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Cancer drug resistance: redox resetting renders a way

Cancer drug resistance: redox resetting renders a way www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 27 Review 1,2,* 2,* 1,* 1 3 2 Yuan Liu , Qifu Li , Li Zhou , Na Xie , Edouard C. Nice , Haiyuan Zhang , 1 4 Canhua Huang and Yunlong Lei State Key Laboratory for Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, P. R. China Department of Neurology, The Affiliated Hospital of Hainan Medical College, Haikou, Hainan, P. R. China Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia Department of Biochemistry and Molecular Biology, and Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, P. R. China These authors have contributed equally to this work Correspondence to: Yunlong Lei, email: leiyunlong@126.com Correspondence to: Canhua Huang, email: hcanhua@hotmail.com Correspondence to: Haiyuan Zhang, email: hyzhang_88@163.com Keywords: drug resistance, cancer therapy, oxidative stress, redox modifications, drug efflux Received: October 28, 2015 Accepted: March 28, 2016 Published: April 05, 2016 ABSTRACT Disruption of redox homeostasis is a crucial factor in the development of drug resistance, which is a major problem facing current cancer treatment. Compared with normal cells, tumor cells generally exhibit higher levels of reactive oxygen species (ROS), which can promote tumor progression and development. Upon drug treatment, some tumor cells can undergo a process of ‘Redox Resetting’ to acquire a new redox balance with higher levels of ROS accumulation and stronger antioxidant systems. Evidence has accumulated showing that the ‘Redox Resetting’ enables cancer cells to become resistant to anticancer drugs by multiple mechanisms, including increased rates of drug efflux, altered drug metabolism and drug targets, activated prosurvival pathways and inefficient induction of cell death. In this article, we provide insight into the role of ‘Redox Resetting’ on the emergence of drug resistance that may contribute to pharmacological modulation of resistance. hydrogen peroxide (H O ), the hydroxyl radical (•OH), INTRODUCTION 2 2 - 1 superoxide(O ) and singlet oxygen ( O ) [4]. Under 2 2 physiological conditions, cells are capable of maintaining Development of drug resistance is an important a balance between cellular oxidants and antioxidants, factor in the failure of anticancer therapeutic treatments called redox homeostasis. Submicromolar levels of ROS [1]. Such resistance results from a variety of factors act as second messengers to regulate cell proliferation, including individual variations in patients and somatic cell death, and other cellular processes [5]. Excessive cell genetic differences in tumors. The ability to evade levels of ROS induce oxidative stress that leads to medicinal drugs is intrinsic to cancer cells. Reasons for various pathological states, including aging, neurological acquisition of anticancer drug resistance include enhanced disorders, and cancer [6]. In general, most tumors exhibit expression of transporters that increases anticancer drugs higher levels of ROS than normal tissues, thus promoting efflux, alterations in drug metabolism, mutations of drug tumor progression and development [5]. Moreover, targets and the activation of survival or inactivation of oxidative stress controls the efficacy of cancer treatments downstream death signaling pathways (Figure 1) [1]. in multiple ways, including chemosensitivity, apoptosis, Studies on cancer drug resistance mechanisms have angiogenesis, metastasis and inflammatory responses [6]. yielded valuable information on how to circumvent However, when ROS concentrations become extremely resistance to improve cancer chemotherapy [1-3]. high, they lead to tumor cell death [7]. Thus, a variety Reactive oxygen species (ROS) are chemical of drugs with direct or indirect effects on ROS induction oxygen species with reactive properties, which comprise have been used for effective cancer therapies (Table 1). www.impactjournals.com/oncotarget 42740 Oncotarget Table 1: Roles of anticancer treatments in regulating ROS levels Name Mechanism of action Effects on ROS Cancer types Refs Photons or particles affect chemical bonds and produce Different types of Ionizing radiation highly ROS, which cause Increases ROS production [160] cancer damage to DNA and other cellular components Triggers ROS associated Different types of Methotrexate Increases ROS production [161] cell apoptosis cancer Triggers cell membrane Significant increases of Different types of Mitoxantrone [162] scrambling ROS formation cancer Promotes cancer cell Tamoxifen Promotes ROS generation Breast, colon cancer [163] senescence Generation of nuclear DNA Induces a mitochondrial- Different types of Cisplatin [164] adducts dependent ROS generation cancer Different types of Paclitaxel (Taxol) Inhibitor of cell division Increases ROS production [165] cancer Reduces cell viability through initiating cell Different types of Adriamycin Increases ROS production [166] apoptosis and strong G2/M cancer phase cell cycle arrest Protein tyrosine kinase Different types of Imatinib inhibitor that induce Increases ROS production [167] cancer apoptosis Quinolone alkaloid that Different types of Camptothecin Increases ROS production [168] induces cytotoxicity cancer Semisynthetic flavonoid that Flavopiridol inhibits cyclin-dependent Increases ROS production Leukemia [169] kinases 6-thioguanine UVA photosensitizer Increases ROS production Skin cancer [170] Isolated DNA could be Lymphoma, primary Procarbazine degraded by procarbazine in Increases ROS production [171] brain cancers the presence of oxygen Glutathione disulphide Alters intracellular GSSG/ Lung, breast and NOV-002 [172] mimetic GSH ratio ovarian cancer Reduces intracellular Inhibitor of cysteine/ Pancreatic and lung [173, Sulphasalazine transport of cysteine glutamate transporter xCT cancer 174] required for GSH synthesis Leukemia, pancreatic [175, L-asparaginase Depletes glutamine Reduces GSH cancer 176] Glutamate-cysteine ligase Inhibits de novo GSH Ovarian and breast [177, Buthionine sulphoximine (BSO) complex inhibitor synthesis cancer, melanoma 178] Induction of ROS owing to Different types of Carboplatin Induction of cell cycle arrest [179] ER stress cancer Selective epidermal growth Activates FOXO3a and in Different types of Gefitinib factor receptor tyrosine [180] turn reduces ROS cancer kinase inhibitor Different types of Irinotecan Topoisomerases inhibitor Causes oxidative stress [181] cancer Neuroblastoma, Etoposide Selective Topo II α inhibitor Increases ROS production [182] breast cancer Glycosylation inhibitor that Triggers ER stress Tunicamycin causes protein accumulation Leukemia [183] production in the ER Sarco(endo)plasmic 2+ reticulum Ca ATPase Triggers ER stress Thapsigargin inhibitor that releases ER Leukemia [183] production 2+ 2+ Ca and stimulates Ca influx www.impactjournals.com/oncotarget 42741 Oncotarget Alkylating agent that causes Chloroethylnitrosoureas Increases ROS production Melanoma tumors [184] DNA damage Temozolomide Alkylating agent Increases ROS production Brain cancer [185] Inhibits cyclooxygenase Colorectal cancer, 2 (COX2) activity but it Induction of ROS owing to myeloma, Burkitt’s Celecoxib also induces ER stress by [186] ER stress lymphoma and causing leakage of calcium prostate cancer from the ER into the cytosol HPV-transformed Originally developed as cervical carcinoma, HIV protease inhibitor but it Induction of ROS owing to head and neck Nelfinavir [187] also induces ER stress by an ER stress cancer, pancreatic unknown mechanism cancer, melanoma and glioma Mantle cell Induces ROS owing to ER [188, Bortezomib Proteasome inhibitor lymphoma, multiple stress 189] myeloma Induce the generation of oxygen-derived free Insert into the DNA of radicals through two main replicating cells and inhibit pathways: anon-enzymatic Anthracyclines (doxorubicin, Different types of topoisomerase II, which pathway that utilizes [190] daunorubicin or epirubicin) cancer prevents DNA and RNA iron, and anenzymatic synthesis. mechanism that involves the mitochondrial respiratory chain Decrease protein homeostasis during oxidative stress by Breast cancer, non- 17-allylaminogeldanamycin HSP90 inhibitor disrupting HSP90–client