Review

Oxidative stress in
oncohematologic diseases: an
update
Expert Rev. Hematol. 6(3), 0000 (2013)

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Department of Clinical and

Experimental Medicine, School and Unit
of Allergy and Clinical Immunology,
University of Messina, Palermo, Italy
2
Division of Hematology, University of
Messina, Palermo, Italy
3
Department Farmaco-Biologico, School
of Pharmacy, University of Messina,
Palermo, Italy
4
Unit Operativa Complessa
di Ematologia, Dipartimento
Oncoematologico, Azienda Ospedaliera
di Cosenza, Cosenza, Italy
5
Department of Clinical and
Experimental Medicine and
Pharmacology, Section of
Pharmacology, University of Messina,
Palermo, Italy
6
Institute of Biomedicine and Molecular
Immunology A. Monroy (IBIM)
Consiglio Nazionale delle Ricerche
(CNR), Palermo, Italy
*Author for correspondence:
Tel.: +39 090 221 2049
Fax: +39 090 694 773
sele19pf@gmail.com

Keywords: AOPPs, AGEs, S-nitrosylated proteins bone marrow transplantation cancer carbonyl groups
chronic lymphocytic leukemia Hodgkins lymphoma multiple myeloma myeloproliferative disorders
oxidative stress

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An increased risk of cancer in various organs has been related to oxidative stress and several
studies have revealed the mechanism by which continued oxidative stress can lead to chronic
inflammation, which in turn could mediate most chronic diseases including cancer. A variety
of transcription factors may be activated in consequence of oxidative stress, leading to the
expression of over 500 different genes, including those for growth factors, inflammatory
cytokines, chemokines, cell cycle regulatory molecules and anti-inflammatory molecules. In this
review, the data related to the action of oxidative stress on the onset of various oncohematologic
diseases are summarized, thus bringing together some of the latest information available on the
pathogenetic role of oxidative stress in cancer. The authors evaluate the most recent publications
on this topic, and, in particular, show the newest evidence of a relationship between oxidative
stress and hematological malignancies, such as chronic lymphocytic leukemia, Hodgkins
lymphoma, multiple myeloma and chronic Ph-negative myeloproliferative diseases. A separate
chapter is devoted to the implications of a change of oxidative stress in patients undergoing
bone marrow transplantation. Finally, particular attention is given to the new markers of oxidative
stress, such as carbonyl groups, advanced glycation end products, advanced oxidation protein
products and S-nitrosylated proteins, which are certainly more stable, reliable, cheaper and
more easily identifiable than those already used in clinical practice. New approaches that aim to
evaluate subcellular and microenvironment redox potential may be useful in developing cancer
diagnostics and therapeutics.

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Selene Imbesi*1,
Caterina Musolino2,
Alessandro Allegra2,
Antonella Saija3,
Fortunato Morabito4,
Gioacchino Calapai5
and Sebastiano
Gangemi1,6

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General consideration on oxidative

stress

In 1954, for the first time, Gershman et al. theorized about the oxygen toxicity due to partially
reduced forms known as free radicals [1] .
Reactive oxygen species (ROS) are products
of normal cellular metabolism. They play a
dual role since they may have both beneficial
and deleterious effects [2] , as low doses of ROS
are involved in cellular responses to infectious
noxae and in some cellular responses to signaling system or mitogenic stimuli. On the other
hand, when the concentration of ROS are high
enough to overcome the antioxidant defences,
the result is a biological damage known as
oxidative stress[35] .
The redox regulation maintains the balance
between the positive and negative effects of
10.1586/EHM.13.21

ROS, as in case of imbalance in redox homeostasis, oxidative stress occurs and becomes
responsible for destructive modifications of
macromolecules, such as DNA, lipids and
proteins [2,6,7] .
The lipid peroxidation is responsible of the
formation of two main products, the malondialdehyde (MDA) and the 4-hydroxy-2-nonenal
(HNE), and both of them play a mutagenic role
and appears to be the major toxic product of lipid
peroxidation [8] .
ROS-mediated protein oxidation may instead
be measured through the concentration of carbonyl groups, advanced oxidation protein products (AOPPs) and advanced glycation end products (AGEs), which are derived from a reaction
between carbohydrates and free amino group
of proteins [8] .

