Reactive oxygen species (ROS) are closely related to tumorgenesis. Under hypoxic environment, increased levels of ROS induce the expression of hypoxia inducible factors (HIFs) in cancer stem cells (CSCs), resulting in the promotion of the upregulation of CSC markers, and the reduction of intracellular ROS level, thus facilitating CSCs survival and proliferation. Although the ROS level is regulated by powerful antioxidant defense mechanisms in cancer cells, it is observed to remain higher than that in normal cells. Cancer cells may be more sensitive than normal cells to the accumulation of ROS; consequently, it is supposed that increased oxidative stress by exogenous ROS generation therapy has an effect on selectively killing cancer cells without affecting normal cells. This paper reviews the mechanisms of redox regulation in CSCs and the pivotal role of ROS in anticancer treatment.
1. Introduction
Reactive oxygen species (ROS) is a collective term for oxygen-containing chemical species that are converted directly or indirectly from free oxygen but are more chemically reactive [1]. Low to moderate levels of ROS are indispensable to normal cellular proliferation, differentiation, and survival [2]. Some reports have shown that the addition of low concentrations of superoxide or hydrogen peroxide (10 Nm–1 μM) to the culture medium is effective for stimulating the growth of hamster and rat fibroblasts in vitro [3, 4]. In general, systems in aerobic organisms are developed to modulate the content of ROS by balancing the generation and scavenging of ROS within a nontoxic range. But once the balance is broken, cells suffer from oxidative stress. Rapid increases in intracellular ROS may lead to cellular transformation and tumorigenesis. For example, researchers have found in BHK-21 cells that deaths of apoptotic cells become obvious after the exposure to 10–100 μM hydrogen peroxide [5]. Substantial growth of ROS brings cells irreversible damage and finally kills them. However, it is just these biological features of ROS that make it possible to be used to kill tumor cells [2].
Since Lapidot discovered leukemia stem cells in 1994, researchers have shed light on the study of cancer stem cells (CSCs) [6]. CSCs are defined by their capacity to self-renew and differentiate into heterogeneous nontumorigenic cancer cell types in accordance with their microenvironment and the status of the whole body [7, 8]. CSCs, which only account for about 0.05%–1% of the whole tumor cell population [9–11], play an important role to tumor formation and development. They are believed to relate closely to chemo- and radioresistance and disease recurrence [12–16]. Therefore, CSCs are considered as good targets for cancer therapy [17]. The study of intracellular ROS in CSCs remains an attractive field for research. Little is known about the biological effects and regulatory mechanism of ROS in the CSC subpopulation. This review focuses on ROS’s regulation effect on CSCs and the therapeutic effect on cancer eradication.
2. Lower ROS Production in CSCs
ROS are mainly composed of free radicals such as superoxide (O2-), hydrogen peroxide (H2O2), and hydroxyl radical (HO∙), which contain oxygen and peroxides tending to form radicals [1]. Under physiological conditions, O2- is principally generated as a consequence of incidental electron leakage from the mitochondrial electron transport chain (ETC) [18] and is usually immediately converted into H2O2 by mitochondrial Mn-containing superoxide dismutase (MnSOD, SOD2), cytosolic Cu/Zn-containing SOD1, or extracellular SOD3 [19, 20]. H2O2 can be catalyzed to release highly toxic HO∙ by gaining an extra electron or be scavenged by the reaction of glutathione peroxiredoxin (Prx), peroxidase (Gpx), or catalase [21–23]. Besides the mitochondrial mechanism, ROS can also be generated by the NADPH oxidase complex (NOX), cyclooxygenase (COX), cytochrome c oxidase, and xanthine oxidase (XO) [24].
The production of cellular ROS must go with scavenging of ROS. The currently available body of evidence shows that powerful scavenger systems, which are mainly divided into two classe: antioxidant enzyme system and sulfur reduction buffer system, can maintain the intracellular ROS at low levels. The former class contains the superoxide dismutase family (SOD1, SOD2, and SOD3), catalase (CAT), and peroxidase. In addition, ascorbic acid and vitamin E are also involved and play vital roles in antioxidant enzyme system [25]. The latter class contains reduced glutathione (GSH), thioredoxin (TRX), and thioredoxin reductase (TRXR). Glutathione peroxidase converts H2O2 to H2O and O2 through coupling with the transformation of GSH to oxidized glutathione [2]. In general, GSH and GSSG maintain homeostasis within cells, and their contents have become important indicators of the antioxidant capacity of cells [26].
Cells maintain redox homeostasis, which is favorable for organisms, through a balance of generation and elimination of ROS. Aerobic organisms actively use ROS in signal transduction pathways to regulate cell proliferation, differentiation, and survival, in a way of interacting with macromolecules by reversible oxidative modifications [27–30], while excessive amounts of ROS, regardless of their source, cause irreversible peroxidation of nucleic acids, lipids, amino acids, and carbohydrates, resulting in cellular senescence, apoptosis, or transformation and triggering a series of pathological processes, such as cardiovascular diseases, neurodegenerative diseases, aging, and cancer [31–36]. For example, ROS induce nuclear DNA mutations by activating oncogene or inactivating tumor suppressor genes and damage nuclear DNA repair mechanisms, resulting in the generation of tumor-initiating cells. Persistent ROS-induced oxidative stress expands the clonal selection of these cells, gradually making them form subsets with new features. Tumor then occurs as a consequence of reduced apoptosis and increased genomic instability and heteromorphism [37, 38].
Compared to differentiated cells, normal stem cells are more glycolytic to reduce more oxidative damage due to ROS [39–41]. Similarly, CSCs present lower energy metabolism rate and produce less ROS compared with non-CSCs [17, 42]. This can be achieved by a combination of mechanisms that is unique to a given tumor, such as (a) upregulation of ROS scavengers, (b) downregulation of ROS-producing enzymes, (c) promotion of glycolysis, (d) reduced mitochondrial mass, and (e) low oxygen consumption [43–46]. As evidenced by Ishimoto et al.’s study, the CSCs of human gastrointestinal tract improve abilities of GSH synthesis with a cystine-glutamate exchange transporter in order to enhance its defensive performance against ROS [47].
3. ROS Activates HIFs in CSCs
The morphology, metabolism, and proliferation of CSCs are critically dependent on their microenvironment. CSCs will not only strive for adapting to their microenvironment but also actively create their preferable niche. Hypoxia is an essential feature of the tumor microenvironment because of the chaotic vasculature and poor oxygen diffusion in solid cancers. The normal oxygen tension in healthy tissue is approximately 7% (53 mmHg), but this tension can show differences in tumors depending on the level of hypoxia, that is, from physiological (~7%) to severe (<1%) hypoxia [48]. It has become increasingly clear that a hypoxic microenvironment is beneficial for the maintenance of CSCs in virtually all tissues of the body [49–51]. For example, in glioblastomas, hypoxia sustains the undifferentiated state of CSCs by elevating some important stem cell markers, such as Oct4 and Sox2, slows down their growth to the quiescent stage, and increases their colony-forming efficiency and migration [52]. Besides, since hypoxia potentiates the CSC-mediated inhibition of T cell proliferation and activation in glioma and further inhibits macrophage phagocytosis compared with normoxia conditions, immunosuppression can be reinforced [53]. Hypoxia also improves CSCs’ abilities of invasion and resistance against therapy, which poses a challenge to anticancer therapeutics [54].
In hypoxic environment, elevated ROS can activate hypoxia inducible factors (HIFs) [48]. HIFs are a type of heterodimers made up from HIF-1α, HIF-2α, or HIF-3α bound to HIF-β/ARNT (aryl hydrocarbon receptor nuclear translocator). While HIF-β is constitutively and ubiquitously expressed among many cell types, all HIF-α subunits are regulated by intracellular oxygen sensors, which are referred to as prolyl hydroxylate enzymes and asparaginyl hydroxylase [55]. Under normoxic conditions, the von Hippel-Lindau (VHL) E3 ligase complex targets HIF-α subunits for proteasomal degradation [56]. Under decreased oxygen level, HIF-α subunits can be stabilized through the activation of intracellular signaling pathways by ROS. Take two simple examples. Activation of the PI3K-AKT-mTOR pathway can promote the synthesis of HIF-α, while inhibition of hydroxylase activity can prevent HIF-α degradation [55, 57, 58]. A wealth of evidence illustrate that HIFs induce metabolic reprogramming from oxidative phosphorylation to anaerobic glycolysis as well as lactic acid fermentation, by activating lactate dehydrogenase A and phosphorylating the E1α subunit of pyruvate dehydrogenase. This metabolic reprogramming is widely accepted as a hallmark of cancer because it can not only earn more ATP for cancer cells but also reduce the cytotoxic ROS levels in order to resolve the energy crisis within vigorous tumors and to help cancer cells survive the state of hypoxia. Additionally, it also enhances resistance to chemotherapy and radiotherapy treatments [59, 60]. HIF-2α promotes the expression of multiple antioxidant enzymes and DNA damage repair enzymes, thereby reducing the intracellular ROS levels and limiting the accumulation of DNA damage [61–63]. Only under hypoxia (1%) can HIF-1α be stabilized, and a low activity is observed at 5% O2 (resembling the end-capillary oxygen conditions) [64]. However, HIF-2α is stabilized at a wider range of oxygen tensions, ranging from severe hypoxia (<1% oxygen) to more physiologically relevant tension in tumors (2–5% oxygen) [64, 65]. HIF-1α and HIF-2α are highly homologous and bind to similar hypoxic response elements [56]. However, due to their unique target genes and expression patterns, they have their individual biological roles. Li et al. found that, under severe hypoxic conditions, HIF-2α is markedly expressed only in glioma stem cells but not in nonstem cells, whereas HIF-1α exists in both tumor subpopulations. It has also been suggested that the HIF-2α-mediated upregulation of Oct4, Glut1, SerpinB9, and VEGF may facilitate CSCs in metabolism, proliferation, survival, and escape from immune surveillance [65]. As evidenced in a number of various tumors in recent studies, hypoxia initially induces a transient activation of HIF-1α followed by persistent HIF-2α expression occurring after more prolonged periods of hypoxia and this hypoxic switch to HIF-2α can enhance the CSC population [66–68]. The expression of HIF is associated with the poor survival of patients with cancer [69].