small-cell lung [191] (17-AAG) protein complexes and cancer promoting the degradation of the client proteins Prodrug that is Colorectal, breast, enzymatically converted to Capecitabine Decreases ROS production gastric, and [192] 5-fluorouracil (5-FU) in the oesophageal cancer body Inhibits thymidylate Colon cancer, rectum synthetase and/or Induces intracellular 5-fluorouracil (5-FU) cancer, and head and [88] incorporates into RNA and increase inO2·- levels neck cancer DNA Inhibits mitochondrial Reacts with cysteine respiratory function, Arsenic trioxide (As2O3) Leukemia, myeloma [193] residues on crucial proteins thereby increasing free radical generation Induces free radicals Prostate cancer, 2-methoxyestradiol(2-ME) Metabolite of estradiol-17β and loss of mitochondrial [194] leukemia membrane potential Induces apoptosis through Prostate cancer, N-(4 hydroxyphenyl)retinamide Synthetic retinoid derivative the production of ROS and breast cancer, [195] (4-HPR) mitochondrial disruption neuroblastoma Reduce the capacity to Inhibit the action of the PARP inhibitors repair ROS-induced DNA Breast cancer [196] enzyme PARP damage Down regulates Alters the mitochondrial V12 RAS -expressing [197, Erastin mitochondrial VDACs and membrane permeability and tumor cells 198] cysteine redox shuttle blocks GSH regeneration www.impactjournals.com/oncotarget 42742 Oncotarget Nonetheless, some tumor cells can overcome drug-induced significant threat to clinical tumor therapy. Several cell oxidative stress by enhancing their antioxidant systems, membrane transporter proteins have been implicated in with the outcome that a new redox balance with a more drug resistance to commonly used chemotherapeutics by higher ROS level is established, the process of ‘Redox promoting drug efflux [1]. Among them, the ATP-binding Resetting’ (Figure 2). Such drug-induced redox resetting cassette (ABC) transporter family is the most notable. has recently been shown to result in drug resistance. For There are 49 members of the ABC transporter family, example, increased levels of reduced glutathione lead to but only multi-drug resistance protein 1 (MDR1), MDR- elevated chemotherapeutic drug resistance in numerous associated protein 1 (MRP1) and breast cancer resistance cancers [8, 9]. protein (BCRP) have been studied extensively in relation Redox resetting has been implicated in drug to multidrug resistance (MDR) [10]. All three transporters resistance at multiple levels, including elevated drug have broad substrate specificity and promote the efflux efflux, altered drug metabolism and mutated drug targets of various hydrophobic cancer chemotherapeutics such [10, 11]. In addition, ROS-induced activation of survival as topoisomerase inhibitors, taxanes, and antimetabolites signaling pathways and inactivation of downstream death [14]. Here, we summarize the effects of redox reactions signaling pathways can lead to drug resistance (Figure 1) and redox signals on these three drug efflux transporters. [1, 12, 13]. Here, we focus on the effects of redox resetting on drug resistance mechanisms and on current research Redox reactions promote conformational changes efforts to reveal the detailed mechanisms of resistance to of the transporters cancer therapies. All ABC transporters contain four domains - INCREASED RATES OF DRUG EFFLUX two nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs) (Figure 3) [15]. These Drug export from cells is a primary cause of four domains can be fused into multi-domain polypeptides the cellular resistance to anticancer drugs and poses a Figure 1: General mechanisms of cancer drug resistance. The anticancer activity of a drug can be limited by reduced drug influx or increased drug efflux, changes in expression levels of drug tar get, mutation of drug target, and a lack of cell death induction. www.impactjournals.com/oncotarget 42743 Oncotarget in a variety of ways. The driving force for drug during drug transport (Figure 3B) [21]. Mutations at transport is achieved by a switch between two principal certain cysteine residues within MSD drastically reduce conformations of the NBD dimer [16]. The conformations drug-transport activities [22, 23]. A previous study has of ABC transporters are maintained by multiple chemical identified that MSD is necessary for the dimerization interactions, including covalent bonds—the intra- and of MRP1, which can be disrupted by treatment with inter-molecular disulfide bond formed between reactive dithiothreitol (DTT), a reducing agent [24, 25]. These cysteine residues [17]. The cellular redox status has a data suggest that dimerization is formed through disulfide great impact on reversible disulfide bond formation and is linkage between cysteine residues. Yang et al [23] essential for proper protein folding as well as transporter investigated the roles of Cys7 and Cys32, which are functions. located in the MSD domain, in MRP1 dimerization The drug transport activity of human MDR1 is (Figure 3B). Mutations at Cys7 caused conformational correlated with the redox states of its two cysteine residues changes and prevented dimerization in MRP1 [26]. In (Cys431 and Cys1074). The ATP hydrolysis activity addition to dimerization, cancer cells activate antioxidant is strongly inhibited by the covalent reaction of either systems after treatment of ROS-inducing anticancer drugs, of these two cysteine residues with N-ethylmaleimide including enhanced expression of glutathione (GSH), (NEM), a sulfhydryl blocker [18]. These two cysteine which can form glutathione S-conjugated molecules to residues are present in NBD1 and NBD2 (Figure 3A), and facilitate drug efflux by MRP1 [27]. are located very close to the bound nucleotide. The ready In contrast to the molecular structures of MDR1 formation of the intramolecular disulfide between Cys431 and MRP1, BCRP comprises six transmembrane domains and Cys1074 shows that the two nucleotide-binding and only one ATP-binding cassette, and is known as sites of MDR1 are structurally very close and capable a ‘half-transporter’ [28]. Human BCRP exists in the of intimate functional interactions, consistent with our plasma membrane as a homodimer due to disulfide- current understanding of the catalytic mechanism [19]. bonded cysteine residues (Figure 3C) [29]. Treatment MRP1 has a topological configuration similar to with 2-mercaptoethanol (2-ME) reduces the BCRP from MDR1, whereas MRP1 has an additional membrane- homodimer to monomer [30]. Three of the cysteine spanning domain located at the N-terminus, called MSD residues, Cys592, Cys 603, and Cys608 in BCRP are [20]. The MSD functions as a plug that controls gating located on the extracellular face between TMD5 and Figure 2: Comparisons of ROS level between different stages of tumor progression and tumor drug-resistance. While in normal cells ROS generation and antioxidants are in balance, increased ROS levels are hallmarks of cancer cells. Marked increase in ROS can be achieved by chemotherapeutic agents, resulting in irreparable cellular damages and cancer cell death. However, some cancer cells can develop drug resistance by redox resetting. www.impactjournals.com/oncotarget 42744 Oncotarget Figure 3: Schematic diagrams showing the structures of MDR1, MRP1 and BCRP. All ABC transporters contain transmembrane and membrane-spanning domains. The disulfide bonds between the cysteine residues identified in the figure are required for maintenance of protein stability and transporter function. www.impactjournals.com/oncotarget 42745 Oncotarget TMD6 (Figure 3C) [31-33]. Cys592 and Cys608 are Redox determine transporter gene expression critical for protein stability by intramolecular disulfide bond formation. Mutations at these two cysteine Apart from the conformational changes of those residues result in protein misfolding and degradation, drug efflux pumps mentioned above, redox-induced thereby increasing drug sensitivity because of inefficient overexpression of efflux pumps provides alternative drug elimination [31-33]. Cys603 is implicated in ‘gates’ by which drugs can be exported from cells. intermolecular disulfide bond formation, resulting in Overexpressed transporters have been frequently observed dimerization of BCRP (Figure 3C). Mutation at Cys603 in many types of human malignancy, and correlated with prevents