2013 Expert Reviews Ltd

ISSN 1747-4086

Imbesi, Musolino, Allegra etal.

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Oxidative DNA damage may involve ssDNA or dsDNA breaks;

purine, pyrimidine or deoxyribose modifications and DNA crosslinks, determining various processes, such as arrest or induction
of transcription, induction of signal transduction pathways, replication errors and genomic instability, all of which are associated
with carcinogenesis [2,8,19] . Mitochondrial DNA seems to be more
sensitive to oxidative stress-induced mutations because it lacks
DNA repair enzymes.
However, ROS may contribute to cancer development through
not only genic mutations but also dysregulation, as in renal cell
carcinoma. In this type of cancer, there is an upregulation of
hypoxia response genes, and elevated concentrations of the
hypoxia-inducible transcription factor (HIF-1) aid angiogenesis,
tumor growth and metastasis [20] .
Moreover, oxidative stress in the tumor stroma mimics the
action of hypoxia, causing an augmented production of ROS.
Excess stromal production of ROS provokes an antioxidant
defense in adjacent neoplastic cells, protecting them from death.
Moreover, excess stromal ROS production leads to DNA damage
and aneuploidy in adjacent cancer cells. Finally, oxidative stress
provokes autophagy in the tumor microenvironment, causing the
stromal synthesis of recycled nutrients (including ketones and
l-lactate). These substance blocks then help drive mitochondrial
biogenesis in neoplastic cells, thereby promoting their anabolic
growth [21] .
Apart from DNA damage, the lipid peroxidation process has
been implicated in the mechanism of carcinogenesis; in fact, as
mentioned above, MDA and HNE are mutagenic products. In
addition, HNE has powerful effects on signal transduction pathways [8] .
Moreover, it has been demonstrated that ROS interfere with
the expression of some genes and signal transduction pathways
involved in regulatory cell growth pathways.
In particular, they seem to be implicated as second messengers
for the activation of activator protein-1 and NF-B via TNF and
IL-1 [22] .
As several studies have documented, tumor cells from blood
neoplasm and also colon, breast, pancreatic cancers activated
express NF-B [2,2224] .
Other ROS interferences have been described in the redox environment involved in the activation of several kinases and critical
apoptosis trigger proteins, such as p53 and Bcl-2 [2527] , and in
the oxidative modification of cell cycle mediated by intracellular
changes in concentration of gluthatione, another factor depleted
when the apoptosis is committed [28] .
It has also been shown that Ras proteins, small GTPase
functioning as molecular switches, in response to particular extracellular signaling, may activate intracellular effector cascades regulating cell proliferation, differentiation and apoptosis. Neoplastic
cells frequently express Ras proteins (Ha-, Ki- and N-Ras) activated by point mutations that contribute to malignant phenotype,
including invasiveness and angiogenesis. Some authors suggest that
Ha- and Ki-Ras may exert an opposite role in regulating intracellular redox status; H-Ras seems to induce ROS production, contributing to the development of the invasive phenotype. Instead,