Early CSC model proposed that CSCs are the driving force of tumorigenesis due to their abilities of self-renewal and irreversible multilineage differentiation through either asymmetric or symmetric cell division. In comparison, their offspring, namely, progenitor cells and differentiated cancer cells, no longer possess tumorigenic potential [70]. Therefore, anticancer treatment targeting CSCs holds great promise [24]. However, recently emerging lines of evidence have revised the earlier model to a dynamic model. It is now suggested that CSCs and non-CSCs can be bidirectional converged, an effect that is governed by their microenvironment; that is, progenitor cells and differentiated cells can reacquire their self-renewal capacity through reprogramming into CSCs [12, 71–75]. HIFs are considered as crucial regulators of the stem cell phenotype through Notch signaling pathways and induce the expression of stem cell markers, such as Oct4 [65], and induce pluripotent stem cell (iPSC) factors, Oct4, Nanog, Sox2, Klf4, and c-Myc, in many cancer cell types, including prostate, brain, kidney, cervix, lung, colon, liver, and breast tumors [76]. Similarly, multiple types of CSC-specific cell-surface markers, including CD133, CD44, and VEGF-A, can be markedly upregulated by HIFs [77–79], modulating the self-renew potential of CSCs. Studies by Heddleston et al. have elucidated that HIF-2α can reprogram the nonstem population of gliomas into CSCs through the upregulation of important stem cell factors, such as Oct4, Nanog, and c-Myc [80]. Consequently, it is necessary to evolve current cancer treatments to target both bulk differentiated cells and CSCs in tumor.
4. Regulation of ROS through CSC Markers in CSCs
CSCs can be identified and isolated primarily by CSC-specific cell-surface marker expression (Table 1). It has been demonstrated that CD34, CD133, CD44, and ALDH1 mark CSCs in leukemia and some solid tumors [81–86]. Nonetheless, there is a lack of a universal expression of surface markers to identify CSCs in all types of tumors [17]. As mentioned above, ROS-induced HIFs can enhance the expression of a variety of CSC biomarkers. For instance, insulin-like growth factor binding protein 3 (IGBP3) can suppress ROS-mediated cytotoxicity by novel insulin-like growth factor (IGF), independent antioxidant activity, thereby increasing CD44H cells in esophageal squamous cell carcinoma (ESCC) and facilitating ESCC cell adaptation and survival under hypoxia [87]. Interestingly, the biomarkers can modulate the level of ROS via different mechanisms.
Surface markers of cancer stem cells in different types of tumors.
It is well known that CD13, which is a marker of liver CSCs, is associated with tumor invasion, angiogenesis, and antiapoptosis [88, 89]. CD13 is a negative ROS regulator that results in the inhibition of apoptosis and the enhancement of the stemness of CSCs [24]. As a consequence, the survival of liver CD13+ CSCs in hypoxic lesions after chemotherapy contributes to the high expression of aminopeptidase N, a ROS scavenger enzyme. In addition, immunohistochemical analyses have indicated that CD13 coexists with N-cadherin in surviving cancer cells [89]. Gclm, which encodes a glutamate-cysteine ligase that catalyzes the rate-limiting step in the synthesis of GSH, is overexpressed in the CD13+CD90− fraction in PLC/PRF/5 cells, the ROS level of which is lower than that of the CD13− population. Both the CD13-neutralizing antibody and CD13 inhibitor ubenimex can stimulate ROS production, increasing the ROS concentration to that found in CD13− cells. In mouse xenograft models, the administration of ubenimex attenuates the self-renewal and tumor-initiation potentials of CD13+ cells [90]. Therefore, CD13-neutralizing antibody or other inhibitors can kill CSCs effectively.
As a cellular adhesion molecule for hyaluronic acid, CD44 is the most prevalent CSC molecular marker [91–93] and is widely expressed in multiple tumors, including breast cancer [94], head and neck squamous cell carcinoma [95], pancreatic cancer [96], colorectal cancer [97], and prostate cancer [83]. Its variant isoform, CD44v, can interact with and stabilizes xCT, a subunit of a glutamate-cystine exchange transporter located at the plasma membrane, thereby promoting cystine uptake for GSH synthesis and contributing to ROS defense [83, 97], and this finding was validated by the study conducted by Ishimoto et al. on gastrointestinal CSCs [47]. These researchers recently forced the expression of miRNA-328 in gastrointestinal cancer cell lines and found that CD44 expression was reduced, resulting in the repression of cancer cell growth in vitro and in vivo, and impaired resistance to ROS [98]. CD44 thus maintains a key role in the GSH-dependent antioxidant system in cancer cells [99].
CD138, which is also called syndecan-1, belongs to the mammalian syndecan family of heparin sulfate proteoglycans. Shimada et al. obtained holoclones harboring the biological properties of stemness from single-cell cultures of the PC3 human prostate cancer cell lines. Syndecan-1 is overexpressed in these holoclones and downregulates the expression of NADPH oxidase, thereby decreasing ROS generation. The in vitro silencing of syndecan-1 strongly destabilizes the holoclones by increasing ROS production, whereas in vivo syndecan-1 deficiency lowers the frequency of primitive cells expressing stem cell markers and markedly represses cancer propagation. It has also been discovered that a high level of Bcl-2 in holoclones is tightly linked to syndecan-1 [167]. This finding is consistent with Lagadinou et al.’s discovery that the overexpression of Bcl-2 in acute myelogenous leukemia CSCs maintains the ROS synthesis rates at low levels and stabilizes the primitive cells in a quiescent state [168]. However, in Waldenstrom’s macroglobulinemia, a lower ROS level is detected in CD20−CD138− cells compared with CD20+CD138− cells and CD20+CD138+ cells [169].
5. ROS Plays a Key Role in Anticancer Therapy
The Warburg effect refers to the phenomenon that cancer cells gain energy primarily from glycolysis even under aerobic conditions, leading to increased ROS production [170]. Although the ROS levels, which are counteracted by elevated antioxidant defense mechanisms in cancer cells, are compatible with cellular biological functions, they are still higher than those observed in normal cells. Cancer cells may be more sensitive than normal cells to the accumulation of ROS, which offers an interesting therapeutic window [43]. Hence, directly increasing ROS to reach a threshold that is incompatible with cell viability and targeting the enhanced antioxidant mechanisms can selectively kill cancer cells, without affecting normal cells [42, 171]. Despite the low level of ROS in CSCs and the active ROS detoxifying systems, elevating the concentration of ROS still has the ability to eliminate CSCs. The anticancer therapies by regulating ROS levels are shown in Table 2.
Anticancer therapies according to their different mechanisms in regulating ROS levels.
Mechanism
Therapy
Reference
Generation of ROS
Mitochondrial respiratory chain
Arsenic trioxide, anthracyclines (doxorubicin, daunorubicin, or epirubicin)
Buthionine sulfoximine, sulfasalazine, NOV-002, 6-anicotinamide, l-asparaginase, small molecule 968
[180–186]
GSSH
Auranofin
[187]
Myeloperoxidase
Parthenolide
[188]
Many antineoplastic chemotherapeutic agents, including taxanes, vinca alkaloids, and platinum coordination complexes, are currently used to induce high levels of ROS, resulting in cell death [189–191]. Paclitaxel, a mitotic inhibitory drug, can stabilize microtubules and therefore interfere with the normal breakdown of microtubules during cell division. In breast cancer cells, paclitaxel causes the translocation of Rac1, which positively regulates the activity of NOX, thereby promoting ROS generation. Paclitaxel-induced ROS is accumulated mainly outside the cell, provoking lethal damage to bystander cancer cells not exposed to paclitaxel, whereas the intracellular ROS levels remained unchanged [174]. The tumor suppressor promyelocytic leukemia protein (PML) has been demonstrated to play a critical role in the maintenance of quiescent chronic myeloid leukemia (CML) stem cells. Arsenic trioxide, which can induce ROS production and PML degradation, is introduced to eradicate CML stem cells [172]. Niclosamide, a potent antineoplastic drug that inactivates the NF-κB pathway and increases the ROS level, can preferentially kill progenitor/stem cells from acute myelogenous leukemia (AML) patients but spare those from normal bone marrow [175]. Consistent with this finding, parthenolide induces the apoptosis of CSCs in AML and blast crisis CML through mechanisms involving the inhibition of NF-κB and the proapoptotic activation of p53 and elevated ROS levels, which are likely obtained by a high level of myeloperoxidase [188].
At present, radiotherapy is widely used in various types of cancer treatments, mainly depending on ROS. Water radiolysis occurs in an extremely short period of time (~10−8 s) after ionizing radiation [192]. Several hours after exposure, intracellular ROS from biological sources are greatly enhanced [193]. Increased ROS generation in human lung carcinoma A549 cells exposed to X-irradiation is accompanied by an enhancement of the mitochondrial membrane potential, a promotion of mitochondrial respiration, and the maintenance of the ETC enzyme activities [194]. Furthermore, mitochondrial dysfunction and upregulation of NOX resulting from ionizing radiation contribute to persistent oxidative stress [176, 195]. Tumor recurrence after radiation is attributed to preferential activation of the DNA damage checkpoint response and increases the DNA repair capacity and antioxidant defense [196, 197]. However, discrepant observations are provided by the recent finding that CSCs are more radiosensitive than non-CSCs [198, 199]. Such contradictory results may be due to the limited experimental techniques or the dynamic characteristics of CSCs, which require further clarification.