homodimerization [33]. However, functional reduced response to chemotherapeutic agents [35]. After analyses demonstrates that mutation at Cys603 do not treatment with anticancer drugs, redox signaling networks change the transport activity of the drugs SN-38 and are activated to regulate these transporters expression in mitoxantrone, even though monomeric BCRP represents multiple layers, including transcriptional, translational, only a half-molecule of a functional ABC transporter [32]. post-translational, and epigenetic levels. Recently, Cys284, Cys374, and Cys438 are also reported Transcriptional regulation to be involved in intramolecular disulfide bond formation and necessary for BCRP function [34]. Accumulating evidence shows that redox-sensing transcription factors take part in the transcriptional regulation of drug efflux transporters (Figure 4). Nuclear factor-erythroid 2 related factor 2 (NRF2), a redox-sensing Figure 4: Redox regulation of drug efflux transporters expression. (a) Oxidation of KEAP1 dissociates NRF2 from the complex, allowing the translocation and activation of NRF2; (b) Oxidative stress promotes the translocation of APE-1, facilitating transcription of numerous gene including MDRs, MRPs and BCRP; (c) FOXO can be activated by interacting with transportin through disulfide linkage under oxidative stress. The activation of these transcription factors contributes to the expression of drug efflux transporters. www.impactjournals.com/oncotarget 42746 Oncotarget transcription factor, can bind to antioxidant response patients [57]. Paradoxically, recent studies showed that element (ARE) and regulates a broad spectrum of genes FOXO3 expression levels were decreased in cisplatin- involved in redox balancing, glutathione synthesis, resistant cells [58], and FOXO3 knockdown increased and drug detoxification [36]. AREs are identified in the cell proliferation and enhanced resistance to cisplatin [59]. promoter region of efflux transporters, such as BCRP and Ataxia telangiectasia mutated (ATM) is a serine/ MRPs [36]. In general, NRF2 is anchored in the cytoplasm threonine protein kinase that participates in activation by Kelch-like ECH-associated protein 1 (KEAP1), of the DNA damage checkpoint, resulting in cell cycle which facilitates NRF2 ubiquitination and proteasomal arrest, DNA repair or apoptosis [60]. Recent studies degradation. Cys273 and Cys288 of KEAP1 are the have revealed a novel mechanism of ATM activation crucial target residues for oxidation. Redox modifications via direct oxidation [61, 62]. When ATM is activated dissociate KEAP1 from NRF2, allowing the translocation by double-strand breaks (DSBs), the protein undergoes of NRF2 to the nucleus, where it transactivates target monomerization that requires free DNA ends and the gene expression (Figure 4) [37]. Recent studies showed Mre11-Rad50-Nbs1 (MRN) complex. By contrast, when that higher levels of NRF2 could promote tumorigenesis ATM is activated by direct oxidation, oxidized ATM and contribute to chemoresistance, suggesting a “dark forms an active dimer covalently linked by intermolecular side” of the NRF2 pathway [38-43]. For example, disulfide bonds [61]. Residue Cys2991 is crucial for ATM the expression of NRF2 is increased during acquired activation by oxidation. A C2991L mutant cannot be resistance to tamoxifen and doxorubicin in breast and activated by H O but can be normally activated by the 2 2 ovarian cancer cells [44, 45]. Nuclear accumulation of MRN complex and DNA [61]. A recent study showed NRF2 can lead to enhanced expression of ARE-containing that both camptothecin and cisplatin treatment not only genes including drug efflux transporters, which facilitate induced ATM activation, but also upregulated MDR- the development of drug resistance [46]. In addition, related genes BCRP and MRP2 expression in NCI-H446 overexpression of NRF2 causes enhanced resistance to cells. Moreover, cisplatin and camptothecin-induced chemotherapeutic agents, including cisplatin, doxorubicin BCRP and MRP2 upregulation can be suppressed by ATM and etoposide [40]. Higher expressions of NRF2 and inhibitors, indicating the role of ATM activation on MDR its target genes are associated with taxol resistance and formation in lung cancer chemotherapy [63]. anchorage-independent growth in MCF-7 and MDA- Post-translational regulation MB-231 mammospheres compared to adherent cells MDR1 is a phosphorylation substrate for a number [47]. Moreover, transport activities of several MRPs are of protein kinases, including protein kinase C (PKC) activated by γ-glutamylcysteine synthetase (γ-GCS, the and protein kinase A (PKA) [64]. PKA is shown to be rate-limiting enzyme for GSH de novo biosynthesis), activated by redox modifications through the formation of which can be induced by NRF2 [48]. intramolecular disulfide bonds which cause a subcellular Forkhead box O (FOXO) proteins, a family translocation, resulting in phosphorylation of established of transcription factors, are deregulated in several protein substrates [65]. PKC catalytic properties can be cancers including prostate, breast, glioblastoma, altered by redox mechanisms, which in turn influence rhabdomyosarcoma, and leukemia [49]. As inactivation the activity of MDR1 [66]. Activation of PKC has been of FOXOs has been determined to be a crucial step reported to increase the phosphorylation of MDR1 in carcinogenesis, increasing their activity could be a in multidrug-resistant cells [67] and decrease drug potential therapeutic strategy for cancer treatment [49, 50]. accumulation and sensitivity [68]. Conversely, treatment FOXOs are not only responsible for the initial therapeutic with PKC inhibitors has been shown to decrease the response to anticancer drugs, but also involved in the phosphorylation of MDR1, resulting in attenuated drug acquisition of drug resistance (Figure 4) [51, 52]. Under efflux activity and MDR1 drug binding [69]. continuous stress induced by anticancer drugs, FOXOs can elicit the expression of relevant genes for drug efflux and Epigenetic regulation antioxidant defense, such as MDR1, MRP2, Mn-SOD and The promoter region of MDR1 is highly GC- catalase [50, 53-55]. For instance, FOXO3 and FOXO1 rich and contains several CpG islands that are prone can induce MDR1 expression in adriamycin-resistant to be methylated for transcriptional silencing. Studies breast cancer cells and K562 leukemic cells [50, 54]. In have demonstrates that the methylation status of addition, the promoter region of the human MRP2 gene the MDR1 promoter is correlated with MDR1 gene contains four FOXO binding sites, and transcription of transcriptional activity [70-72]. The methylation is MRP2 gene is stimulated by overexpressed FOXO1 in catalyzed by DNA methyltransferases (DNMTs) and MCF-7 cells [53]. FOXO1 expression is significantly use of S-adenosylmethionine (SAM) as a methyl donor. upregulated in a paclitaxel resistant cells and further SAM is the first metabolite in the methionine cycle enhanced by exposure to paclitaxel [56]. Furthermore, catalyzed by S-adenosylmethionine synthetase (also FOXO1 overexpression has been frequently observed known as methionine adenosyltransferase, MAT). The in cancer tissue samples obtained from chemoresistant activities of MATs are profoundly correlated with redox www.impactjournals.com/oncotarget 42747 Oncotarget conditions, through the maintenance of a homotetrameric ALTERED DRUG METABOLISM conformation [73]. The methionine cycle is the primary source of cysteine, a precursor of GSH in the Besides increased rates of drug efflux, altered drug transsulfuration pathway. Intracellular GSH levels are metabolism is another important resistance mechanism, essential in the maintenance of methylated DNA. GSH including drug inactivation or deficient drug activation. depletion by hepatotoxin bromobenzene results in a The redox resetting induced by anticancer drugs may reduction of intracellular methionine pools and genome- hinder the therapeutic effects by such mechanisms. wide DNA hypomethylation [74]. Antioxidant systems can directly inhibit the antitumor activity of some anticancer agents, such as paclitaxel [75], bortezomib [76] and radiation therapy [77]. For example, buthionine sulphoximine (BSO) significantly increases paclitaxel cytotoxicity through ROS accumulation [75]. Figure 