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AOPPs and AGEs are proinflammatory mediators capable of

inducing the onset of cardiovascular disease and immune deregulation as they can damage biological membranes and endothelium,
as well as impair high-density lipoprotein metabolism [9] .
Moreover, the function of many proteins can be modified by
nitrosylation, a post-translational modification involving the
attachment of a nitric oxide (NO) group to a cysteine or transition metal. Protein S-nitrosylation mediates a wide range of cellular functions and phenotypes and regulates various pathways
such as G-protein-coupled receptor signaling, death receptormediated apoptosis, vesicular trafficking, stimulation of prostaglandin synthesis, hemoglobin function and the unfolded protein
response [8] .
The immune cells produce both the superoxide anion and NO
during the oxidative burst triggered by inflammatory processes.
In this case, NO and the superoxide anion may react together
to produce a much more oxidatively active molecule, known as
peroxynitrite anion, which is able to induce DNA fragmentation
and lipid oxidation [10] .
Protein 3-nitrotyrosine is a post-translational modification
of the amino acid tyrosine, with the covalent substitution of a
nitrite group located in the three-position of the aromatic phenol
of tyrosine. The modification is provoked by reactive nitrogen
species from the reactive nitrating intermediate peroxynitrite
(ONOO-), that is formed via the reaction between superoxide
(O2-) and nitric oxide (NO -) produced by NADPH oxidase
and the enzyme NO synthase [11] . As such, the 3-nitrotyrosine
has been found to be high during several diseases including
cancer[12] .
Several methods have been used to study the different markers
of oxidative stress [13] . However, most of the biomarkers get influenced by numerous factors such as nutrition, life style and types of
systems studied. Less reproducibility adds another disadvantage to
consider most of the marker of stress. Furthermore, most of them
are time consuming or use costly substances and instrumentation
[14] . Protein oxidation is a good marker of oxidative stress due to
the long half-life of oxidized proteins, while other new biomarkers
of oxidative stress are fast and easy to carry out, and the results
are very reproducible.
The use of such procedures would provide useful data on the
importance of several oxidants, and information of the damage
on different target biomolecules.
Moreover, free radicals may react with all components of the
DNA molecule (purine and pyrimidine bases and also the deoxyribose backbone). For this reason, the oxidative damage that
induces permanent modification of genetic material represents
the first step in mutagenesis, carcinogenesis and ageing [8] .

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Oxidative stress & cancer

Oxidation has been implicated in carcinogenesis as it seems to

play an important role in cell proliferation and cell signaling regulation [15] . Accumulation of ROS leads to genomic instability, and
it is known that carcinogenesis is induced by DNA mutations.
Elevated levels of oxidative DNA lesions have been observed in
several neoplasms [1618] .
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Expert Rev. Hematol. 6(3), (2013)

Oxidative stress in oncohematologic diseases

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Several works have pointed out relationships between oxidative stress and blood neoplasms, in particular acute and chronic
lymphoproliferative diseases. Through the mechanisms mentioned
above, abnormalities in oxidativeantioxidative balance have
been observed in acute lymphoblastic leukemia [31,32] , B-chronic
lymphocytic leukemia (B-CLL) [25,33] , multiple myeloma (MM)
[22] , thymic lymphoma associated to ataxia-telangiectasia [34] and
Hodgkins lymphoma (HL) [35] .
In this review, the authors focus on the biomarkers of oxidative
stress in several neoplastic hematological diseases.
CLL (B-CLL) is characterized by the progressive accumulation of small immature B lymphocytes, which do not undergo
apoptosis due to an underlying defect [36] .
There is a known relationship between leukemia and oxidative
stress; leukemic cells, in fact, produce more concentrations of
ROS than nonleukemic cells [37] .
Lymphocyte production of superoxide anion, H2O2 and MDA
is increased in B-CLL patients [32] , and also significantly higher
plasma levels of MDA and catalase compared with controls has
been measured [38] .
Recently, a characterization of the survival-inducing cross-talk
of CLL cells with their microenvironment has been made by
Schulz et al., who described the role of the nuclear factor (erythroid-derived2)-like2, which is a transcription factor in favor of
the antioxidant responses. Impaired (erythroid-derived2)-like2
function in fact could contribute to CLL cell survival since it
seems to be involved in NF-B activation [39] .
The authors group has previously analyzed the serum concentrations of AOPPs, AGEs and protein nitrosylation in order
to evaluate the oxidative stress in patients with B-CLL. In the
same patients, the authors also evaluated IgVH gene analysis, CD38 positivity, Zap-70 expression and two multidrug
resistance-1 gene (MDR-1) polymorphisms the G2677T
polymorphism in exon 21 and the C3435T polymorphism in
exon 26 to evaluate a possible correlation between biomarkers for oxidative stress and gene polymorphisms or biological
risk. According to emerging evidence, our data confirmed a
significant increase of AOPPs, AGE and S-nitrosylated proteins in B-CLL patients compared with healthy controls. The
authors also reported a relationship between AOPP and AGE
with MDR-1 polymorphisms. The mutant 2677GT genotype was found to be associated with higher AGEs levels with
respect to wild-type genotype, and as far as the C3435T25
MDR-1 polymorphism is concerned, patients presenting wildtype genotype showed higher values of AOPPs with respect to
heterozygous genotype [25] .