An enhanced GSH concentration within cancer cells appears to be actively involved in mechanisms of chemoradioresistance [200]. Due to the high content of GSH, tumor cells are more sensitive to drugs affecting GSH metabolism than normal cells [171]. Glutamate-cysteine ligase (GCL), as the rate-limiting enzyme in GSH synthesis, has been targeted in anticancer therapy. Buthionine sulfoximine (BSO), which can inhibit GCL activity, is the only clinically used drug to suppress de novo GSH synthesis [180]. In addition, sulfasalazine, an anti-inflammatory drug with specific xCT inhibitory activity, markedly reduces the cystine uptake, GSH level, and growth and viability of human pancreatic cancer cells and chronic lymphocytic leukemia cells both in vitro and in vivo [181, 182].
With the exception of GSH, thioredoxin is also an important component of intracellular redox systems. Auranofin is a gold-containing compound that functions as an antirheumatic drug and a thioredoxin inhibitor. Apoptosis is accompanied by an increased generation of H2O2 in ovarian cancer cells, which reflects the importance of the thioredoxin metabolism in tumor cell survival [187]. The simultaneous administration of auranofin and BSO has been validated to induce oxidative stress and clonogenic killing in human head and neck squamous carcinoma cells and to increase their sensitivity to epidermal growth factor receptor inhibitors [201].
In most cases, combined therapy lends credence to the success of cancer treatment. To cite some effective examples, ionizing radiation combined with arsenic trioxide improves the therapeutic efficacy in human prostate cancer cells because the combined treatment results in enhanced ROS production compared with each individual treatment, thereby provoking autophagy and apoptosis by inhibition of the Akt/mTOR signaling pathways [202]. Mechanistically, the sulforaphane and imatinib combined treatment can kill CD34+CD38− leukemia stem cells by inducing ROS production and decreasing the GSH level [203]. The combination of a CSC marker inhibitor with ROS-inducing therapy, such as chemo- and radiotherapy, can eradicate CSCs and thereby annihilate the whole tumor. In mouse xenograft models, the combination of a CD13 inhibitor with 5-fluorouracil therapy improves the treatment of liver cancer [90].
Because ROS are a central contributor in tumor occurrence and progression, antioxidants should prevent tumorigenesis through the elimination of excessive ROS and restoration of the redox balance [204]. In addition to their protective role as preventive reagents against cancer, there is evidence that antioxidant supplementation during chemotherapy presents promising potential to reduce dose-limiting toxicities [205]. A large epidemiologic study (including 132,837 women and men) conducted in China demonstrated that vitamin E intake, either from diet or supplements, may reduce the risk of liver cancer [206]. The opposite result was found in another large study conducted in England, which revealed that the combination of β-carotene and vitamin A had no benefit and may have an adverse effect on the incidence and mortality of lung cancer [207]. In a two-stage mouse skin carcinogenesis model, a diet consisting of Nrf2 activators against oxidative stress significantly decreased the incidence of skin tumors [208]. In vitro experiments have proven that some nutrients with antioxidant characteristics, that is, vitamins A and D, genistein, (-)-epigallocatechin-3-gallate, sulforaphane, curcumin, piperine, theanine, and choline, can modify the self-renewal capacity of CSCs [209]. That being said, further research is needed to confirm the utility of antioxidants in cancer prevention. The titration of the amount of antioxidant should be strictly controlled because too-high or too-low levels may promote tumor survival and development.
6. Conclusion
CSCs have evolved to maintain a low level of intracellular ROS as a consequence of the modulation of redox systems, metabolic reprogramming, and reduced mitochondrial DNA levels. Increasing evidence proposes that a low concentration of ROS can maintain the stemness of CSCs and contribute to tumorigenesis and development. Therefore, HIF stabilization induced by ROS in CSCs plays a critical role. However, the underlying mechanisms in these processes remain to be elucidated in depth. There exist various systems for the regulation of ROS in CSCs, such as through CSC surface markers, and these help maintain the ROS at a favorable level. Consequently, the induction of oxidative stress appears to be a promising approach for the preferential killing of cancer cells, including CSCs. In addition, a more detailed investigation of therapies with direct or indirect effects on ROS will help define a made-to-order therapeutic schedule with a lower tendency toward promoting the development of resistance to treatment.
Conflict of Interests
The authors declare that there is no conflict of interests associated with the contents of this paper.
GuptaS. C.HeviaD.PatchvaS.ParkB.KohW.AggarwalB. B.Upsides and downsides of reactive oxygen species for Cancer: the roles of reactive oxygen species in tumorigenesis, prevention, and therapy201216111295132210.1089/ars.2011.44142-s2.0-84859864623TrachoothamD.AlexandreJ.HuangP.Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?20098757959110.1038/nrd28032-s2.0-67650071137BurdonR. H.Rice-EvansC.Free radicals and the regulation of mammalian cell proliferation19896634535810.3109/107157689090879182-s2.0-0024389273StorzG.ImlayJ. A.Oxidative stress19992218819410.1016/s1369-5274(99)80033-22-s2.0-0033118910BurdonR. H.Superoxide and hydrogen peroxide in relation to mammalian cell proliferation199518477579410.1016/0891-5849(94)00198-s2-s2.0-0028918334LapidotT.SirardC.VormoorJ.MurdochB.HoangT.Caceres-CortesJ.MindenM.PatersonB.CaligiuriM. A.DickJ. E.A cell initiating human acute myeloid leukaemia after transplantation into SCID mice1994367646464564810.1038/367645a02-s2.0-0028091194NguyenL. V.VannerR.DirksP.EavesC. J.Cancer stem cells: an evolving concept201212213314310.1038/nrc31842-s2.0-84856226651ClarkeM. F.DickJ. E.DirksP. B.EavesC. J.JamiesonC. H. M.JonesD. L.VisvaderJ.WeissmanI. L.WahlG. M.Cancer stem cells—perspectives on current status and future directions: AACR workshop on cancer stem cells200666199339934410.1158/0008-5472.can-06-31262-s2.0-33750313208LiY.KongD.AhmadA.BaoB.SarkarF. H.Pancreatic cancer stem cells: emerging target for designing novel therapy201333819410010.1016/j.canlet.2012.03.0182-s2.0-84882890729KoenemanK. S.Prostate cancer stem cells, telomerase biology, epigenetic modifiers, and molecular systemic therapy for the androgen-independent lethal phenotype200624211912110.1016/j.urolonc.2005.11.0312-s2.0-33644782566EconomopoulouP.KaklamaniV. G.SiziopikouK.The role of cancer stem cells in breast cancer initiation and progression: potential cancer stem cell-directed therapies201217111394140110.1634/theoncologist.2012-01632-s2.0-84869379939GuptaP. B.ChafferC. L.WeinbergR. A.Cancer stem cells: mirage or reality?20091591010101210.1038/nm0909-10102-s2.0-69949129056ClarkeM. F.FullerM.Stem cells and cancer: two faces of eve200612461111111510.1016/j.cell.2006.03.0112-s2.0-33646045010ShackletonM.QuintanaE.FearonE. R.MorrisonS. J.Heterogeneity in cancer: cancer stem cells versus clonal evolution2009138582282910.1016/j.cell.2009.08.0172-s2.0-69449096005DeanM.FojoT.BatesS.Tumour stem cells and drug resistance20055427528410.1038/nrc15902-s2.0-16844368698ReyaT.MorrisonS. J.ClarkeM. F.WeissmanI. L.Stem cells, cancer, and cancer stem cells2001414685910511110.1038/351021672-s2.0-0035499267ZhaoY.AlakhovaD. Y.KabanovA. V.Can nanomedicines kill cancer stem cells?20136513-141763178310.1016/j.addr.2013.09.0162-s2.0-84888205371BalabanR. S.NemotoS.FinkelT.Mitochondria, oxidants, and aging2005120448349510.1016/j.cell.2005.02.0012-s2.0-13944278132ChanceB.SiesH.BoverisA.Hydroperoxide