressing BCR-ABL, whereas the basal levels of
autophagy in BCR-ABL-expressing cells were low (Altman et al.,
2011). The authors also found that knockout of the autophagy-
related gene Atg3 or autophagy inhibitors signicantly induced
apoptosis (Altman et al., 2011). Transplantation of BCR-ABL cells
into mice caused leukemia 20 days after transplantation (Altman
et al., 2011). These results suggest that autophagy plays an essential
role in the development of BCR-ABL-mediated leukemia and that
the survival of BCR-ABL cells might depends mainly on autophagy.
Different from its role in CML, autophagy may play a distinct role
in the development of AML. Waston et al. declared that if there was
autophagy defect in the process of bone marrow hematopoiesis, a
large number of bone marrow progenitor cells would accumulate,
which would lead to the dysfunctions of hematopoietic stem cell
and myeloid differentiation, and severe myeloid invasion, a symp-
tom extremely similar to that in acute myeloid leukemia. Irregular
myeloid proliferation occurred in the bone marrow of autophagy-
related gene (Atg) 7 knockout mice, which was similar to the
process of myelody splastic syndrome (MDS) to AML in human.
It hints that autophagic defects may be associated with the devel-
opment of MDS to AMI (Watson et al., 2011a). Hu et al. reported
that the expression of BECLIN-1 and the number of autophagic vac-
uoles in bone marrow mononuclear cells (BMMNC) from patients
with MDS progression and patients with MDS-transformed AML
were gradually declining (Hu et al., 2015). Besides, plenty of rela-
tive studies had obtained the analogous results (Wan et al., 2013;
Zare-Abdollahi et al., 2016). Totally, it suggests that autophagy may
be closely related to the progression of AML.
4. ROS autophagy interaction implicated in the evolution
of MDS to AML
Recent studies show that a variety of cell homeostasis mecha-
nisms work together to reduce ROS damage to cells and maintain
cell survival. Autophagy is one of the major mechanisms maintain-
ing cellular homeostasis. ROS and autophagy play important roles
in stress response in cells through a number of complicated sig-
naling pathways and molecules (Underwood et al., 2010; Xu et al.,
2006; Cao et al., 2009; Kongsuphol et al., 2009; Chen et al., 2014b).
A variety of stresses, such as nutritional deprivation, hypoxia,
ischemia-reperfusion, and cellular stress, can increase intracellu-
lar ROS production, which subsequently induces autophagy (Essick
and Sam, 2010). This sequence of events has been described
in a number of diseases, such as diabetes, rheumatoid arthri-
tis, heart failure, neurodegenerative diseases, cancer, and cystic
brosis (Essick and Sam, 2010). In addition, a variety of exoge-
nous substances can induce autophagy by increasing ROS levels.
The pathways involved in ROS-induced autophagy are affected by
numerous factors, such as cell types, different stimuli, and the
experimental environment. Regulation of autophagy by ROS is
shown in Fig. 2.
Recent studies had demonstrated that some types of tumor cells,
such as breast cancer, liver cancer, stomach cancer, colorectal can-
cer, and cervical cancer cells, possess higher levels of autophagy
activity (Ahn et al., 2007; Tang et al., 2009; Karantza-Wadsworth
and White, 2007; Sun et al., 2010). Tumor cells often reside in a
hypoxic environment with nutritional deciencies. Autophagy may
be an important tumor cell survival mechanism via the degrada-
tion of intracellular organelles and proteins to provide energy and
nutrients for tumor cell growth. In addition, autophagy can remove
or repair ROS-damaged DNA and proteins, reducing cytotoxicity
and protecting cells (Sun et al., 2010; Lisanti et al., 2010; He and
Klionsky, 2009). However, autophagy may fail to remove excess
ROS when ROS levels exceed the autophagy capacity, resulting in
excess autophagy and autophagic cell death (Dadakhujaev et al.,
2009).