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Oxidative stress & neoplastic hematological diseases

Hematologic malignancies have been related to the malfunction of

MDR-1 because of a lower protection against specific P-gp-dependent
carcinogens; moreover, MDR-1 is involved in the metabolism of several drugs, and this could be relevant in patients affected by B-CLL
as CCL cells are susceptible to oxidative stress [40,41] .
A pathogenic role for oxidative stress has also been recognized
in other lymphoproliferative disorders, such as HL. The pathogenesis of HL is still largely undiscovered, as one of the mechanisms singled out is the cellular injury induced by oxidative stress.
Morabito etal. conducted a study in which serum levels of MDA,
HNE and carbonyl groups were measured, respectively, as biomarkers of lipid peroxidation and protein oxidation in order to
quantify the oxidative stress in untreated HL patients during
advanced disease stages [35] . With regard to MDA/HNE serum
levels, results showed a significant increase in serum levels from
HL patients compared with healthy controls.
Previously, other authors had reported similar data, and in
addition, observed high MDA concentration associated with a
dysregulation of antioxidant system (i.e., low levels of selenium,
zinc and glutathione peroxidase [GPX] activity in HL) [42] .
There was also an increase in circulating protein carbonyl
groups found in HL patients [35] , according to several models
of experimental carcinogenesis, which have shown that elevated
levels of protein carbonyl groups are early targets of this process.
In literature, elevated protein carbonylation measured in platelets from HL patients [43] and the involvement of oxidative stress
in thymic lymphomagenesis in Atm-/- mice are also reported. In
the latter case, ROS accumulation in Atm-/- thymocytes has been
associated with increased DNA synthesis and oncoprotein c-Myc
expression, both of which participate in the process of tumorigenesis [34,44] .
In a recent study, some authors evaluated the immunohisto
chemical expression and clinical correlations of oxidative stress
markers and several essential antioxidant enzymes in B-cell lymphomas. Paraffin-embedded diagnostic tissue samples from diffuse large B-cell lymphomas (DLBCL), follicular lymphomas,
HL, CLL, mantle cell lymphomas and mucosa-associated lymphoid tissue lymphomas were stained for o xidative stress markers 8-hydroxydeoxyguanosine and nitrotyrosine and antioxidant
enzymes manganese superoxide dismutase (SOD), thioredoxin
and -glutamyl cysteine synthetase. An increasing expression of
oxidative stress markers and antioxidant enzymes were showed
in a series of lymph node samples evolving from reactive lymph
nodes to indolent and aggressive lymphomas [45] .
Oxidative stress in relation to the clinical stages and grades
of non-HL was examined by Nojima and coworkers [46] . They
measured oxidation activity by the reactive oxygen metabolites
(ROMs)derived compounds test and antioxidation activity
by biological antioxidant potential (BAP) test. In the ROMs
derived compounds test, ROMs (primarily hydroperoxides) of
a serum sample are able to generate alkoxyl and peroxyl radicals
in the presence of iron released from serum proteins by an acidic
buffer[47] .
In the BAP test, a photometrical measure is assessed and is proportional to the antioxidant capacity of a serum sample [48] . The

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Ki-Ras seems not to be able to promote oxidative stress and could

contribute to cancer progression and invasiveness through activation of MAPK and PI3K [29] .
On the other hand, it has been reported that antioxidants
have a negative influence on the initiation and promotion of
carcinogenesis as well as opposing cell immortalization and
transformation [30] .