metabolism in mammalian organs19795935276052-s2.0-0018776894PervaizS.TanejaR.GhaffariS.Oxidative stress regulation of stem and progenitor cells200911112777278910.1089/ars.2009.28042-s2.0-70350685238CohenG.HochsteinP.Glutathione peroxidase: the primary agent for the elimination of hydrogen peroxide in erythrocytes1963261420142810.1021/bi00906a0382-s2.0-33947476438HofmannB.HechtH. J.FlohéL.Peroxiredoxins20023833-434736410.1515/bc.2002.0402-s2.0-0036249816MichielsC.RaesM.ToussaintO.RemacleJ.Importance of SE-glutathione peroxidase, catalase, and Cu/Zn-SOD for cell survival against oxidative stress199417323524810.1016/0891-5849(94)90079-52-s2.0-0028170326ShiX.ZhangY.ZhengJ.PanJ.Reactive oxygen species in cancer stem cells201216111215122810.1089/ars.2012.45292-s2.0-84859829553HalliwellB.Free radicals and antioxidants: updating a personal view201270525726510.1111/j.1753-4887.2012.00476.x2-s2.0-84860331697DrögeW.Free radicals in the physiological control of cell function200282147952-s2.0-0036086130RajL.IdeT.GurkarA. U.FoleyM.SchenoneM.LiX.TollidayN. J.GolubT. R.CarrS. A.ShamjiA. F.SternA. M.MandinovaA.SchreiberS. L.LeeS. W.Selective killing of cancer cells by a small molecule targeting the stress response to ROS2011475735523123410.1038/nature101672-s2.0-79960427057ChenZ. X.PervaizS.Bcl-2 induces pro-oxidant state by engaging mitochondrial respiration in tumor cells20071491617162710.1038/sj.cdd.44021652-s2.0-34548036251SattlerM.WinklerT.VermaS.ByrneC. H.ShrikhandeG.SalgiaR.GriffinJ. D.Hematopoietic growth factors signal through the formation of reactive oxygen species1999939292829352-s2.0-0033135256ClémentM.-V.StamenkovicI.Superoxide anion is a natural inhibitor of FAS-mediated cell death19961522162252-s2.0-0030065418AchantaG.SasakiR.FengL.CarewJ. S.LuW.PelicanoH.KeatingM. J.HuangP.Novel role of p53 in maintaining mitochondrial genetic stability through interaction with DNA Pol γ200524193482349210.1038/sj.emboj.76008192-s2.0-27144488229HaghdoostS.CzeneS.NäslundI.SkogS.Harms-RingdahlM.Extracellular 8-oxo-dG as a sensitive parameter for oxidative stress in vivo and in vitro200539215316210.1080/107157605000431322-s2.0-15844387160PanJ.SheM.XuZ.-X.SunL.YeungS.-C. J.Farnesyltransferase inhibitors induce DNA damage via reactive oxygen species in human cancer cells20056593671368110.1158/0008-5472.CAN-04-27442-s2.0-18144363210WisemanR. L.ChinK.-T.HaynesC. M.StanhillA.XuC.-F.RoguevA.KroganN. J.NeubertT. A.RonD.Thioredoxin-related protein 32 is an arsenite-regulated thiol reductase of the proteasome 19 S particle200928422152331524510.1074/jbc.m109.0021212-s2.0-67649363856NishikawaM.Reactive oxygen species in tumor metastasis20082661535910.1016/j.canlet.2008.02.0312-s2.0-44449142812WinterbournC. C.Reconciling the chemistry and biology of reactive oxygen species20084527828610.1038/nchembio.852-s2.0-42249088093CookeM. S.EvansM. D.DizdarogluM.LunecJ.Oxidative DNA damage: mechanisms, mutation, and disease200317101195121410.1096/fj.02-0752rev2-s2.0-0038799736MarnettL. J.Oxyradicals and DNA damage200021336137010.1093/carcin/21.3.3612-s2.0-0034011261RehmanJ.Empowering self-renewal and differentiation: the role of mitochondria in stem cells2010881098198610.1007/s00109-010-0678-22-s2.0-78149408058FolmesC. D. L.DzejaP. P.NelsonT. J.TerzicA.Metabolic plasticity in stem cell homeostasis and differentiation201211559660610.1016/j.stem.2012.10.0022-s2.0-84868347607LonerganT.BrennerC.BavisterB.Differentiation-related changes in mitochondrial properties as indicators of stem cell competence2006208114915310.1002/jcp.206412-s2.0-33744908287SosaV.MolinéT.SomozaR.PaciucciR.KondohH.LLeonartM. E.Oxidative stress and cancer: an overview201312137639010.1016/j.arr.2012.10.0042-s2.0-84870554511DiehnM.ChoR. W.LoboN. A.KaliskyT.DorieM. J.KulpA. N.QianD.LamJ. S.AillesL. E.WongM.JoshuaB.KaplanM. J.WapnirI.DirbasF. M.SomloG.GarberoglioC.PazB.ShenJ.LauS. K.QuakeS. R.BrownJ. M.WeissmanI. L.ClarkeM. F.Association of reactive oxygen species levels and radioresistance in cancer stem cells2009458723978078310.1038/nature077332-s2.0-64749093574PiaoL. S.HurW.KimT.-K.HongS. W.KimS. W.ChoiJ. E.SungP. S.SongM. J.LeeB.-C.HwangD.YoonS. K.CD133+ liver cancer stem cells modulate radioresistance in human hepatocellular carcinoma2012315212913710.1016/j.canlet.2011.10.0122-s2.0-84355162060YeX.-Q.WangG.-H.HuangG.-J.BianX.-W.QianG.-S.YuS.-C.Heterogeneity of mitochondrial membrane potential: a novel tool to isolate and identify cancer stem cells from a tumor mass?20117115316010.1007/s12015-010-9122-92-s2.0-78751642921YeX.-Q.LiQ.WangG.-H.SunF.-F.HuangG.-J.BianX.-W.YuS.-C.QianG.-S.Mitochondrial and energy metabolism-related properties as novel indicators of lung cancer stem cells2011129482083110.1002/ijc.259442-s2.0-79959723691IshimotoT.NaganoO.YaeT.TamadaM.MotoharaT.OshimaH.OshimaM.IkedaT.AsabaR.YagiH.MasukoT.ShimizuT.IshikawaT.KaiK.TakahashiE.ImamuraY.BabaY.OhmuraM.SuematsuM.BabaH.SayaH.CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc− and thereby promotes tumor growth201119338740010.1016/j.ccr.2011.01.0382-s2.0-79952528125HeddlestonJ. M.LiZ.LathiaJ. D.BaoS.HjelmelandA. B.RichJ. N.Hypoxia inducible factors in cancer stem cells2010102578979510.1038/sj.bjc.66055512-s2.0-77649273107YeJ.WuD.WuP.ChenZ.HuangJ.The cancer stem cell niche: cross talk between cancer stem cells and their microenvironment20143553945395110.1007/s13277-013-1561-x2-s2.0-84891802460LouieE.NikS.ChenJ.-S.SchmidtM.SongB.PacsonC.ChenX. F.ParkS.JuJ.ChenE. I.Identification of a stem-like cell population by exposing metastatic breast cancer cell lines to repetitive cycles of hypoxia and reoxygenation2010126, article R9410.1186/bcr27732-s2.0-78149243774BhaskaraV. K.MohanamI.RaoJ. S.MohanamS.Intermittent hypoxia regulates stem-like characteristics and differentiation of neuroblastoma cells201272e3090510.1371/journal.pone.00309052-s2.0-84857186454LiP.ZhouC.XuL.XiaoH.Hypoxia enhances stemness of cancer stem cells in glioblastoma: an in vitro study201310439940710.7150/ijms.54072-s2.0-84874786113WeiJ.WuA.KongL.-Y.WangY.FullerG.FoktI.MelilloG.PriebeW.HeimbergerA. B.Hypoxia potentiates glioma-mediated immunosuppression201161e1619510.1371/journal.pone.00161952-s2.0-79251620102FeigC.GopinathanA.NeesseA.ChanD. S.CookN.TuvesonD. A.The pancreas cancer microenvironment201218164266427610.1158/1078-0432.CCR-11-31142-s2.0-84865080615PouysségurJ.DayanF.MazureN. M.Hypoxia signalling in cancer and approaches to enforce tumour regression2006441709243744310.1038/nature048712-s2.0-33745303045BertoutJ. A.PatelS. A.SimonM. C.The impact of O2 availability on human cancer200881296797510.1038/nrc25402-s2.0-57149142495YuanG.NanduriJ.KhanS.SemenzaG. L.PrabhakarN. R.Induction of HIF-alpha expression by intermittent hypoxia: involvement of NADPH oxidase, Ca2+ signaling, prolyl hydroxylases, and mTOR2008217367468510.1002/jcp.215372-s2.0-54049088213KlimovaT.ChandelN. S.Mitochondrial complex III regulates hypoxic activation of HIF200815466066610.1038/sj.cdd.44023072-s2.0-40949126440RohwerN.CramerT.Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways201114319120110.1016/j.drup.2011.03.0012-s2.0-79958191830ZhaoT.ZhuY.MorinibuA.KobayashiM.ShinomiyaK.ItasakaS.YoshimuraM.GuoG.HiraokaM.HaradaH.HIF-1-mediated metabolic reprogramming reduces ROS levels and facilitates the metastatic colonization of cancers in lungs20144, article 379310.1038/srep03793BertoutJ. A.MajmundarA. J.GordanJ. D.LamJ. C.DitsworthD.KeithB.BrownE. J.NathansonK. L.SimonM. C.HIF2alpha inhibition promotes p53 pathway activity, tumor cell death, and radiation responses200910634143911439610.1073/pnas.09073571062-s2.0-70149106164GordanJ. D.LalP.DondetiV. R.LetreroR.ParekhK. N.OquendoC. E.GreenbergR. A.FlahertyK. T.RathmellW. K.KeithB.SimonM. C.NathansonK. L.HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma200814643544610.1016/j.ccr.2008.10.0162-s2.0-56849096837ScortegagnaM.DingK.OktayY.GaurA.ThurmondF.YanL.