5: 5-FU resistance in cancer cells by TYMS oxidation. The fluoropyrimidines (5-FU) are broken down into three metabolites, fluorodeoxyuridine monophosphate (FdUMP), fluoro-deoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate (FUTP). The principal mechanism of action of 5-FU is the inhibition of thymidylate synthase (TYMS), but alternative pharmacodynamic pathways acting through incorporation of drug metabolites into DNA and RNA. TYMS can also be activated through direct oxidation that leads to 5-FU resistance. www.impactjournals.com/oncotarget 42748 Oncotarget Also, platinum drugs, which generate extremely high ROS cytotoxic chemotherapy drugs in a range of tumor cells. levels, can be inactivated by GSH [78]. Hypermethylation of the DNA promoter regions of the Alternatively, the cellular redox state is correlated drug targets results in cell resistance to anticancer drugs, with enzymic expression required for the conversion such as cisplatin and carboplatin [91, 92]. In addition, of antimetabolites, such as 5 fluorouracil (5-FU) and methylation of genes involved in apoptosis, including methotrexate, to their most active forms [79, 80]. the DNA mismatch repair (MMR) gene human mutL Capecitabine is a fluoropyrimidine prodrug that is homolog 1 (hMLH1), can occur in drug-resistant tumor converted into 5-FU by thymidinephosphorylase [81]. The models. This has led to the concept that the use of a DNA gene encoding thymidinephosphorylase can be inactivated demethylating agent such as 2′-deoxy-5-azacytidine by DNA methylation, thereby causing capecitabine in combination with anticancer drugs may reverse this resistance [82]. These epigenetic alterations have been resistance mechanism [93]. shown to be induced by H O , where DNMT1 binds more 2 2 tightly to chromatin after H O treatment and then alters INEFFECTIVE INDUCTION OF CELL 2 2 the methylation status of CpG regions [83]. As observed DEATH in the case of the topoisomerase inhibitor irinotecan, the inactivation by UDP glucuronosyl transferase 1 Following the action of an activated drug on its (UGT1A1) is induced by the redox-sensing NRF2-KEAP1 cellular target, the therapeutic outcome is then determined pathway [84]. Epigenetic silencing can also promote drug by the next key process; the response of cancer cells to activity, and the expression of UGT1A1 is reduced by drug treatment. Generally, oxidative stress causes by DNA methylation of the promoter. Therefore, in this case, anticancer drugs in turn leads to some cellular damage promoter methylation promotes irinotecan activity [85, (e.g., DNA damage) that is tightly coupled to the induction 86]. of cell death. Nevertheless, some intrinsic redox adaptive responses can be triggered to enable the cancer cells to ALTERATIONS IN THE DRUG TARGETS survive through inhibition of cell death and activation of cellular survival pathways, thus providing a mechanism of Drug response and resistance are also determined resistance to treatment with anticancer agents [7]. by alterations in the drug target, such as mutations or changes in expression level. The deregulated or prolonged Deregulation of apoptosis production of cellular oxidants has been linked to mutations (induced by oxidant-mediated DNA damage), as It is well known that resistance to apoptosis is a well as modification of gene expression [87]. Thus, target hallmark of cancer [94]. Thus, deregulation of apoptosis alteration is more likely to happen with anticancer drugs will protect cancer cells from cell death caused by drug- that induce high ROS levels. induced cellular damage. Cleavage of caspase-3 is known The fluoropyrimidine 5-FU is widely used to play a central role in apoptosis. Substantial evidence in the treatment of a variety of cancers, including reveals that the activity of caspase-3 is inhibited via colorectal, breast, and aerodigestive tract cancer redox modifications [95]. Caspase-3 has been found to [88]. It is converted intracellularly to three active be constitutively S-glutathionylated in human umbilical metabolites: fluorodeoxyuridinemonophosphate vein endothelial cells (HUVECs) [96]. Upon tumor (FdUMP), fluorodeoxyuridinetriphosphate (FdUTP) and necrosis factor α (TNFα) stimulation, de-glutathionylation fluorouridine triphosphate(FUTP) (Figure 5).These active of caspase-3 occurs mediated by glutaredoxin (Grx). metabolites disrupt RNA synthesis and the function of Knockdown of Grx notably inhibit TNFα-induced thymidylate synthase (TYMS). TYMS plays a crucial cell death owing to attenuated caspase-3 cleavage, role in catalyzing deoxyuridylate (dUMP) to thymidylate concomitant with enhanced caspase-3 S-glutathionylation (dTMP), which provides the sole intracellular de novo [96]. Mutations of key S-glutathionylation sites of source of dTMP [89]. Human TYMS protein can caspase-3 (C163S, C184S, and C220S) enhance cleavage specifically bind to its own TYMS mRNA and functions compared with wild-type caspase-3 [97]. Furthermore, as a translational repressor. The RNA binding activity is S-glutathionylated caspase-3 inhibits its cleavage by determined by its redox state. In the presence of reducing caspase-8 in vitro (Figure 6) [97]. In addition, caspase-3 agents, the RNA binding activity of TYMS protein is can also be S-nitrosylated at Cys163 [98]. Upon the first significantly enhanced. In contrast, treatment of TYMS apoptosis signal (Fas) ligation, de-nitrosylated caspase-3 protein with the oxidizing agent diamide inhibits RNA leads to caspase-3 activation (Figure 6) [99]. Collectively, binding [90]. These results demonstrate that the oxidation the higher ROS levels in drug-resistant cells may of TYMS, resulting in loss of translational repressor contribute to their escape from apoptosis by caspase-3 function, could lead to 5-FU resistance in cancer cells. S-glutathionylation and S-nitrosylation. Drug target changes through epigenetic events Upon Fas ligand (FasL) binding, Fas interacts have also been shown to be involved in resistance to www.impactjournals.com/oncotarget 42749 Oncotarget with Fas-associated protein with death domain (FADD) produce excessive cellular damage and even lead to cell and procaspase 8 or 10, to form an active death death, thus attenuating the drug resistance activity of inducing signaling complex (DISC) [100]. The FADD cancer cells [106]. On the other hand, autophagy has a and procaspase-8 interaction can be inhibited by Flice role in maintaining cancer cell survival during conditions inhibitory protein (FLIP) through competitive binding of stress and might mediate resistance to anticancer to FADD [100, 101]. Intriguingly, the activity of FLIP therapies [107, 108]. For example, co-administration is shown to be enhanced by S-nitrosylation [102]. Loss of cisplatin and an autophagy inhibitor chloroquine of S-nitrosylation increases FLIP degradation, which in significantly suppress tumor survival whereas cisplatin turn facilitates DISC complex formation, and results in monotherapy fails to show anticancer activity in nude activation of the downstream apoptosis cascade (Figure 6) mice xenografts using EC109/CDDP cells [109]. Another [102]. FLIP have been shown to be involved in cisplatin- study demonstrated that in chronic lymphocytic leukemia resistance to bladder cancer cells [103]. Also, fibroblast (CLL), autophagy was induced by multiple stimuli and growth factor receptor 4 (FGFR4) has been indicated to be acted as a mechanism of resistance against flavopiridol, an an inducer of chemoresistance in colorectal cancer through endoplasmic reticulum (ER)-stress-mediating agent [110]. regulation of FLIP expression [104]. Thus, inhibition of Redox resetting has been shown to regulate FLIP may be a promising therapeutic strategy in numerous autophagy at multiple levels. To start with, high drug-resistant cancer scenarios [105]. Taken together, cellular ROS accumulation has been widely proven these studies described herein highlight that apoptosis to induce autophagy [111]. In response to ER stress is deregulated at multiple layers via redox-associated induced by tunicamycin, but not thapsigargin, NADPH mechanisms. oxidase 4 (Nox4)-mediated production of H O leads 2 2 to cytoprotective autophagy in HUVEC cells [112]. Treatment with either the antioxidant N-acetyl-L-cysteine Activation of autophagy (NAC) or catalase hinder