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Imbesi, Musolino, Allegra etal.

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myeloid leukemia patients as compared with the healthy participants. The plasma levels of nonenzymatic antioxidant status
continued to decrease significantly during the disease progression
[60,61] . Moreover, BCR-ABL oncoprotein-expressing cells were
associated with a relative increase of intracellular ROS, which is
thought to play a role in transformation [62] .
For the oxidative stress in patients with Ph-negative myeloproliferative disorders, Vener etal. studied oxidative stress in patients
with myelofibrosis, showing an unbalanced oxidative status with
higher ROS and lower total antioxidant capacity levels than the
controls [63] .
In a previous article, the authors evaluated oxidative stress in
patients affected by polycythemia vera and essential thrombocythemia (ET), and the authors found higher levels of AOPPs and
S-nitrosylated proteins in both diseases and an increase of AGEs
in ET patients with respect to controls [64] .
The role of oxidative stress in Ph-negative myeloproliferative
disease pathogenesis may be linked to mechanisms similar to
those described above, that is the interference on redox-sensitive
transcription factors, enzymes, kinases, oncogenes and other
effectors.
Moreover, the authors found a correlation between S-nitrosylated
proteins and Hb value in polycythemia vera patients and between
AGEs and thrombotic events in ET patients. This suggests a
potential role of ROS in the onset of myeloproliferative associated thrombotic risk. In the literature, there are some data that
link oxidative stress and endothelial dysfunction with subsequent
promotion of vasospasm, thrombosis, vascular inflammation and
proliferation of v ascular smooth muscle cells [65] .
Finally, it is possible that a modification of the oxidative balance can intervene in some new therapeutic practices such as
bone marrow transplantation and the use of new drugs such as
growth factors.
The major source of stem cells used for autologous and allogeneic transplantations is the mobilized cells following treatment
with cytokines [66,67] . G-CSF is the primary factor used for the
mobilization of stem cells in current clinical practice. It is able to
release the proteinases elastase and cathepsin G from neutrophils
[68] , and capable of causing an increase in oxidative stress in neutrophils by increasing the NADPH oxidase activity and stimulating the expression of enzymes such as myeloperoxidase (MPO),
during the first phase of myeloid differentiation [69] . MPO utilizes H2O2 to convert chloride to HOCl, which is an oxidant for
substrates such as lipids, DNA and, in particular, proteins [70] .
The authors group investigated the changes in neutrophil
oxidative products (in particular plasma MPO levels) following
invivo recombinant human G-CSF (rHuG-CSF) administration
in a group of donors before leukapheresis [71] . The administration
of rHuG-CSF increases the ROS levels in bone marrow hematopoietic cells, activating the already demonstrated G-CSF/Hferritin/LIP/ROS pathway [72] . Moreover, the authors observed
a significant increase, after 5days of rHuG-CSF administration,
in plasma levels of MPO.
In another study, the invivo time course of plasmatic levels
of protein carbonyl groups in a group of stem cell donors given