-J.MarckB. T.MatsumotoA. M.SheltonJ. M.RichardsonJ. A.BennetM. J.GarciaJ. A.Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice200335433134010.1038/ng12662-s2.0-0344826529Holmquist-MengelbierL.FredlundE.LöfstedtT.NogueraR.NavarroS.NilssonH.PietrasA.Vallon-ChristerssonJ.BorgÅ.GradinK.PoellingerL.PåhlmanS.Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma: HIF-2α promotes an aggressive phenotype200610541342310.1016/j.ccr.2006.08.0262-s2.0-33750630119LiZ.BaoS.WuQ.WangH.EylerC.SathornsumeteeS.ShiQ.CaoY.LathiaJ.McLendonR. E.HjelmelandA. B.RichJ. N.Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells200915650151310.1016/j.ccr.2009.03.0182-s2.0-65749106405IidaH.SuzukiM.GoitsukaR.UenoH.Hypoxia induces CD133 expression in human lung cancer cells by up-regulation of OCT3/4 and SOX220124017179KohM. Y.PowisG.Passing the baton: the HIF switch201237936437210.1016/j.tibs.2012.06.0042-s2.0-84865429409KohM. Y.LemosR.Jr.LiuX.PowisG.The hypoxia-associated factor switches cells from HIF-1α- to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion201171114015402710.1158/0008-5472.can-10-41422-s2.0-79957440998Branco-PriceC.ZhangN.SchnelleM.EvansC.KatschinskiD. M.LiaoD.ElliesL.JohnsonR.Endothelial cell HIF-1α and HIF-2α differentially regulate metastatic success2012211526510.1016/j.ccr.2011.11.0172-s2.0-84862909156LeeH. E.KimJ. H.KimY. J.ChoiS. Y.KimS.-W.KangE.ChungI. Y.KimI. A.KimE. J.ChoiY.RyuH. S.ParkS. Y.An increase in cancer stem cell population after primary systemic therapy is a poor prognostic factor in breast cancer2011104111730173810.1038/bjc.2011.1592-s2.0-79957608448ChafferC. L.BrueckmannI.ScheelC.KaestliA. J.WigginsP. A.RodriguesL. O.BrooksM.ReinhardtF.SucY.PolyakK.ArendtL. M.KuperwasserC.BierieB.WeinbergR. A.Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state2011108197950795510.1073/pnas.11024541082-s2.0-79956351015OdouxC.FohrerH.HoppoT.GuzikL.StolzD. B.LewisD. W.GollinS. M.GamblinT. C.GellerD. A.LagasseE.A stochastic model for cancer stem cell origin in metastatic colon cancer200868176932694110.1158/0008-5472.CAN-07-57792-s2.0-52049117849MalanchiI.Santamaria-MartínezA.SusantoE.PengH.LehrH.-A.DelaloyeJ.-F.HuelskenJ.Interactions between cancer stem cells and their niche govern metastatic colonization20124817379859110.1038/nature106942-s2.0-84855425160ScheelC.EatonE. N.LiS. H.-J.ChafferC. L.ReinhardtF.KahK.-J.BellG.GuoW.RubinJ.RichardsonA. L.WeinbergR. A.Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast2011145692694010.1016/j.cell.2011.04.0292-s2.0-79958265710DriessensG.BeckB.CaauweA.SimonsB. D.BlanpainC.Defining the mode of tumour growth by clonal analysis2012488741252753010.1038/nature113442-s2.0-84865222310MathieuJ.ZhangZ.ZhouW.WangA. J.HeddlestonJ. M.PinnaC. M. A.HubaudA.StadlerB.ChoiM.BarM.TewariM.LiuA.VessellaR.RostomilyR.BornD.HorwitzM.WareC.BlauC. A.ClearyM. A.RichJ. N.Ruohola-BakerH.HIF induces human embryonic stem cell markers in cancer cells201171134640465210.1158/0008-5472.CAN-10-33202-s2.0-79959908506KrishnamacharyB.PenetM.-F.NimmagaddaS.MironchikY.RamanV.SolaiyappanM.SemenzaG. L.PomperM. G.BhujwallaZ. M.Hypoxia regulates CD44 and its variant isoforms through HIF-1α in triple negative breast cancer201278e4407810.1371/journal.pone.00440782-s2.0-84865507272PlatetN.LiuS. Y.AtifiM. E.OliverL.ValletteF. M.BergerF.WionD.Influence of oxygen tension on CD133 phenotype in human glioma cell cultures2007258228629010.1016/j.canlet.2007.09.0122-s2.0-36148995870GabhannF. M.PopelA. S.Systems biology of vascular endothelial growth factors200815871573810.1080/107396808020959642-s2.0-57149102486HeddlestonJ. M.LiZ.McLendonR. E.HjelmelandA. B.RichJ. N.The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype20098203274328410.4161/cc.8.20.97012-s2.0-70350225829SchepersH.van GosligaD.WierengaA. T. J.EggenB. J. L.SchuringaJ. J.VellengaE.STAT5 is required for long-term maintenance of normal and leukemic human stem/progenitor cells200711082880288810.1182/blood-2006-08-0390732-s2.0-35548954735StinglJ.EirewP.RicketsonI.ShackletonM.VaillantF.ChoiD.LiH. I.EavesC. J.Purification and unique properties of mammary epithelial stem cells2006439707999399710.1038/nature044962-s2.0-30144432901CollinsA. T.BerryP. A.HydeC.StowerM. J.MaitlandN. J.Prospective identification of tumorigenic prostate cancer stem cells20056523109461095110.1158/0008-5472.can-05-20182-s2.0-28244472369SinghS. K.HawkinsC.ClarkeI. D.SquireJ. A.BayaniJ.HideT.HenkelmanR. M.CusimanoM. D.DirksP. B.Identification of human brain tumour initiating cells2004432701539640110.1038/nature031282-s2.0-9244241576XuW.DebebB. G.LacerdaL.LiJ.WoodwardW. A.Tetrandrine, a compound common in Chinese traditional medicine, preferentially kills breast cancer tumor initiating cells (TICs) in vitro2011322274228510.3390/cancers30222742-s2.0-79959701824BholaN. E.BalkoJ. M.DuggerT. C.KubaM. G.SánchezV.SandersM.StanfordJ.CookR. S.ArteagaC. L.TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer201312331348135810.1172/JCI654162-s2.0-84874607100NatsuizakaM.KinugasaH.KagawaS.IGFBP3 promotes esophageal cancer growth by suppressing oxidative stress in hypoxic tumor microenvironment2014412941MishimaY.Matsumoto-MishimaY.TeruiY.KatsuyamaM.YamadaM.MoriM.IshizakaY.IkedaK.WatanabeJ.-I.MizunumaN.HayasawaH.HatakeK.Leukemic cell-surface CD13/aminopeptidase N and resistance to apoptosis mediated by endothelial cells200294131020102810.1093/jnci/94.13.10202-s2.0-0037014744KimH. M.HaraguchiN.IshiiH.OhkumaM.OkanoM.MimoriK.EguchiH.YamamotoH.NaganoH.SekimotoM.DokiY.MoriM.Increased CD13 expression reduces reactive oxygen species, promoting survival of liver cancer stem cells via an epithelial-mesenchymal transition-like phenomenon2012193, supplementS539S54810.1245/s10434-011-2040-52-s2.0-84864987692HaraguchiN.IshiiH.MimoriK.TanakaF.OhkumaM.KimH. M.AkitaH.TakiuchiD.HatanoH.NaganoH.BarnardG. F.DokiY.MoriM.CD13 is a therapeutic target in human liver cancer stem cells201012093326333910.1172/jci425502-s2.0-77956388547AillesL. E.WeissmanI. L.Cancer stem cells in solid tumors200718546046610.1016/j.copbio.2007.10.0072-s2.0-36148991764ZöllerM.CD44: can a cancer-initiating cell profit from an abundantly expressed molecule?201111425426710.1038/nrc30232-s2.0-79953042645LoboN. A.ShimonoY.QianD.ClarkeM. F.The biology of cancer stem cells200723167569910.1146/annurev.cellbio.22.010305.1041542-s2.0-34548831213Al-HajjM.WichaM. S.Benito-HernandezA.MorrisonS. J.ClarkeM. F.Prospective identification of tumorigenic breast cancer cells200310073983398810.1073/pnas.05302911002-s2.0-0037388204PrinceM. E.SivanandanR.KaczorowskiA.WolfG. T.KaplanM. J.DalerbaP.WeissmanI. L.ClarkeM. F.AillesL. E.Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma2007104397397810.1073/pnas.06101171042-s2.0-33846512398HermannP. C.HuberS. L.HerrlerT.AicherA.EllwartJ. W.GubaM.BrunsC. J.HeeschenC.Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer20071331332310.1016/j.stem.2007.06.0022-s2.0-34548455927DalerbaP.DyllaS. J.ParkI.-K.LiuR.WangX.ChoR. W.HoeyT.GurneyA.HuangE. H.SimeoneD. M.SheltonA. A.ParmianiG.CastelliC.ClarkeM. F.Phenotypic characterization of human colorectal cancer stem cells200710424101581016310.1073/pnas.07034781042-s2.0-34547193404IshimotoT.SugiharaH.WatanabeM.SawayamaH.IwatsukiM.BabaY.OkabeH.HidakaK.YokoyamaN.MiyakeK.YoshikawaM.NaganoO.KomoharaY.TakeyaM.SayaH.BabaH.Macrophage-derived reactive oxygen species suppress miR-328 targeting CD44 in cancer cells and promote redox adaptation20143551003101110.1093/carcin/bgt402NaganoO.OkazakiS.SayaH.Redox regulation in stem-like cancer cells by CD44 variant isoforms201332445191519810.1038/onc.2012.6382-s2.0-84887043495BonnetD.DickJ. E.Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell19973773073710.1038/nm0797-7302-s2.0-0030789242JinL.HopeK. J.ZhaiQ.Smadja-JoffeF.DickJ. E.Targeting of CD44 eradicates human acute myeloid leukemic stem cells200612101167117410.1038/nm14832-s2.0-33749515476JinL.LeeE. M.RamshawH. S.BusfieldS. J.PeopplA. G.WilkinsonL.GuthridgeM. A.ThomasD.BarryE. F.BoydA.GearingD. P.VairoG.LopezA. F.DickJ. E.LockR. B.Monoclonal antibody-mediated targeting of CD123, IL-3 receptor α chain, eliminates human acute myeloid leukemic stem cells200951314210.1016/j.stem.2009.04.0182-s2.0-67649200331MajetiR.ChaoM. P.AlizadehA. A.PangW. W.JaiswalS.GibbsK. D.Jr.van RooijenN.WeissmanI. L.CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells2009138228629910.1016/j.cell.2009.05.0452-s2.0-67650632683JordanC. T.UpchurchD.SzilvassyS. J.GuzmanM. L.HowardD. S.PettigrewA. L.MeyerroseT.RossiR.GrimesB.RizzieriD. A.LugerS. M.PhillipsG. L.The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stems cells200014101777178410.1038/sj.leu.24019032-s2.0-0033815950CoxC. V.EvelyR. S.OakhillA.PamphilonD. H.GouldenN. J.BlairA.Characterization of acute lymphoblastic leukemia progenitor cells200410492919292510.1182/blood-2004-03-09012-s2.0-7244223336YangY. M.ChangJ. W.Bladder cancer initiating cells (BCICs) are among EMA−CD44v6+ subset: novel methods for isolating undetermined cancer stem (initiating) cells200826772573310.1080/073579008019418452-s2.0-48249150771HeX.MarchionniL.HanselD. E.YuW.SoodA.YangJ.ParmigianiG.MatsuiW.BermanD. M.Differentiation of a highly tumorigenic basal cell compartment in urothelial carcinoma20092771487149510.1002/stem.922-s2.0-68049148065ChanK. S.EspinosaI.ChaoM.WongD.AillesL.DiehnM.GillH.PrestiJ.Jr.ChangH. Y.Van De RijnM.ShortliffeL.WeissmanI. L.Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells200910633140161402110.1073/pnas.09065491062-s2.0-69549114870GinestierC.HurM. H.Charafe-JauffretE.MonvilleF.DutcherJ.BrownM.JacquemierJ.ViensP.KleerC. G.LiuS.SchottA.HayesD.BirnbaumD.WichaM. S.DontuG.ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome20071555556710.1016/j.stem.2007.08.0142-s2.0-35848955428XuJ.-X.MoriiE.LiuY.NakamichiN.IkedaJ.-I.KimuraH.AozasaK.High tolerance to apoptotic stimuli induced by serum depletion and ceramide in side-population cells: high expression of CD55 as a novel character for side-population200731391877188510.1016/j.yexcr.2007.03.0062-s2.0-34247486847MeyerM. J.FlemingJ. M.LinA. F.HussnainS. A.GinsburgE.VonderhaarB. K.CD44posCD49fhiCD133/2hi defines xenograft-initiating cells in estrogen receptor-negative breast cancer201070114624463310.1158/0008-5472.can-09-36192-s2.0-77953163539LinW.-M.KarstenU.GoletzS.ChengR.-C.CaoY.Expression of CD176 (Thomsen-Friedenreich antigen) on lung, breast and liver cancer-initiating cells20119229710510.1111/j.1365-2613.2010.00747.x2-s2.0-79952807457GuW.YeoE.McMillanN.YuC.Silencing oncogene expression in cervical cancer stem-like cells inhibits their cell growth and self-renewal ability2011181289790510.1038/cgt.2011.582-s2.0-81155130805LópezJ.PoitevinA.Mendoza-MartínezV.Pérez-PlasenciaC.García-CarrancáA.Cancer-initiating cells derived from established cervical cell lines exhibit stem-cell markers and increased radioresistance201212, article 4810.1186/1471-2407-12-482-s2.0-84858077204Ricci-VitianiL.LombardiD. G.PilozziE.BiffoniM.TodaroM.PeschleC.De MariaR.Identification and expansion of human colon-cancer-initiating cells2007445712311111510.1038/nature053842-s2.0-33846095137KemperK.GrandelaC.MedemaJ. P.Molecular identification and targeting of colorectal cancer stem cells.2010163873952-s2.0-79957467315O'BrienC. A.PollettA.GallingerS.DickJ. E.A human colon cancer cell capable of initiating tumour growth in immunodeficient mice2007445712310611010.1038/nature053722-s2.0-33846100356HuangE. H.HynesM. J.ZhangT.GinestierC.DontuG.AppelmanH.FieldsJ. Z.WichaM. S.BomanB. M.Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis20096983382338910.1158/0008-5472.CAN-08-44182-s2.0-65949112714BarkerN.RidgwayR. A.van EsJ. H.van de WeteringM.BegthelH.Van Den BornM.DanenbergE.ClarkeA. R.SansomO. J.CleversH.Crypt stem cells as the cells-of-origin of intestinal cancer2009457722960861110.1038/nature076022-s2.0-59049106578OkumuraT.TsunodaS.MoriY.ItoT.KikuchiK.WangT. C.YasumotoS.ShimadaY.The biological role of the low-affinity p75 neurotrophin receptor in esophageal squamous cell carcinoma200612175096510310.1158/1078-0432.CCR-05-28522-s2.0-33749004013SmitJ. K.FaberH.NiemantsverdrietM.BaanstraM.BussinkJ.HollemaH.Van OsR. P.PlukkerJ. T. M.CoppesR. P.Prediction of response to radiotherapy in the treatment of esophageal cancer using stem cell markers2013107343444110.1016/j.radonc.2013.03.0272-s2.0-84881474210TangK. H.DaiY. D.TongM.ChanY. P.KwanP. S.FuL.QinY. R.TsaoS. W.LungH. L.LungM. L.TongD. K.LawS.ChanK. W.MaS.GuanX. Y.A CD90+ tumor-initiating cell population with an aggressive signature and metastatic capacity in esophageal cancer20137372322233210.1158/0008-5472.can-12-29912-s2.0-84875981178ShiC.TianR.WangM.WangX.JiangJ.ZhangZ.LiX.HeZ.GongW.QinR.CD44+ CD133+ population exhibits cancer stem cell-like characteristics in human gallbladder carcinoma201010111182119010.4161/cbt.10.11.136642-s2.0-79959594835WangM.XiaoJ.JiangJ.QinR.CD133 and ALDH may be the molecular markers of cholangiocarcinoma stem cells201112881996199710.1002/ijc.255192-s2.0-79951996059ChenT.YangK.YuJ.MengW.YuanD.BiF.LiuF.LiuJ.DaiB.ChenX.WangF.ZengF.XuH.HuJ.MoX.Identification and expansion of cancer stem cells in tumor tissues and peripheral blood derived from gastric adenocarcinoma patients201222124825810.1038/cr.2011.1092-s2.0-84855473976JiangJ.ZhangY.ChuaiS.WangZ.ZhengD.XuF.ZhangY.LiC.LiangY.ChenZ.Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype201231667168210.1038/onc.2011.2822-s2.0-84856963775ChristensenK.Aaberg-JessenC.AndersenC.GoplenD.BjerkvigR.KristensenB. W.Immunohistochemical expression of stem cell, endothelial cell, and chemosensitivity markers in primary glioma spheroids cultured in serum-containing and serum-free medium201066593394710.1227/01.NEU.0000368393.45935.462-s2.0-77951689749MishimaK.KatoY.KanekoM. K.NishikawaR.HiroseT.MatsutaniM.Increased expression of podoplanin in malignant astrocytic tumors as a novel molecular marker of malignant progression2006111548348810.1007/s00401-006-0063-y2-s2.0-33646259475SonM. J.WoolardK.NamD.-H.LeeJ.FineH. A.SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma20094544045210.1016/j.stem.2009.03.0032-s2.0-65349115320TchoghandjianA.BaezaN.ColinC.CayreM.MetellusP.BeclinC.OuafikL.Figarella-BrangerD.A2B5 cells from human glioblastoma have cancer stem cell properties201020121122110.1111/j.1750-3639.2009.00269.x2-s2.0-71549129570AnidoJ.Sáez-BorderíasA.Gonzàlez-JuncàA.RodónL.FolchG.CarmonaM. A.Prieto-SánchezR. M.BarbaI.Martínez-SáezE.PrudkinL.CuartasI.RaventósC.Martínez-RicarteF.PocaM. A.García-DoradoD.LahnM. M.YinglingJ. M.RodónJ.SahuquilloJ.BaselgaJ.SeoaneJ.TGF-β receptor inhibitors target the CD44high/Id1high glioma-initiating cell population in human glioblastoma201018665566810.1016/j.ccr.2010.10.0232-s2.0-78649986150ChenY.-C.ChenD.-T.ChenY.-W.HsuH.-S.TsengL.-M.HuangP.-I.LuK.-H.TaiL.-K.YungM.-C.ChangS.-C.KuH.-H.ChiouS.-H.LoW.-L.Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer2009385330731310.1016/j.bbrc.2009.05.0482-s2.0-67349209852YangZ. F.HoD. W.NgM. N.LauC. K.YuW. C.NgaiP.ChuP. W. K.LamC. T.PoonR. T. P.FanS. T.Significance of CD90+ cancer stem cells in human liver cancer200813215316610.1016/j.ccr.2008.01.0132-s2.0-38549139140ZhuZ.HaoX.YanM.YaoM.GeC.GuJ.LiJ.Cancer stem/progenitor cells are highly enriched in CD133+CD44+ population in hepatocellular carcinoma201012692067207810.1002/ijc.248682-s2.0-77949891635TerrisB.CavardC.PerretC.EpCAM, a new marker for cancer stem cells in hepatocellular carcinoma201052228028110.1016/j.jhep.2009.10.0262-s2.0-75549088882KimuraO.TakahashiT.IshiiN.InoueY.UenoY.KogureT.FukushimaK.ShiinaM.YamagiwaY.KondoY.InoueJ.KakazuE.IwasakiT.KawagishiN.ShimosegawaT.SugamuraK.Characterization of the epithelial cell adhesion molecule (EpCAM)+ cell population in hepatocellular carcinoma cell lines2010101102145215510.1111/j.1349-7006.2010.01661.x2-s2.0-77957051282EramoA.LottiF.SetteG.PilozziE.BiffoniM.Di VirgilioA.ConticelloC.RucoL.PeschleC.De MariaR.Identification and expansion of the tumorigenic lung cancer stem cell population200815350451410.1038/sj.cdd.44022832-s2.0-39449088496LeungE. L.