Mitochondria are the main organelles responsible for ROS pro-
duction and degradation, but they are also highly sensitive to
ROS damage. Mitochondrial damage or dysfunction reduces the
production of ATP and increases the production of ROS, increas-
ing oxidative damage to cells (Gobe and Crane, 2010). To date,
numerous studies have suggested that mitochondrial dysfunc-
tion is associated with the development of Parkinsons disease,
Alzheimers disease, diabetes, and many other diseases (de Moura
et al., 2010; Jung and Lee, 2010; Pallard et al., 2010). Abnormal
mitochondria, such as increased numbers of mitochondria with an
irregular morphology displaying a destroyed mitochondrial matrix
and membrane and disorganized cristae, have also been observed
in leukemia cells (Schumacher et al., 1975; Szekely et al., 1976;
Herrera-Goepfert et al., 1986; Iwama and Eguchi, 1986). There-
fore, it has been proposed that the oxygen-peroxide features of
mitochondria are involved in leukemogenesis (Lyu et al., 2008).
MDS was recognized as hematopoietic dysfunction due to
abnormal proliferation and differentiation of HSCs. Approximately
one third of MDS patients will nally develop into AML. Interest-
ingly, elevated ROS levels accompanied by mitochondrial damage
was observed in mononuclear bone marrow cells of MDS patients
(Farquhar and Bowen, 2003). As mentioned before, mitochondrial
damage is a direct cause of many human diseases, and mitochon-
drial autophagy is an important regulatory mechanism of cells
via the removal of damaged mitochondria and maintaining their
homeostasis. When the cells are autophagy defects, it will lead
to intracellular damage and a large number of aggregation in the
aged mitochondria, thereby promoting the development of tumor.
Boultwood et al. conducted quantitative analyses of mitochon-
drial DNA (mtDNA) in the peripheral blood of AML patients and
healthy individuals. They found a signicantly greater quantity of
mtDNA in AML patients compared with healthy individuals, sug-
gesting that mitochondrial autophagy defect may exist in AML
cells, leading to an increase in the number of mitochondria, and
that the mitochondrial autophagy defect may involved in the
development of AML (Boultwood et al., 1996). Houwerzijl et al.
reported that mitophagy activity in erythroid precursors was signif-
icantly increased in patients with AML-high-risk myelodysplastic
syndrome (MDS) compared with those with AML-low-risk MDS,
suggesting that mitophagy is an important protective mechanism
for the degradation of abnormal mitochondria and inhibition of ROS
accumulation in cells (Houwerzijl et al., 2009). Some investigators
have proposed that high cellular levels of ROS cause DNA dam-
age and increase the risk of developing AML. Therefore, functional
autophagy may be an important mechanism for the prevention of
MDS into AML (Watson et al., 2011b).
5. Exploiting ROS for overcoming drug resistance in
leukemia
Great progress have been achieved in the treatment of leukemia;
however, the emergence of drug resistance often leads to treatment
failure. Therefore, understanding the mechanisms underlying drug
resistance in leukemia is critically important to predict treatment
outcomes. Drug resistance in leukemia involves complicated mech-
anisms, such as enhanced drug efux, proto-oncogene mutations,
the amplication of drug resistance genes, increased activities of
 Y.-F. Chen et al. / Critical Reviews in Oncology/Hematology 112 (2017) 2130 25

Fig. 2. Regulation of autophagy by reactive oxygen species (ROS). ROS are mainly produced in mitochondria. Increased ROS production caused by nutrient starvation, drugs,
and radiation, regulates autophagy via several signaling pathways such as the AMPK-mTOR and PI3K-Akt-mTOR pathways (Jung and Lee, 2010). In addition, increased ROS
production also leads to a redox imbalance in cells through the release of GSH into the environment via MRP1, which decreases the GSH/GSSG ratio and oxidized thiols and
causes autophagy (Pallard et al., 2010).