the conversion of LC3-I to LC3-II which is a key step in autophagy induction, Autophagy plays paradoxical roles in acquired thereby decreasing the formation of LC3-II positive resistance to anticancer drugs. On one hand, cytotoxic autophagosomes, and reducing starvation-induced protein drug treatment triggers persistent autophagy, which will Figure 6: ROS-induced deregulation of apoptosis. S-nitrosylation of FLIP inhibits the interaction between procaspase-8 and FADD, leading to inactivation of caspase-8. S-glutathionylation and S-nitrosylation of caspase-3 inhibit cleavage to the active form. The high ROS level in drug-resistant cells may contribute to escape from apoptosis by S-nitrosylation of FLIP, as well as S-glutathionylation and S-nitrosylation of caspase-3. www.impactjournals.com/oncotarget 42750 Oncotarget degradation [113]. The activity of Atg4, which has been pancreatic carcinoma [129]. APE-1 can be activated by shown to be involved in the processing of LC3, has also nontoxic levels of ROS that promote translocation into the 2+ been proved to be sensitive to H O [113]. However, nucleus (Figure 4) [130]. ROS production following Ca 2 2 antioxidant activity is also essential for autophagy mobilization via purinergic receptors-induced extracellular induction. For example, overexpression of catalase ATP stimulation is responsible for the localization of APE- increases LC3-II levels in both HCT116 cells and H460 1 [131]. Furthermore APE-1 phosphorylation by PKC cells with low levels of endogenous catalase [114, 115]. after an oxidative challenge has been shown to increase Inhibition or knockdown of catalase attenuates LC3-II the activity of the APE-1 redox domain [132]. accumulation in HCT116, H1299 as well as WI38 cells In addition, the activities of other DNA-repair [114, 115]. Due to the paradoxical roles autophagy plays proteins such as Ku, ATM, and human replication protein in cancers, a better understanding of how redox regulation A (RPA) have been also reported to be altered by the distinguishes between the survival-supporting and death- redox resetting. In the nonhomologous end joining promoting roles of autophagy is necessary [116]. (NHEJ) double-strand DNA repair pathway, Ku DNA binding is lower in an oxidizing environment, although the mechanism is not clear [133]. Ku is a heterodimer that DNA damage repair encircles broken DNA ends during repair and can recruit the DNA-PK catalytic subunit (DNA-PKcs) [134]. The The anticancer activity of most chemotherapy duration of binding of Ku to the DNA is needed to improve drugs relies on the induction of DNA damage in rapidly recruitment of DNA-PKcs to the DNA-PK complex [135]. cycling tumor cells with inadequate DNA repair [117]. Ku is inactivated during oxidative stress in glucose-6- The cellular response to DNA damage is either repair or phosphate dehydrogenase (G6PD) null mutant Chinese cell death. Therefore, the DNA damage repair capacity of hamster ovary cells [136]. ATM is subsequently activated cancer cells has a significant influence on the efficacy of through oxidation at specific cysteine residues [61]. DNA-damaging drugs. Evidence also shows that ATM can promote an antioxidant The redox environment is capable of directly response via regulation of the pentose phosphate modulating DNA repair. One of the initial pieces of pathway—one of the primary sources of NADPH [137]. evidence is that both an increase in 8-oxoguanine (8-oxoG) An additional example of a DNA repair pathway protein and a reduction in DNA repair occurs in vitro following involved in oxidative stress is human RPA. RPA is a treatment with cadmium [118]. This is subsequently shown DNA-binding protein involved in replication, repair, and to be due to cysteine modification of 8-oxoguanine DNA recombination. In an oxidizing environment, the cysteines glycosylase 1 (OGG1) [119]. Furthermore, an interaction in the zinc-finger motif of the p70 subunit form disulfide between OGG1 and poly (ADP-ribose) polymerase 1 bonds that impair its DNA binding [138]. (PARP-1), a sensor of DNA damage involved in DNA It has been established that the detection of MMR repair, has recently been described [120]. This interaction is associated with resistance to many, but not all, DNA- is enhanced by oxidative stress and can stimulate damaging anticancer agents, such as monofunctional PARP-1 activity [120]. Oxidative stress also causes the alkylating agents, cisplatin, and the antimetabolite translocation of the Y-box binding protein (YB-1) to the 6-thioguanine [139]. Alkylating agents, including the nucleus, where it has a stable interaction with nei-like 2 chloroethylnitrosoureas (carmustine [BCNU], lomustine, protein (NEIL2) and increases NEIL2 activity in the base and fotemustine), temozolomide, and procarbazine, are excision repair (BER) pathway [121]. A further example of commonly used for the treatment of malignant brain redox regulation of DNA damage repair is the interaction tumors [140]. These agents add alkyl groups to DNA between oxidized XRCC1 (x-ray cross-complementing causing DNA damage and apoptosis [141]. Resistance group 1) and DNA polymerase b (Pol b) which is enhanced to alkylating agents through direct DNA repair by O6- due to the formation of a disulfide bond [122]. methylguanine methyltransferase (MGMT) remains a Apurinic-apyrimidinic endonuclease 1 (APE- significant barrier to successful treatments of patients with 1) is a versatile protein that has both DNA repair and malignant glioma [142, 143]. The relative expressions of transcriptional regulatory functions by facilitating MGMT in tumor cells may determine the response to transcription factors binding to DNA [123, 124]. alkylating agents [141]. Moreover, promoter methylation Overexpression of APE-1 has been found in can silence MGMT expression in gliomas [144]. Recent several cancers and are correlated with the tumor studies showed that oxidative damage induced the radiosensitivity [125]. For example, APE-1 contributes formation of a large complex containing the DNMTs to radioresistance [126] and alkylating agent resistance and polycomb repressive complex 4 (PRC4) members, [127] in human glioma cells, as well as also promotes which could lead to MGMT promoter methylation [145]. resistance to radiation combined with chemotherapy in Early clinical studies showed that glioma patients with medulloblastoma, primitive neuroectodermal tumors methylated MGMT promoters had a survival benefit and pediatric ependymomas [128]. Knockdown of APE- treated with radiotherapy [146]. 1 dramatically sensitizes cancer cells to radiotherapy in www.impactjournals.com/oncotarget 42751 Oncotarget also reported to be effective for relapsed or refractory TARGETING REDOX ALTERATIONS IN multiple myeloma in a clinical study [159]. CANCER THERAPY CONCLUSIONS In general, cancer cells exhibit higher levels of ROS than normal cells that facilitate tumorigenesis and tumor Due to significant advances in the research arena progression. Therefore, the treatment of antioxidants can in the last few decades, cancer drug resistance is now suppress cancer initiation or progression. A number of realized to be more complicated than originally conceived. studies suggest that antioxidants could diminish cancer The emergence of drug resistance is the result of dynamic initiation by suppressing DNA damage and genomic battles between cancer cells and chemotherapeutic instability. For example, ATM-deficiency-accelerated agents. Although new anticancer drugs will continue to transgenic murine lymphomagenesis is suppressible be developed, it is anticipated that novel drug-resistance by NAC [147]. Another study has also claimed that mechanisms will follow. Therefore, deciphering the NAC slowed tumor progression in a p53-dependent intrinsic mechanisms of drug resistance induction may be mouse lymphomagenesis model, seemingly by reducing an effective strategy to solve this significant problem in genomic instability [148]. Furthermore, a recent study has cancer therapy. also observed that NAC and vitamin C have significant Redox resetting, which usually occurs in anticancer antitumorigenic effects in vivo. But in stark contrast to drug treatment, is a protective response from tumor cells earlier studies, they found that the effect of NAC and that can buffer drug-induced stresses