-H.FiscusR. R.TungJ. W.TinV. P.-C.ChengL. C.SihoeA. D.-L.FinkL. M.MaY.WongM. P.Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties2010511e1406210.1371/journal.pone.00140622-s2.0-78649522166SalcidoC. D.LarochelleA.TaylorB. J.DunbarC. E.VarticovskiL.Molecular characterisation of side population cells with cancer stem cell-like characteristics in small-cell lung cancer2010102111636164410.1038/sj.bjc.66056682-s2.0-77952885076ZhangW. C.Shyh-ChangN.YangH.RaiA.UmashankarS.MaS.SohB. S.SunL. L.TaiB. C.NgaM. E.BhakooK. K.JayapalS. R.NichaneM.YuQ.AhmedD. A.TanC.SingW. P.TamJ.ThirugananamA.NoghabiM. S.PangY. H.AngH. S.RobsonP.KaldisP.SooR. A.SwarupS.LimE. H.LimB.Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis20121481-225927210.1016/j.cell.2011.11.0502-s2.0-84856087055BoikoA. D.RazorenovaO. V.van de RijnM.SwetterS. M.JohnsonD. L.LyD. P.ButlerP. D.YangG. P.JoshuaB.KaplanM. J.LongakerM. T.WeissmanI. L.Human melanoma-initiating cells express neural crest nerve growth factor receptor CD2712010466730213313710.1038/nature091612-s2.0-77954238710FangD.HerlynM.NguyenT. K.LeishearK.FinkoR.KulpA. N.HotzS.Van BelleP. A.XuX.ElderD. E.A tumorigenic subpopulation with stem cell properties in melanomas200565209328933710.1158/0008-5472.can-05-13432-s2.0-27144557960QuintanaE.ShackletonM.FosterH. R.FullenD. R.SabelM. S.JohnsonT. M.MorrisonS. J.Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized201018551052310.1016/j.ccr.2010.10.0122-s2.0-78249250559RoeschA.Fukunaga-KalabisM.SchmidtE. C.ZabierowskiS. E.BraffordP. A.VulturA.BasuD.GimottyP.VogtT.HerlynM.A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth2010141458359410.1016/j.cell.2010.04.0202-s2.0-77952502408SchattonT.MurphyG. F.FrankN. Y.YamauraK.Waaga-GasserA. M.GasserM.ZhanQ.JordanS.DuncanL. M.WeishauptC.FuhlbriggeR. C.KupperT. S.SayeghM. H.FrankM. H.Identification of cells initiating human melanomas2008451717634534910.1038/nature064892-s2.0-38349165576SuJ.XuX.-H.HuangQ.LuM.-Q.LiD.-J.XueF.YiF.RenJ.-H.WuY.-P.Identification of cancer stem-like CD44+ cells in human nasopharyngeal carcinoma cell line2011421152110.1016/j.arcmed.2011.01.0072-s2.0-79952081749WuA.LuoW.ZhangQ.YangZ.ZhangG.LiS.YaoK.Aldehyde dehydrogenase 1, a functional marker for identifying cancer stem cells in human nasopharyngeal carcinoma2013330218118910.1016/j.canlet.2012.11.0462-s2.0-84873091842ZhuangH.-W.MoT.-T.HouW.-J.XiongG.-X.ZhuX.-L.FuQ.-L.WenW.-P.Biological characteristics of CD133+ cells in nasopharyngeal carcinoma2013301576310.3892/or.2013.24082-s2.0-84878180209ZhangQ.ShiS.YenY.BrownJ.TaJ. Q.LeA. D.A subpopulation of CD133+ cancer stem-like cells characterized in human oral squamous cell carcinoma confer resistance to chemotherapy2010289215116010.1016/j.canlet.2009.08.0102-s2.0-76849098162NotoZ.YoshidaT.OkabeM.KoikeC.FathyM.TsunoH.TomiharaK.AraiN.NoguchiM.NikaidoT.CD44 and SSEA-4 positive cells in an oral cancer cell line HSC-4 possess cancer stem-like cell characteristics201349878779510.1016/j.oraloncology.2013.04.0122-s2.0-84880050211GibbsC. P.KukekovV. G.ReithJ. D.TchigrinovaO.SuslovO. N.ScottE. W.GhivizzaniS. C.IgnatovaT. N.SteindlerD. A.Stem-like cells in bone sarcomas: implications for tumorigenesis200571196797610.1593/neo.053942-s2.0-33644825465AdhikariA. S.AgarwalN.WoodB. M.PorrettaC.RuizB.PochampallyR. R.IwakumaT.CD117 and Stro-1 identify osteosarcoma tumor-initiating cells associated with metastasis and drug resistance201070114602461210.1158/0008-5472.CAN-09-34632-s2.0-77953170540VeselskaR.HermanovaM.LojaT.ChlapekP.ZamboI.VeselyK.ZitterbartK.SterbaJ.Nestin expression in osteosarcomas and derivation of nestin/CD133 positive osteosarcoma cell lines20088, article 30010.1186/1471-2407-8-3002-s2.0-57149138305SainiV.HoseC. D.MonksA.NagashimaK.HanB.NewtonD. L.MillioneA.ShahJ.HollingsheadM. G.HiteK. M.BurkettM. W.DeloshR. M.SilversT. E.ScudieroD. A.ShoemakerR. H.Identification of CBX3 and ABCA5 as putative biomarkers for tumor stem cells in osteosarcoma201278e4140110.1371/journal.pone.00414012-s2.0-84864542596CurleyM. D.TherrienV. A.CummingsC. L.SergentP. A.KoulourisC. R.FrielA. M.RobertsD. J.SeidenM. V.ScaddenD. T.RuedaB. O. R.FosterR.CD133 expression defines a tumor initiating cell population in primary human ovarian cancer200927122875288310.1002/stem.2362-s2.0-73349125059ZhangS.BalchC.ChanM. W.LaiH.-C.MateiD.SchilderJ. M.YanP. S.HuangT. H.-M.NephewK. P.Identification and characterization of ovarian cancer-initiating cells from primary human tumors200868114311432010.1158/0008-5472.can-08-03642-s2.0-49249091523ZiebarthA. J.NowsheenS.StegA. D.ShahM. M.KatreA. A.DobbinZ. C.HanH.-D.Lopez-BeresteinG.SoodA. K.ConnerM.YangE. S.LandenC. N.Jr.Endoglin (CD105) contributes to platinum resistance and is a target for tumor-specific therapy in epithelial ovarian cancer201319117018210.1158/1078-0432.CCR-12-10452-s2.0-84871962714MeirellesK.BenedictL. A.DombkowskiD.PepinD.PrefferF. I.TeixeiraJ.TanwarP. S.YoungR. H.MacLaughlinD. T.DonahoeP. K.WeiX.Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance201210972358236310.1073/pnas.11207331092-s2.0-84857137036LuoL.ZengJ.LiangB.ZhaoZ.SunL.CaoD.YangJ.ShenK.Ovarian cancer cells with the CD117 phenotype are highly tumorigenic and are related to chemotherapy outcome201191259660210.1016/j.yexmp.2011.06.0052-s2.0-79961119901LiC.LeeC. J.SimeoneD. M.YuJ. S.Identification of human pancreatic cancer stem cells2009568Clifton, NJ, USAHumana Press161173Methods in Molecular BiologyXinL.LawsonD. A.WitteO. N.The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis2005102196942694710.1073/pnas.05023201022-s2.0-18744377702ReiterR. E.GuZ.WatabeT.ThomasG.SzigetiK.DavisE.WahlM.NisitaniS.YamashiroJ.Le BeauM. M.LodaM.WitteO. N.Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer1998954, article 173510.1073/pnas.95.4.17352-s2.0-13144250150Dall'EraM. A.TrueL. D.SiegelA. F.PorterM. P.SherertzT. M.LiuA. Y.Differential expression of CD10 in prostate cancer and its clinical implication20077, article 310.1186/1471-2490-7-32-s2.0-33947409944HavensA. M.JungY. H.SunY. X.WangJ.ShahR. B.BühringH. J.PientaK. J.TaichmanR. S.The role of sialomucin CD164 (MGC-24v or endolyn) in prostate cancer metastasis20066, article 19510.1186/1471-2407-6-1952-s2.0-33748201733MalanchiI.PeinadoH.KassenD.HussenetT.MetzgerD.ChambonP.HuberM.HohlD.CanoA.BirchmeierW.HuelskenJ.Cutaneous cancer stem cell maintenance is dependent on β-catenin signalling2008452718765065310.1038/nature068352-s2.0-41649089525SchoberM.FuchsE.Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-β and integrin/focal adhesion kinase (FAK) signaling201110826105441054910.1073/pnas.11078071082-s2.0-79960573076ShimadaK.AnaiS.FujiiT.TanakaN.FujimotoK.KonishiN.Syndecan-1 (CD138) contributes to prostate cancer progression by stabilizing tumour-initiating cells2013231449550410.1002/path.42712-s2.0-84887542459LagadinouE. D.SachA.CallahanK.RossiR. M.NeeringS. J.MinhajuddinM.AshtonJ. M.PeiS.GroseV.O'DwyerK. M.LiesveldJ. L.BrookesP. S.BeckerM. W.JordanC. T.BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells201312332934110.1016/j.stem.2012.12.0132-s2.0-84875143073WadaN.ZhanM.HoriY.HonmaK.IkedaJ.-I.MoriiE.Characterization of subpopulation lacking both B-cell and plasma cell markers in Waldenstrom macroglobulinemia cell line2014941798810.1038/labinvest.2013.1292-s2.0-84891512631CairnsR. A.HarrisI. S.MakT. W.Regulation of cancer cell metabolism2011112859510.1038/nrc29812-s2.0-79251517382GorriniC.HarrisI. S.MakT. W.Modulation of oxidative stress as an anticancer strategy2013121293194710.1038/nrd40022-s2.0-84889575198ItoK.BernardiR.MorottiA.MatsuokaS.SaglioG.IkedaY.RosenblattJ.AviganD. E.Teruya-FeldsteinJ.PandolfiP. P.PML targeting eradicates quiescent leukaemia-initiating cells200845371981072107810.1038/nature070162-s2.0-44349166602ŠimůnekT.