AMPK: AMP-activated protein kinase; ATG4: autophagy-related gene 4; Bcl-2: B-cell lymphoma-2; Beclin-1: Bcl-2 interacting coiled-coil protein-1; ERk 1/2: extracellular
signal-regulated kinase1/2; FOXO: Forkhead box-containing protein O subfamily; GSH: reduced glutathione; GSSG: oxidized glutathione; JNK: cJun n-terminal kinase; LC3-II:
microtubule associate protein 1 light chain 3-II; MRP1: multidrug resistance protein 1; mTOR: mammalian target of rapamycin; PI3K: phosphatidylinositol 3-kinase; PKB/Akt:
protein kinase B; PTEN: phosphatase and tensin homologue deleted on chromosome10; TSC1/2: tuberous sclerosis complex 1/2; Ulk1/2: unc-51-like kinase 1/2.
26 Y.-F. Chen et al. / Critical Reviews in Oncology/Hematology 112 (2017) 2130
drug-metabolizing enzymes, and inhibition of apoptosis (Frame,
2007; Chauncey, 2001). In recent years, the role of ROS in tumor
resistance has received much attention. The elevation of drug
resistance genes expression was reported as one of the poten-
tial mechanisms of ROS affecting tumor resistance (Hwang et al.,
2007; Tien Kuo and Savaraj, 2006). Besides, ROS may also affect
tumor resistance through a variety of ways. Yi et al. found that
the intracellular ROS level determined the sensitivity of leukemia
cells to arsenic trioxide (Yi et al., 2002). For example, a higher
level of intracellular ROS in leukemia cells was associated with an
elevated sensitivity to arsenic trioxide. Zhou et al. also reported
that CLL cells with a higher basal level of ROS were more sensi-
tive to the chemotherapeutic agent 2-methoxyestradiol than CLL
cells with a lower basal level of ROS (Zhou et al., 2003). All these
studies indicated that ROS level in leukemia cells might be tightly
associated with related cell resistance, low ROS level with greater
resistance, and high ROS level followed by weaker resistance. Zhou
et al. proved that the raise of ROS production improved the anti-
leukemic activity of 2-methoxyestradiol (Zhou et al., 2003). In
addition, some studies have also demonstrated that abrogation of
the redox balance in leukemia cells by increasing the production of
ROS is an efcient strategy to overcome drug resistance in leukemia
(Ruvolo et al., 2010; Tonino et al., 2011; Kim et al., 2014; Changchien
et al., 2015).
According to reports in the literature, the anti-leukemic prop-
erties of a variety of chemotherapy drugs that are used to treat
leukemia, such as doxorubicin, vincristine, and arabinoside, have
been attributed to the generation of ROS in leukemia cells(Mizutani
et al., 2005; Groninger et al., 2002; Romano et al., 2000; Kanno et al.,
2004; Guzman et al., 2005; Yang et al., 2006; Inoue et al., 1994; Chen
et al., 2005; Yaseen et al., 2012; Ka et al., 2003; Efferth et al., 2007).
Mizutani et al. compared the sensitivity to doxorubicin between
the human promyelocytic leukemia cell line HL-6 and its subclone
cell line HP100, which is resistant to H2 O2 (Mizutani et al., 2005).
Apoptosis of HL-6 but not HP100 cells was observed after cultur-
ing the cells in the presence of doxorubicin for 7 h, suggesting that
H2 O2 is involved in doxorubicin-induced apoptosis in leukemia
cells (Mizutani et al., 2005). Vincristine, a microtubule interfering
anti-cancer agent, was found to be able to induce the production of
ROS in Jurkat cells at a very early stage, with the application of ROS
scavenger, Jurkat cells apoptosis was inhibited, which indicated
that ROS may play a key role in initiating apoptosis in Jurkat cells
(Groninger et al., 2002). Cytarabine, an important anti-metabolite
used for the treatment of acute leukemia, can activate a number of
tumor suppressor genes, such as NF-B and p53, by increasing the
production of ROS, leading to apoptosis in leukemia cells (Romano
et al., 2000; Kanno et al., 2004). In addition, several natural ingre-
dients and biological products, including parthenolide (Guzman
et al., 2005), Toona sinensis (Yang et al., 2006), gallic acid (Inoue
et al., 1994), curcumin (Chen et al., 2005), resveratrol (Yaseen et al.,
2012), cinnamaldehyde (Ka et al., 2003), and artesunate (Efferth
et al., 2007), exhibit anti-leukemic effects by inducing leukemia
cell apoptosis through ROS.