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authors found a high level of the oxidative stress index (obtained

from the ROMs/BAP ratio) in DLBCL and a tight relationship
between this index and the malignant grade and clinical stages
of the disease [46] . Moreover, Peroja etal. suggested that excessive
antioxidant and high nitrotyrosine expression are associated with
a worst prognosis in DLBCL patients [49] .
The role of oxidative stress in MM pathogenesis may be linked
to several mechanisms. In MM, patients with elevated MDA
levels and shortened levels of SOD, GPX, catalase (enzymatic
antioxidants) and vitamin C and E (nonenzymatic antioxidants)
have been reported [50] . Moreover, it has been demonstrated that
IL-6, an established growth factor for MM cells, induces myeloma
therapy resistance [51] . In fact, IL-6-induced resistance to dexamethasone and radiation in myeloma cells has been related to an
increase of manganese superoxide expression [52] .
Other oxidative alterations have been reported relating to proteins involved in apoptosis induction, such as Bik/Bcl-2, p53 and
oridonin [53,54] . Furthermore, the treatment of MM cells with
a MUC1-C inhibitor promotes the production of ROS, oxidation of mitochondrial cardiolipin, loss of the m itochondrial
transmembrane potential and downregulates p53 [55] .
There are data that associate these mechanisms with carcinogenesis in S-nitrosylation of proteins, such as Bcl-2 and
FLICE-inhibitory protein and S-nitrosoglutathione reductase
deficiency[56,57] .
In a previous study, the authors analyzed the serum levels of
AOPPs, AGEs and protein nitrosylation in order to quantify the
oxidative stress in untreated MM patients and in patients affected
by monoclonal gammopathy of uncertain significance [22] .
The authors showed that serum levels of AOPPs and
S-nitrosylated proteins were significantly increased in MM
patients compared with controls and to monoclonal gammopathy
of uncertain significance patients. Moreover, the authors found a
significant increased trend in patients with bone lesions compared
with those without lytic bone lesions. The same datum has been
found regarding AGEs serum levels according to the evidences
that show the potential ability of AGEs in the bone matrix to
affect growth and function of osteoblasts [58] .
The authors also investigated serum levels of carbonyl groups,
and these were significantly higher in MM patients as compared
with healthy controls, in particular in the more advanced stage
of disease [59] .
Further investigation may provide an insight to understand if
the increased concentrations of circulating biomarkers of oxidative
stress may be linked with MM onset and progression.
However, an altered oxidative balance does not appear to be just
the prerogative of the lymphoid cells, but has also been observed
in the myeloid compartment, and a protumoral role of oxidative
stress in myeloproliferative neoplasms has been already demonstrated in several studies. There was a significant increase in the
plasma levels of lipid peroxidation products in chronic myeloid
leukemia patients as compared with the healthy volunteers. The
plasma levels of lipid peroxidation products continued to rise significantly as the disease progressed, while the nonenzymatic antioxidant status was found to be significantly decreased in chronic

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Expert Rev. Hematol. 6(3), (2013)

Oxidative stress in oncohematologic diseases

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Antioxidant strategies have been suggested to regulate the immune

system and limit inflammation. In support of this idea, vegetarians, who consume a diet rich in antioxidants, have reduced
rates of cancer incidence and have longer life expectancies [74] .
However, although a vegetarian alimentation can cause a decrease
in oxidative DNA damage in blood cells [75] , it is not proven that
the reduced percentage of cancer in this kind of patients is due
to a different oxidative stress.
Some clinical trials have instead shown that ROS scavenging
by antioxidant vitamins is ineffective so it has been hypothesized
that the approach aimed on prevention of ROS formation should
target specific molecular pathways. Some authors have suggested
as potential targets, involved in ROS generation and their activation of proinflammatory cascades, NADPH oxidase, xanthine
oxidase, endothelial NO synthase and mitochondrial oxidases [76] .
Antioxidants already used, although in relatively small clinical
studies, are N-acetyl-cysteine for melanoma chemoprevention [77]
and metformin therapy, which seems to reduce mitochondrial
oxidative stress and has been associated with a lower risk of various
epithelial cancers in diabetic patients [78,79] .
In a preclinical animal study, Goh etal. have shown that blocking mitochondrial ROS inhibits metastasis. They evaluated the
ability of N-acetyl-cysteine, mitochondrial SOD and M-catalase
(mitochondrially targeted catalase) in breast cancer, obtaining a
reduction of tumor progression [80] .
However, in the literature, there are conflicting opinions on the
administration of antioxidants during cancer therapy. It is still
largely unaccepted because some oncologists believe that it may
reduce the effectiveness of chemotherapies, which are based on
increasing oxidative stress.
Hewish etal. have shown that cytarabine was toxic to MLH1and MSH2-deficient tumor cells, but this cytotoxicity was
reduced by antioxidants [81] .
On the other hand, many recent studies support the reduction
in mitochondrial oxidative stress in both cancer cells and their
surrounding tumor stroma for preventing tumor progression and
metastasis [82] .