ŠtěrbaM.PopelováO.AdamcováM.HrdinaR.GeršiV.Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron200961115417110.1016/s1734-1140(09)70018-02-s2.0-66949171305AlexandreJ.HuY.LuW.PelicanoH.HuangP.Novel action of paclitaxel against cancer cells: bystander effect mediated by reactive oxygen species20076783512351710.1158/0008-5472.can-06-39142-s2.0-34248582844JinY.LuZ.DingK.LiJ.DuX.ChenC.SunX.WuY.ZhouJ.PanJ.Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells: inactivation of the NF-κB pathway and generation of reactive oxygen species20107062516252710.1158/0008-5472.can-09-39502-s2.0-77950212486YoshidaT.GotoS.KawakatsuM.UrataY.LiT.-S.Mitochondrial dysfunction, a probable cause of persistent oxidative stress after exposure to ionizing radiation201246214715310.3109/10715762.2011.6452072-s2.0-84863069814LosmanJ.-A.LooperR. E.KoivunenP.LeeS.SchneiderR. K.McMahonC.CowleyG. S.RootD. E.EbertB. L.KaelinW. G.Jr.(R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible201334061271621162510.1126/science.12316772-s2.0-84875496294WangF.TravinsJ.DeLaBarreB.Penard-LacroniqueV.SchalmS.HansenE.StraleyK.KernytskyA.LiuW.GliserC.YangH.GrossS.ArtinE.SaadaV.MylonasE.QuivoronC.Popovici-MullerJ.SaundersJ. O.SalituroF. G.YanS.MurrayS.WeiW.GaoY.DangL.DorschM.AgrestaS.SchenkeinD. P.BillerS. A.SuS. M.De BottonS.YenK. E.Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation2013340613262262610.1126/science.12347692-s2.0-84877620952ZhuJ.SongX.LinH.-P.YoungD. C.YanS.MarquezV. E.ChenC.-S.Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents200294231745175710.1093/jnci/94.23.17452-s2.0-0037021658GriffithO. W.Mechanism of action, metabolism, and toxicity of buthionine sulfoximine and its higher homologs, potent inhibitors of glutathione synthesis19822572213704137122-s2.0-0020444895LoM.LingV.LowC.WangY. Z.GoutP. W.Potential use of the anti-inflammatory drug, sulfasalazine, for targeted therapy of pancreatic cancer20101739162-s2.0-77953117152GoutP. W.BuckleyA. R.SimmsC. R.BruchovskyN.Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the Xc- cystine transporter: a new action for an old drug200115101633164010.1038/sj.leu.24022382-s2.0-0034772516MonteroA. J.Diaz-MonteroC. M.DeutschY. E.HurleyJ.KoniarisL. G.RumboldtT.YasirS.JordaM.Garret-MayerE.AvisarE.SlingerlandJ.SilvaO.WelshC.SchuhwerkK.SeoP.PegramM. D.GlückS.Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II-IIIc breast cancer2012132121522310.1007/s10549-011-1889-02-s2.0-84857916510BelfiC. A.ChatterjeeS.GoskyD. M.BergerS. J.BergerN. A.Increased sensitivity of human colon cancer cells to DNA cross-linking agents after GRP78 up-regulation1999257236136810.1006/bbrc.1999.04722-s2.0-0033551118PietersR.HungerS. P.BoosJ.RizzariC.SilvermanL.BaruchelA.GoekbugetN.SchrappeM.PuiC.-H.L-asparaginase treatment in acute lymphoblastic leukemia2011117223824910.1002/cncr.254892-s2.0-78650976352LeA.LaneA. N.HamakerM.BoseS.GouwA.BarbiJ.TsukamotoT.RojasC. J.SlusherB. S.ZhangH.ZimmermanL. J.LieblerD. C.SlebosR. J. C.LorkiewiczP. K.HigashiR. M.FanT. W. M.DangC. V.Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells201215111012110.1016/j.cmet.2011.12.0092-s2.0-84855453655MarzanoC.GandinV.FoldaA.ScutariG.BindoliA.RigobelloM. P.Inhibition of thioredoxin reductase by auranofin induces apoptosis in cisplatin-resistant human ovarian cancer cells200742687288110.1016/j.freeradbiomed.2006.12.0212-s2.0-33847014053GuzmanM. L.RossiR. M.KarnischkyL.LiX.PetersonD. R.HowardD. S.JordanC. T.The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells2005105114163416910.1182/blood-2004-10-41352-s2.0-16844363378KaufmannS. H.EarnshawW. C.Induction of apoptosis by cancer chemotherapy20002561424910.1006/excr.2000.48382-s2.0-0034630167ConklinK. A.Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness20043429430010.1177/15347354042703352-s2.0-9244261938BarreraG.Oxidative stress and lipid peroxidation products in cancer progression and therapy201220122113728910.5402/2012/137289RileyP. A.Free radicals in biology: oxidative stress and the effects of ionizing radiation1994651273310.1080/095530094145500412-s2.0-0027954494TateishiY.SasabeE.UetaE.YamamotoT.Ionizing irradiation induces apoptotic damage of salivary gland acinar cells via NADPH oxidase 1-dependent superoxide generation2008366230130710.1016/j.bbrc.2007.11.0392-s2.0-37449006299YamamoriT.YasuiH.YamazumiM.WadaY.NakamuraY.NakamuraH.InanamiO.Ionizing radiation induces mitochondrial reactive oxygen species production accompanied by upregulation of mitochondrial electron transport chain function and mitochondrial content under control of the cell cycle checkpoint201253226027010.1016/j.freeradbiomed.2012.04.0332-s2.0-84862284114WangY.LiuL.PazhanisamyS. K.LiH.MengA.ZhouD.Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells201048234835610.1016/j.freeradbiomed.2009.11.0052-s2.0-72649103214BaoS.WuQ.McLendonR. E.HaoY.ShiQ.HjelmelandA. B.DewhirstM. W.BignerD. D.RichJ. N.Glioma stem cells promote radioresistance by preferential activation of the DNA damage response2006444712075676010.1038/nature052362-s2.0-33845317573RopoloM.DagaA.GrifferoF.ForestaM.CasartelliG.ZuninoA.PoggiA.CappediE.ZonaG.SpazianteR.CorteG.FrosinaG.Comparative analysis of DNA repair in stem and nonstem glioma cell cultures20097338339210.1158/1541-7786.MCR-08-04092-s2.0-62549142665McCordA. M.JamalM.WilliamsE. S.CamphausenK.TofilonP. J.CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines200915165145515310.1158/1078-0432.ccr-09-02632-s2.0-69349095324KimS.-Y.RheeJ. G.SongX.ProchownikE. V.SpitzD. R.LeeY. J.Breast cancer stem cell-like cells are more sensitive to ionizing radiation than non-stem cells: role of ATM2012711e5042310.1371/journal.pone.00504232-s2.0-84869779399TaiD.-J.JinW.-S.WuC.-S.SiH.-W.CaoX.-D.GuoA.-J.ChangJ.-C.Changes in intracellular redox status influence multidrug resistance in gastric adenocarcinoma cells20124229129610.3892/etm.2012.5912-s2.0-84862658808SobhakumariA.Love-HomanL.FletcherE. V. M.MartinS. M.ParsonsA. D.SpitzD. R.KnudsonC. M.SimonsA. L.Susceptibility of human head and neck cancer cells to combined inhibition of glutathione and thioredoxin metabolism2012710e4817510.1371/journal.pone.00481752-s2.0-84868286860ChiuH.-W.ChenY.-A.HoS.-Y.WangY.-J.Arsenic trioxide enhances the radiation sensitivity of androgen-dependent and -independent human prostate cancer cells201272e3157910.1371/journal.pone.00315792-s2.0-84857411790LinL.-C.YehC.-T.KuoC.-C.LeeC.-M.YenG.-C.WangL.-S.WuC.-H.YangW.-C. V.WuA. T. H.Sulforaphane potentiates the efficacy of imatinib against chronic leukemia cancer stem cells through enhanced abrogation of Wnt/β-catenin function201260287031703910.1021/jf301981n2-s2.0-84863924338KovacicP.JacinthoJ. D.Mechanisms of carcinogenesis: focus on oxidative stress and electron transfer20018777379610.2174/09298670133730842-s2.0-0035025124BlockK. I.KochA. C.MeadM. N.TothyP. K.NewmanR. A.GyllenhaalC.Impact of antioxidant supplementation on chemotherapeutic toxicity: a systematic review of the evidence from randomized controlled trials2008123612271239ZhangW.ShuX.-O.LiH.YangG.CaiH.JiB.-T.GaoJ.GaoY.-T.ZhengW.XiangY.-B.Vitamin intake and liver cancer risk: a report from two cohort studies in China2012104151174118210.1093/jnci/djs2772-s2.0-84864958532OmennG. S.GoodmanG. E.ThornquistM. D.BalmesJ.CullenM. R.GlassA.KeoghJ. P.MeyskensF. L.Jr.ValanisB.WilliamsJ. H.Jr.BarnhartS.HammarS.Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease1996334181150115510.1056/nejm1996050233418022-s2.0-9244262406LiuJ.GuX.RobbinsD.LiG.ShiR.McCordJ. M.ZhaoY.Protandim, a fundamentally new antioxidant approach in chemoprevention using mouse two-stage skin carcinogenesis as a model200944e528410.1371/journal.pone.00052842-s2.0-67649224733KimY. S.FarrarW.ColburnN. H.MilnerJ. A.Cancer stem cells: potential target for bioactive food components201223769169810.1016/j.jnutbio.2012.03.0022-s2.0-84862318675