and damage by vitamin C highly relied on hypoxia-inducible factor 1 rebuilding redox homeostasis and activating multiple (HIF-1) rather than on reduction of genomic instability redox signaling pathways, thereby leading to drug in a MYC-dependent lymphoma model [149]. However, resistance. The versatility of redox signaling is such that it other studies showed that supplementation with vitamin can affect almost every cell and involve multiple signaling E significantly increased the risk of prostate cancer processes. Thus it is anticipated that redox signaling will [150] and taking b-carotene, vitamin A or E supplements continue to be an important stimulator in the development increased the incidence of lung cancer [151]. A recent of drug resistance with new therapeutic agents. Therefore, study showing that NAC promotes melanoma progression it is essential to reveal and understand the molecular supports these findings [152]. Likewise, a study showed mechanisms underlying redox resetting-induced drug that NAC increased melanoma metastasis in vivo through resistance. the small guanosine triphosphatase (GTPase) RHOA Despite the universality of redox resetting in activation [153]. chemotherapeutic treatments, different agents for distinct Based on the intrinsic oxidative stress of cancer cancer types, patients with individual variations, and cells, further ROS inductions have been shown to be genetic heterogeneity in tumors may lead to inequable efficient in preferentially killing malignant cells, with situations. Therefore, only when we have screened and some showing promise in clinical studies. However, identified enough usable drug-resistant biomarkers related upregulated antioxidant capacity has been found in some to redox resetting, will it be feasible to overcome drug cancer cells, especially those in advanced stages. This resistance by monitoring and regulating the process of redox adaptation enables the cancer cells to survive under redox resetting. The use of modern genomic, proteomic increased oxidative stress, and provides a mechanism and other omics techniques has dramatically promoted of drug resistance. For example, elevated levels and the ability to identify novel genes and signaling networks activity of catalase are found in multidrug resistant HL-60 involved in tumor responsiveness to drug treatment. leukaemia cells [154]. Upregulation of HMOX1, SOD1 Moreover, high-throughput techniques combined with and GSH are found to be associated with arsenic trioxide bioinformatics approaches has allowed the identification resistance [155]. Also, several studies suggest that the of genotypes and molecular signatures also aided the resistance to doxorubicin, paclitaxel or platinum-based interrogation of clinical samples, facilitating the prediction drugs, which induce intracellular ROS production, is of drug responses to certain drugs. These will provide correlated with increased antioxidant capacity [156, 157]. abundant data that can be used to identify potential For those cancer cells that have adapted to higher predictive biomarkers for patient stratification. level of oxidative stress by increasing their antioxidant capacity, simply ROS-generating agents treatment might not be effective. It is possible to combine ROS-generating Abbreviations drugs with compounds that restrain the cellular antioxidant capacity. For example, a combination of arsenic trioxide ROS : Reactive oxygen species and 2-Me, a SOD inhibitor, shows significantly enhanced ABC : the ATP-binding cassette cytotoxic activity in primary chronic lymphocytic MDR : multidrug resistance leukaemia (CLL) cells [158]. A combination of arsenic MRP : MDR-associated protein trioxide and ascorbic acid, mediating GSH depletion, are www.impactjournals.com/oncotarget 42752 Oncotarget BCRP : breast cancer resistance protein approach? Nature reviews Drug discovery. 2009; 8:579- NRF2: Nuclear factor-erythroid 2 related factor 2 591. ARE : antioxidant response element 8. Traverso N, Ricciarelli R, Nitti M, Marengo B, Furfaro FOXO : Forkhead box O AL, Pronzato MA, Marinari UM and Domenicotti C. Role ATM: Ataxia telangiectasia mutated of glutathione in cancer progression and chemoresistance. DNMTs : DNA methyltransferases Oxidative medicine and cellular longevity. 2013; 5-FU: 5 fluorouracil 2013:972913. 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Cancer drug resistance: redox resetting renders a way

Oncotarget , Volume 7 (27) – Apr 5, 2016

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Abstract

www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 27 Review 1,2,* 2,* 1,* 1 3 2 Yuan Liu , Qifu Li , Li Zhou , Na Xie , Edouard C. Nice , Haiyuan Zhang , 1 4 Canhua Huang and Yunlong Lei State Key Laboratory for Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, P. R. China Department of Neurology, The Affiliated Hospital of Hainan Medical College, Haikou, Hainan, P. R. China Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia Department of Biochemistry and Molecular Biology, and Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, P. R. China These authors have contributed equally to this work Correspondence to: Yunlong Lei, email: leiyunlong@126.com Correspondence to: Canhua Huang, email: hcanhua@hotmail.com Correspondence to: Haiyuan Zhang, email: hyzhang_88@163.com Keywords: drug resistance, cancer therapy, oxidative stress, redox modifications, drug efflux Received: October 28, 2015 Accepted: March 28, 2016 Published: April 05, 2016 ABSTRACT Disruption of redox homeostasis is a crucial factor in the development of drug resistance, which is a major problem facing current cancer treatment. Compared with normal cells, tumor cells generally exhibit higher levels of reactive oxygen species (ROS), which can promote tumor progression and development. Upon drug treatment, some tumor cells can undergo a process of ‘Redox Resetting’ to acquire a new redox balance with higher levels of ROS accumulation and stronger antioxidant systems. Evidence has accumulated showing that the ‘Redox Resetting’ enables cancer cells to become resistant to anticancer drugs by multiple mechanisms, including increased rates of drug efflux, altered drug metabolism and drug targets, activated prosurvival pathways and inefficient induction of cell death. In this article, we provide insight into the role of ‘Redox Resetting’ on the emergence of drug resistance that may contribute to pharmacological modulation of resistance. hydrogen peroxide (H O ), the hydroxyl radical (•OH), INTRODUCTION 2 2 - 1 superoxide(O ) and singlet oxygen ( O ) [4]. Under 2 2 physiological conditions, cells are capable of maintaining Development of drug resistance is an important a balance between cellular oxidants and antioxidants, factor in the failure of anticancer therapeutic treatments called redox homeostasis. Submicromolar levels of ROS [1]. Such resistance results from a variety of factors act as second messengers to regulate cell proliferation, including individual variations in patients and somatic cell death, and other cellular processes [5]. Excessive cell genetic differences in tumors. The ability to evade levels of ROS induce oxidative stress that leads to medicinal drugs is intrinsic to cancer cells. Reasons for various pathological states, including aging, neurological acquisition of anticancer drug resistance include enhanced disorders, and cancer [6]. In general, most tumors exhibit expression of transporters that increases anticancer drugs higher levels of ROS than normal tissues, thus promoting efflux, alterations in drug metabolism, mutations of drug tumor progression and development [5]. Moreover, targets and the activation of survival or inactivation of oxidative stress controls the efficacy of cancer treatments downstream death signaling pathways (Figure 1) [1]. in multiple ways, including chemosensitivity, apoptosis, Studies on cancer drug resistance mechanisms have angiogenesis, metastasis and inflammatory responses [6]. yielded valuable information on how to circumvent However, when ROS concentrations become extremely resistance to improve cancer chemotherapy [1-3]. high, they lead to tumor cell death [7]. Thus, a variety Reactive oxygen species (ROS) are chemical of drugs with direct or indirect effects on ROS induction oxygen species with reactive properties, which