6. Targeting autophagy to overcome drug resistance in
leukemia
Many studies have shown that a variety of drugs used to
treat leukemia cause autophagy. Wang et al. reported that Borte-
zomib inhibited proliferation, increased apoptosis, and activated
autophagy in B-cell acute lymphoblastic leukemia (B-ALL) cells
(Wang et al., 2015). However, resistance to Bortezomib was
observed in B-ALL cells, and inhibitors of autophagy improved
the anti-leukemic activity of Bortezomib (Wang et al., 2015).
Evangelisti et al. also reported that triciribine induced apoptosis
and increased autophagy in T-cell acute lymphoblastic leukemia
(T-ALL) cells, and the autophagy inhibitor chloroquine signi-
cantly improved apoptosis in T-ALL cells induced by triciribine
(Evangelisti et al., 2011). In addition, inhibition of autophagy has
been shown to restore the effects of Dasatinib on apoptosis in CLL
cells (Amrein et al., 2011). Histone deacetylase inhibitors inhibit
autophagy and improve apoptosis in myeloid leukemia cells by
increasing ROS production, and these phenomena are reversed by
the activation of autophagy (Stankov et al., 2014). Taken together,
these results suggest that autophagy is a self-protective mecha-
nism of leukemia cells and that targeting autophagy is an efcient
approach to resolve the challenge of drug resistance in the treat-
ment of leukemia.
Recent studies have identied that numerous signaling
molecules and pathways are involved in the regulation of
autophagy. Some of these signaling molecules, such as High mobil-
ity group protein 1 (HMGB1), miRNAs, and p53, are directly or
indirectly involved in the drug resistance of leukemia cells. HMGB1
is a nuclear DNA-binding protein and a member of the damage-
associated molecular patterns (DAMPs). HMGB1 has been shown
to be a positive regulator of autophagy that is released from cells
under stress conditions such as injury and infections (Yu et al.,
2012a). Liu et al. reported that leukemia cells secreted HMGB1 in
response to the toxic effects of chemotherapeutic agents, which
activated autophagy to protect the cells (Liu et al., 2011). Anti-
HMGB1 antibody improved the sensitivity of leukemia cells to
chemotherapeutic agents, suggesting that HMGB1 is associated
with the drug resistance of leukemia cells. In addition, blocking
the PI3KMEKERK pathway inhibited leukemia cell autophagy
induced by HMGB1 (Liu et al., 2011). miRNAs are a class of reg-
ulatory RNA that plays an important role in the development,
metastasis, and treatment of tumors (Yu et al., 2012b). Recent
studies have suggested that miRNAs are involved in the regula-
tion of autophagy. As a member of the miRNAs family, miR-30a
has recently become a research hotspot in autophagy regulatio
(Zhu et al., 2009). Our previous study demonstrated that miR-
30a inhibited autophagy by suppressing the expression of the
autophagy-related gene Beclin-1. We observed increased expres-
sion of Beclin-1 and an increased number of LC3-positive autophagy
events in cancer cells in which the expression of miR-30a was sup-
pressed by cis-DDP or Taxol, suggesting that the chemotherapeutic
agents cis-DDP and Taxol improve autophagy of cancer cells by
inhibiting the expression of miR-30a (Zou et al., 2012). In addition,
lentiviral-induced over-expression of miR-30a down-regulated
cancer cell autophagy in a Beclin-1-mediated manner (Zou et al.,
2012). These results suggest that miR-30a may be a potential
target for resolving the drug resistance problem encountered in
cancer. Yu et al. found that miR-30a mimics or Beclin-1/ATG5
knockout increased apoptosis in CML cells (Yu et al., 2012b).
In addition, antagomiR-30a promoted autophagy and inhibited
imatinib-induced apoptosis in CML cells. These results suggest
that miR-30a inhibition is involved in the drug resistance of CML
cells (Yu et al., 2012b). A recent study demonstrated that p53, a
tumor suppressor protein, affected the chemotherapeutic effects of
leukemia by regulating leukemia cell autophagy. Cytoplasmic p53
inhibits autophagy; however, p53 in nuclei induces autophagy via
the expression of certain transcription factors (Feng et al., 2007).