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Oxidation & cancer therapy

and hypoxia/reoxygenation cycles are examples of pathways tied

to the redox imbalance in cancer cells. High levels of oxidative
stress may be advantageous for cancer progression, as they may
lead to increased rates of genetic mutation that could contribute
to the acquisition of a malignant phenotype. Moreover, several
studies confirmed that oxidative stress supports the regulation of
blood cell homeostasis. Erythrocytes and hematopoietic stem cells
are in fact sensitive to accumulation of ROS, while ROS build up
compromises the function of hematopoietic stem cells damaging
their DNA. These abnormalities may cause accelerated aging of
hematopoietic stem cells or oncohematologic disease [83] .
Therefore, the study of oxidative stress could perhaps clarify
some aspects of the pathophysiology of hematologic malignancies and indicate possible new therapeutic approaches. In particular, the assessment of the effects of oxidative stress on the
so-called cancer stem cells could be particularly beneficial for
the treatment of minimal residual disease and the prevention
of relapse in the course of hematological malignancies. In fact,
several factors associated with inflammation, such as the oxidative stress, are able to cause the activation of specific pathways
that can modify the persistence, differentiation and proliferation
of cancer cells [84,85] .
However, other aspects of the connection between cancer and
oxidative stress expect to be clarified. Although oxidative stress
itself causes malignancies, there are several mechanisms how
oxidative stress is increased during carcinogenesis, being a consequence, not solely a reason for carcinogenesis. It is well known,
in fact, that reactive species are generated as a consequence of
metabolic reactions in the mitochondria of eukaryotic cells. In
normal cells, low concentrations of these substances are necessary
for signal transduction. However, cancer cells, which exhibit an
accelerated metabolism, demand high concentrations to preserve
their proliferation rate [86] .
Probably, within a few years, we will know if a direct intervention on mediators of oxidative stress or their molecular targets,
alone or in combination with other modalities, will be clinically
useful treatments for various hematologic diseases.

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rHuG-CSF were also assessed, showing a significant increase after

administration [73] .
It is probable that oxidative stress products, acting as a second messenger, stimulate the proliferation and differentiation of
hematopoietic progenitor cells, the release of mature granulocytes
from bone marrow and mobilization of CD34 + hematopoietic
progenitor cells in circulating blood.

Review

Conclusions

Oxidative stress has become a major topic in all areas of medicine,

as the balance between oxidation and reduction reactions plays an
essential role in numerous cell-signaling cascades, including those
associated with proliferation, inflammatory responses, apoptosis
and senescence. In fact, many tumors and carcinoma cell lines
are characterized by elevated oxidative stress. Mitochondrial dysfunction, activation of oncogenes, aberrant oxidative metabolism
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Expert commentary

Numerous experimental experiences suggest that oxidative stress

is involved in the pathogenesis of cancer. Although the mechanisms by which oxidative stress exerts its action are known, we do
not yet know the specific pathways through which stress acts. It
also remains to study the correlations between biological response,
duration of stress, exposure levels and the nature of the mediators
involved. Only through the acquisition of this knowledge can we
handle the oxidative stress for the treatment of cancer, to maximize the effects of chemo- and radiation-therapy and to develop
a selective and targeted therapeutic intervention.
Five-year view

Impaired redox status is relevant not only in oncogenesis but also

for selective therapy. Several substances that areable to modify the
redox homeostasis in cancer cell are being tested in preclinical
trials and will be used in clinical practice [87] .
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Imbesi, Musolino, Allegra etal.