comprise have been used for effective cancer therapies (Table 1). www.impactjournals.com/oncotarget 42740 Oncotarget Table 1: Roles of anticancer treatments in regulating ROS levels Name Mechanism of action Effects on ROS Cancer types Refs Photons or particles affect chemical bonds and produce Different types of Ionizing radiation highly ROS, which cause Increases ROS production [160] cancer damage to DNA and other cellular components Triggers ROS associated Different types of Methotrexate Increases ROS production [161] cell apoptosis cancer Triggers cell membrane Significant increases of Different types of Mitoxantrone [162] scrambling ROS formation cancer Promotes cancer cell Tamoxifen Promotes ROS generation Breast, colon cancer [163] senescence Generation of nuclear DNA Induces a mitochondrial- Different types of Cisplatin [164] adducts dependent ROS generation cancer Different types of Paclitaxel (Taxol) Inhibitor of cell division Increases ROS production [165] cancer Reduces cell viability through initiating cell Different types of Adriamycin Increases ROS production [166] apoptosis and strong G2/M cancer phase cell cycle arrest Protein tyrosine kinase Different types of Imatinib inhibitor that induce Increases ROS production [167] cancer apoptosis Quinolone alkaloid that Different types of Camptothecin Increases ROS production [168] induces cytotoxicity cancer Semisynthetic flavonoid that Flavopiridol inhibits cyclin-dependent Increases ROS production Leukemia [169] kinases 6-thioguanine UVA photosensitizer Increases ROS production Skin cancer [170] Isolated DNA could be Lymphoma, primary Procarbazine degraded by procarbazine in Increases ROS production [171] brain cancers the presence of oxygen Glutathione disulphide Alters intracellular GSSG/ Lung, breast and NOV-002 [172] mimetic GSH ratio ovarian cancer Reduces intracellular Inhibitor of cysteine/ Pancreatic and lung [173, Sulphasalazine transport of cysteine glutamate transporter xCT cancer 174] required for GSH synthesis Leukemia, pancreatic [175, L-asparaginase Depletes glutamine Reduces GSH cancer 176] Glutamate-cysteine ligase Inhibits de novo GSH Ovarian and breast [177, Buthionine sulphoximine (BSO) complex inhibitor synthesis cancer, melanoma 178] Induction of ROS owing to Different types of Carboplatin Induction of cell cycle arrest [179] ER stress cancer Selective epidermal growth Activates FOXO3a and in Different types of Gefitinib factor receptor tyrosine [180] turn reduces ROS cancer kinase inhibitor Different types of Irinotecan Topoisomerases inhibitor Causes oxidative stress [181] cancer Neuroblastoma, Etoposide Selective Topo II α inhibitor Increases ROS production [182] breast cancer Glycosylation inhibitor that Triggers ER stress Tunicamycin causes protein accumulation Leukemia [183] production in the ER Sarco(endo)plasmic 2+ reticulum Ca ATPase Triggers ER stress Thapsigargin inhibitor that releases ER Leukemia [183] production 2+ 2+ Ca and stimulates Ca influx www.impactjournals.com/oncotarget 42741 Oncotarget Alkylating agent that causes Chloroethylnitrosoureas Increases ROS production Melanoma tumors [184] DNA damage Temozolomide Alkylating agent Increases ROS production Brain cancer [185] Inhibits cyclooxygenase Colorectal cancer, 2 (COX2) activity but it Induction of ROS owing to myeloma, Burkitt’s Celecoxib also induces ER stress by [186] ER stress lymphoma and causing leakage of calcium prostate cancer from the ER into the cytosol HPV-transformed Originally developed as cervical carcinoma, HIV protease inhibitor but it Induction of ROS owing to head and neck Nelfinavir [187] also induces ER stress by an ER stress cancer, pancreatic unknown mechanism cancer, melanoma and glioma Mantle cell Induces ROS owing to ER [188, Bortezomib Proteasome inhibitor lymphoma, multiple stress 189] myeloma Induce the generation of oxygen-derived free Insert into the DNA of radicals through two main replicating cells and inhibit pathways: anon-enzymatic Anthracyclines (doxorubicin, Different types of topoisomerase II, which pathway that utilizes [190] daunorubicin or epirubicin) cancer prevents DNA and RNA iron, and anenzymatic synthesis. mechanism that involves the mitochondrial respiratory chain Decrease protein homeostasis during oxidative stress by Breast cancer, non- 17-allylaminogeldanamycin HSP90 inhibitor disrupting HSP90–client small-cell lung [191] (17-AAG) protein complexes and cancer promoting the degradation of the client proteins Prodrug that is Colorectal, breast, enzymatically converted to Capecitabine Decreases ROS production gastric, and [192] 5-fluorouracil (5-FU) in the oesophageal cancer body Inhibits thymidylate Colon cancer, rectum synthetase and/or Induces intracellular 5-fluorouracil (5-FU) cancer, and head and [88] incorporates into RNA and increase inO2·- levels neck cancer DNA Inhibits mitochondrial Reacts with cysteine respiratory function, Arsenic trioxide (As2O3) Leukemia, myeloma [193] residues on crucial proteins thereby increasing free radical generation Induces free radicals Prostate cancer, 2-methoxyestradiol(2-ME) Metabolite of estradiol-17β and loss of mitochondrial [194] leukemia membrane potential Induces apoptosis through Prostate cancer, N-(4 hydroxyphenyl)retinamide Synthetic retinoid derivative the production of ROS and breast cancer, [195] (4-HPR) mitochondrial disruption neuroblastoma Reduce the capacity to Inhibit the action of the PARP inhibitors repair ROS-induced DNA Breast cancer [196] enzyme PARP damage Down regulates Alters the mitochondrial V12 RAS -expressing [197, Erastin mitochondrial VDACs and membrane permeability and tumor cells 198] cysteine redox shuttle blocks GSH regeneration www.impactjournals.com/oncotarget 42742 Oncotarget Nonetheless, some tumor cells can overcome drug-induced significant threat to clinical tumor therapy. Several cell oxidative stress by enhancing their antioxidant systems, membrane transporter proteins have been implicated in with the outcome that a new redox balance with a more drug resistance to commonly used chemotherapeutics by higher ROS level is established, the process of ‘Redox promoting drug efflux [1]. Among them, the ATP-binding Resetting’ (Figure 2). Such drug-induced redox resetting cassette (ABC) transporter family is the most notable. has recently been shown to result in drug resistance. For There are 49 members of the ABC transporter family, example, increased levels of reduced glutathione lead to but only multi-drug resistance protein 1 (MDR1), MDR- elevated chemotherapeutic drug resistance in numerous associated protein 1 (MRP1) and breast cancer resistance cancers [8, 9]. protein (BCRP) have been studied extensively in relation Redox resetting has been implicated in drug to multidrug resistance (MDR) [10]. All three transporters resistance at multiple levels, including elevated drug have broad substrate specificity and promote the efflux efflux, altered drug metabolism and mutated drug targets of various hydrophobic cancer chemotherapeutics such [10, 11]. In addition, ROS-induced activation of survival as topoisomerase inhibitors, taxanes, and antimetabolites signaling pathways and inactivation of downstream death [14]. Here, we summarize the effects of redox reactions signaling pathways can lead to drug resistance (Figure 1) and redox signals on these three drug efflux transporters. [1, 12, 13]. Here, we focus on the effects of redox resetting on drug resistance mechanisms and on current research Redox reactions promote conformational changes efforts to reveal the detailed mechanisms of resistance to of the transporters cancer therapies. All ABC transporters contain four domains - INCREASED RATES OF DRUG EFFLUX two nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs) (Figure 3) [15]. These Drug export from cells is a primary cause of four domains can be fused into multi-domain polypeptides the cellular resistance to anticancer drugs and poses a Figure 1: General mechanisms of cancer drug resistance. The anticancer activity of a drug can be limited by reduced drug influx or increased drug efflux, changes in expression levels of drug tar get, mutation of drug target, and a lack of cell death induction. www.impactjournals.com/oncotarget 42743 Oncotarget in a variety of ways. The driving force for drug during drug transport (Figure 