It has been reported that p53 induces autophagy by activating the
AMPK/mTOR pathway and upregulating damage-regulated mod-
ulator of AP (DRAM) (Feng et al., 2005). Amrein et al. found that
p53-mediated autophagy was involved in dasatinib resistance in
CLL cells (Amrein et al., 2011).
It is currently believed that autophagy is a double-edged sword
during the development of a tumor. Proper autophagy is impor-
tant for maintaining cell survival and cellular homeostasis, but
excessive autophagy can cause autophagic cell death, inhibiting
 Y.-F. Chen et al. / Critical Reviews in Oncology/Hematology 112 (2017) 2130
tumor growth (Gozuacik and Kimchi, 2007). Thus, the induction of
the autophagic death of tumor cells may be an effective approach
to overcome the drug resistance of leukemia cells. Glucocorti-
coid (GC) is commonly used for the treatment of ALL; however,
GC resistance is a common problem during the clinical treat-
ment of ALL. The activities of mTOR and AKT were found to be
increased in GC-resistant ALL cells, which inhibited autophagy in
these cells (Bornhauser et al., 2007). The combination of dexam-
ethasone and obatoclax, a Bcl-2 family antagonist, was found to
signicantly reduce the phosphorylation of mTOR-targeted pro-
tein s6 and trigger autophagy-dependent programmed necrosis
in ALL cells (Bonapace et al., 2010). Obatoclax also induces BAK-
dependent apoptosis in ALL cells (Heidari et al., 2010). Given that
obatoclax has a dual effect of inducing apoptosis and autophagic
cell death, the combination of obatoclax and dexamethasone may
be able to overcome the drug resistance of ALL cells. It was reported
that the anti-leukemia effects of arsenic trioxide (As2 O3 ) in ALL also
depend mainly on the induction of autophagic cell death, and the
inhibition of autophagy blocks the anti-leukemia effects of As2 O3
(Goussetis et al., 2010). The tyrosine kinase inhibitor imatinib is cur-
rently the rst-line drug for the treatment of CML. It was found that
imatinib induced CML cell autophagy by increasing the expression
of Beclin-1 and ATG5, and it is believed that imatinib induced cell
death is achieved by autophagy. (Can et al., 2011). Taken together,
these results suggest that the induction of leukemia cell autophagy
through the use of drugs is an effective approach for the treatment
of leukemia.
7. ROS-induced autophagy as a therapeutic strategy for
treatment of leukemia
As an important signaling molecule that regulates cell
autophagy, ROS play an important role in autophagic cell death.
Under normal conditions, ROS-induced autophagy reduces dam-
age caused by oxidative stress to protect cells. However, ROS
can also cause autophagic cell death under certain circumstances.
The mechanisms underlying the balance between ROS-induced
autophagic protection and autophagic cell death remain unclear.
It has been reported that the activation of autophagy increases ROS
production; however, caspase inhibition leads to the preferential
degradation of catalase, resulting in the accumulation of ROS in
mitochondria and cell death. These results suggest that catalase
degradation plays a critically important role in the balance between
ROS-induced autophagic protection and autophagic cell death (Yu
et al., 2006).