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of cancer with the most recent advances in technology [93] . The

possibility to intervene with new nanotechnology for the handling
of oxidative stress in patients with solid tumors or hematological
cancers is of particular interest [94] .
The nanotechnology research has, in fact, led to the development of nanomaterials with huge potential. However, there is
increasing evidence of their action in oncogenicity, and several
studies have been made on the genotoxic and carcinogenic potential of mineral-based nanoparticles [95] . Moreover, invitro studies
demonstrated that zinc oxide nanoparticles (ZnONPs) induce
genotoxicity in normal cells through oxidative stress. ZnONPs,
in fact, reduced the levels of glutathione, glutathione-S-transferase
and GPX with an increase in MDA level and catalase, while an
increase in oxidative DNA damage was observed by the comet
assay in cells treated with ZnONPs [96] .
On the other hand, it was demonstrated that silica nanoparticles
induce cytotoxicity and apoptosis in epithelial cells, which is
mediated through oxidative stress [97] . Such an approach could
perhaps open up new scenarios in the treatment of neoplastic
diseases.
Financial & competing interests disclosure

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Leukemic B cells are sensitive to radiotherapy and cytotoxic

drugs that modify cellular redox status such as anthracycline
derivatives, imexon and nonsteroidal anti-inflammatory drugs.
Unmethylated CG dinucleotides was found to induce IL-12
secretion in macrophages via ROS generated by NOX enzymes.
In a recently PhaseI clinical trial, Kapoor etal. have combined
zevalin with unmethylated CG dinucleotides to obtain a better
response in B-cell non-HL [88] .
Arsenic trioxide (ATO) has a well known efficacy in acute promyelocytic leukemia and MM. In acute myeloid leukemia, ATO
was found to inhibit NF-B activity via depletion of GSH levels
and accumulation of H2O2 with downregulation of cyclo-oxygenase-2 expression [89] , and studies have shown that ATO exerts
cytotoxic effects by elevating oxidative stress and by inhibiting
the proper function of the GSH/ GPx system [90] . Furthermore,
ATO has been used with trolox or polyunsaturated fatty acid
docosahexaenoic acid with increased oxidative cell death of B-cell
neoplasms [91] .
Bera etal. showed that combining dexamethasone with radiation augmented the oxidative stress, and this is able to increase
the killing of myeloma cells and to inhibit the release of IL-6 from
irradiated bone marrow stromal cells [92] .
In the next few years, we will probably find a novel biochemical rationale for combining oxidative stressors with radiotherapy
and chemotherapy that may lead to the design of more effective
treatment strategies for B-cell malignancies.
Finally, the challenge in the coming years will be to integrate
our knowledge on the action of oxidative stress in the pathogenesis

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Key issue

The authors have no relevant affiliations or financial involvement with any

organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

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Oxidation has been implicated in carcinogenesis because it seems to play an important role in cell proliferation and cell-signaling
regulation.
Oxidative stress is responsible for destructive modifications of macromolecules, such as DNA, lipids and proteins.
Elevated levels of oxidative DNA lesions have been observed in several neoplasms.
The authors focused on the biomarkers of oxidative stress in single neoplastic hematological diseases.
There is a significant increase in biomarkers of oxidative stress in B-chronic lymphocytic leukemia patients compared with healthy
controls.
Abnormalities in oxidativeantioxidative balance have been also observed in acute lymphoblastic leukemia, multiple myeloma, thymic
lymphoma associated to ataxia-telangiectasia and Hodgkins lymphoma.
The study of oxidative stress in cancer patients could indicate possible new therapeutic approaches.

References

Papers of special note have been highlighted as:

of interest
of considerable interest

Evidence for involvement of the oxidative

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