Numerous chemotherapeutic agents induce the autophagic cell
death of tumor cells by increasing the production of ROS. Han
et al. found that tetraarsenic hexoxide (As4 O6 ) inhibited the growth
and induced caspase-dependent apoptosis and Beclin-1-mediated
autophagic cell death in human leukemia U937 cells in a dose
and time-dependent manner (Han et al., 2012). In addition, the
antioxidant N-acetylcysteine inhibited autophagic cell death and
apoptosis induced by As4 O6 , suggesting that ROS are involved in
As4 O6 -induced autophagic cell death and apoptosis in U937 cells
(Han et al., 2012). Shinohara et al. reported that AIC-47, a fatty-acid
derivative, induced autophagic cell death in CML cells by down-
regulating the expression of C-Myc and the fused gene BCR-ABL
through the PPAR/-catenin pathway and increasing the pro-
duction of ROS (Shinohara et al., 2015). Eupalinin A, a natural
phytoalexin in Eupatorium chinense L., induces HL60 cell death by
increasing the production of ROS (Itoh et al., 2008). Eupalinin A has
been shown to increase the production of ROS and LC3II and to
reduce the mitochondrial membrane potential in HL60 cells, lead-
ing to HL60 cell death characterized mainly by autophagic cell death
(Itoh et al., 2008). In addition, piperlongumine (Xiong et al., 2015),
27
resazurin (Erikstein et al., 2010), dihydroartemisinin (Wang et al.,
2012), and sesbania grandiora (Roy et al., 2013) have also been
reported to induce autophagic cell death in leukemia cells through
an increase in ROS production.
8. Summary
Autophagy is a common cellular activity that is involved in the
growth, differentiation, and proliferation of eukaryotic cells. ROS,
especially ROS produced in mitochondria, are signaling molecules
that are involved in numerous signal transduction processes. The
balance between ROS and autophagy plays an important role
in maintaining cellular homeostasis. Both redox imbalance and
mitophagy affect the homeostasis of cells and are involved in many
pathological processes. Numerous studies have shown that ROS and
autophagy play critically important roles in the development of
leukemia. Current studies suggest that ROS and autophagy have
extensive effects on cells and that the underlying mechanisms are
highly complicated. While a number of ROS-mediated autophagic
pathways have been identied, details regarding the signaling
molecules and interactions among them are largely unknown.
In recent years, studies investigating ROS and autophagy have
signicantly improved our understanding of the pathogenesis of
leukemia and provide novel targets for the treatment of leukemia.
Many chemotherapeutic drugs that are currently used clinically for
the treatment of leukemia induce autophagic cell death and/or apo-
ptosis in leukemia cells by increasing ROS production. In addition,
inhibition of ROS production represses the anti-leukemia effects
of chemotherapeutic drugs, suggesting that ROS play a critically
important role in the chemotherapy used to treat leukemia. How-
ever, ROS are a double-edged sword in the treatment of tumors.
High levels of ROS induce not only tumor cell death but also
oxidative damage to cell organelles, proteins, and DNA, leading to
genomic instability and abnormality of cell function. In addition,
ROS can activate NF-B, PI3K, MAPK, and other tumor growing
signals. Low levels of ROS can improve the growth of tumor cells
rather than induce autophagy in tumor cells. Therefore, optimiza-
tion of the concentration of intracellular ROS to achieve the best
anti-tumor effects is an important task. Monitoring the concentra-
tion of ROS in chemotherapy may allow physicians to better control
the dose of chemotherapeutic drugs for individualized treatment.
In addition, leukemia has a complex and diverse etiology, and dif-
ferent types of leukemia at different stages may be associated with
distinct levels of ROS and autophagic activity. Therefore, ROS and
autophagy have different roles in the development of leukemia,
and the same chemotherapeutic drugs may have different effects
in different types and at different stages of leukemia.
Current knowledge regarding autophagy and autophagic cell
death is still limited. The signaling molecules and pathways
involved in autophagy and its pathophysiological signicance
require further investigation. With an improved understanding of
the molecular mechanisms underlying autophagy in the devel-
opment of tumors, especially the association between ROS and
autophagy, we may be able to identify more effective treatments
for cancers by through the regulation of autophagy in tumor cells.
Conict of interest statement
The authors have no other relevant afliations or nancial
involvement with any organizational entity with a nancial inter-
est in or nancial conicts with the subject matter or materials
discussed in the manuscript apart from those previously disclosed.
28 Y.-F. Chen et al. / Critical Reviews in Oncology/Hematology 112 (2017) 2130
Funding
This study was supported by the Public Welfare Technology
Application Research Project of Zhejiang Province under Grant No.
2015C37122, Zhejiang, China, and the National Natural Science
Foundation of China under Grant No. 81373139.
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