3B) [21]. Mutations at transport is achieved by a switch between two principal certain cysteine residues within MSD drastically reduce conformations of the NBD dimer [16]. The conformations drug-transport activities [22, 23]. A previous study has of ABC transporters are maintained by multiple chemical identified that MSD is necessary for the dimerization interactions, including covalent bonds—the intra- and of MRP1, which can be disrupted by treatment with inter-molecular disulfide bond formed between reactive dithiothreitol (DTT), a reducing agent [24, 25]. These cysteine residues [17]. The cellular redox status has a data suggest that dimerization is formed through disulfide great impact on reversible disulfide bond formation and is linkage between cysteine residues. Yang et al [23] essential for proper protein folding as well as transporter investigated the roles of Cys7 and Cys32, which are functions. located in the MSD domain, in MRP1 dimerization The drug transport activity of human MDR1 is (Figure 3B). Mutations at Cys7 caused conformational correlated with the redox states of its two cysteine residues changes and prevented dimerization in MRP1 [26]. In (Cys431 and Cys1074). The ATP hydrolysis activity addition to dimerization, cancer cells activate antioxidant is strongly inhibited by the covalent reaction of either systems after treatment of ROS-inducing anticancer drugs, of these two cysteine residues with N-ethylmaleimide including enhanced expression of glutathione (GSH), (NEM), a sulfhydryl blocker [18]. These two cysteine which can form glutathione S-conjugated molecules to residues are present in NBD1 and NBD2 (Figure 3A), and facilitate drug efflux by MRP1 [27]. are located very close to the bound nucleotide. The ready In contrast to the molecular structures of MDR1 formation of the intramolecular disulfide between Cys431 and MRP1, BCRP comprises six transmembrane domains and Cys1074 shows that the two nucleotide-binding and only one ATP-binding cassette, and is known as sites of MDR1 are structurally very close and capable a ‘half-transporter’ [28]. Human BCRP exists in the of intimate functional interactions, consistent with our plasma membrane as a homodimer due to disulfide- current understanding of the catalytic mechanism [19]. bonded cysteine residues (Figure 3C) [29]. Treatment MRP1 has a topological configuration similar to with 2-mercaptoethanol (2-ME) reduces the BCRP from MDR1, whereas MRP1 has an additional membrane- homodimer to monomer [30]. Three of the cysteine spanning domain located at the N-terminus, called MSD residues, Cys592, Cys 603, and Cys608 in BCRP are [20]. The MSD functions as a plug that controls gating located on the extracellular face between TMD5 and Figure 2: Comparisons of ROS level between different stages of tumor progression and tumor drug-resistance. While in normal cells ROS generation and antioxidants are in balance, increased ROS levels are hallmarks of cancer cells. Marked increase in ROS can be achieved by chemotherapeutic agents, resulting in irreparable cellular damages and cancer cell death. However, some cancer cells can develop drug resistance by redox resetting. www.impactjournals.com/oncotarget 42744 Oncotarget Figure 3: Schematic diagrams showing the structures of MDR1, MRP1 and BCRP. All ABC transporters contain transmembrane and membrane-spanning domains. The disulfide bonds between the cysteine residues identified in the figure are required for maintenance of protein stability and transporter function. www.impactjournals.com/oncotarget 42745 Oncotarget TMD6 (Figure 3C) [31-33]. Cys592 and Cys608 are Redox determine transporter gene expression critical for protein stability by intramolecular disulfide bond formation. Mutations at these two cysteine Apart from the conformational changes of those residues result in protein misfolding and degradation, drug efflux pumps mentioned above, redox-induced thereby increasing drug sensitivity because of inefficient overexpression of efflux pumps provides alternative drug elimination [31-33]. Cys603 is implicated in ‘gates’ by which drugs can be exported from cells. intermolecular disulfide bond formation, resulting in Overexpressed transporters have been frequently observed dimerization of BCRP (Figure 3C). Mutation at Cys603 in many types of human malignancy, and correlated with prevents homodimerization [33]. However, functional reduced response to chemotherapeutic agents [35]. After analyses demonstrates that mutation at Cys603 do not treatment with anticancer drugs, redox signaling networks change the transport activity of the drugs SN-38 and are activated to regulate these transporters expression in mitoxantrone, even though monomeric BCRP represents multiple layers, including transcriptional, translational, only a half-molecule of a functional ABC transporter [32]. post-translational, and epigenetic levels. Recently, Cys284, Cys374, and Cys438 are also reported Transcriptional regulation to be involved in intramolecular disulfide bond formation and necessary for BCRP function [34]. Accumulating evidence shows that redox-sensing transcription factors take part in the transcriptional regulation of drug efflux transporters (Figure 4). Nuclear factor-erythroid 2 related factor 2 (NRF2), a redox-sensing Figure 4: Redox regulation of drug efflux transporters expression. (a) Oxidation of KEAP1 dissociates NRF2 from the complex, allowing the translocation and activation of NRF2; (b) Oxidative stress promotes the translocation of APE-1, facilitating transcription of numerous gene including MDRs, MRPs and BCRP; (c) FOXO can be activated by interacting with transportin through disulfide linkage under oxidative stress. The activation of these transcription factors contributes to the expression of drug efflux transporters. www.impactjournals.com/oncotarget 42746 Oncotarget transcription factor, can bind to antioxidant response patients [57]. Paradoxically, recent studies showed that element (ARE) and regulates a broad spectrum of genes FOXO3 expression levels were decreased in cisplatin- involved in redox balancing, glutathione synthesis, resistant cells [58], and FOXO3 knockdown increased and drug detoxification [36]. AREs are identified in the cell proliferation and enhanced resistance to cisplatin [59]. promoter region of efflux transporters, such as BCRP and Ataxia telangiectasia mutated (ATM) is a serine/ MRPs [36]. In general, NRF2 is anchored in the cytoplasm threonine protein kinase that participates in activation by Kelch-like ECH-associated protein 1 (KEAP1), of the DNA damage checkpoint, resulting in cell cycle which facilitates NRF2 ubiquitination and proteasomal arrest, DNA repair or apoptosis [60]. Recent studies degradation. Cys273 and Cys288 of KEAP1 are the have revealed a novel mechanism of ATM activation crucial target residues for oxidation. Redox modifications via direct oxidation [61, 62]. When ATM is activated dissociate KEAP1 from NRF2, allowing the translocation by double-strand breaks (DSBs), the protein undergoes of NRF2 to the nucleus, where it transactivates target monomerization that requires free DNA ends and the gene expression (Figure 4) [37]. Recent studies showed Mre11-Rad50-Nbs1 (MRN) complex. By contrast, when that higher levels of NRF2 could promote tumorigenesis ATM is activated by direct oxidation, oxidized ATM and contribute to chemoresistance, suggesting a “dark forms an active dimer covalently linked by intermolecular side” of the NRF2 pathway [38-43]. For example, disulfide bonds [61]. Residue Cys2991 is crucial for ATM the expression of NRF2 is increased during acquired activation by oxidation. A C2991L mutant cannot be resistance to tamoxifen and doxorubicin in breast and activated by H O but can be normally activated by the 2 2 ovarian cancer cells [44, 45]. Nuclear accumulation of MRN complex and DNA [61]. A recent study showed NRF2 can lead to enhanced expression of ARE-containing that both camptothecin and cisplatin treatment not only genes including drug efflux transporters, which facilitate induced ATM activation, but also upregulated MDR- the development of drug resistance [46]. In addition, related genes BCRP and MRP2 expression in NCI-H446 overexpression of NRF2 causes enhanced resistance to cells. Moreover, cisplatin and camptothecin-induced chemotherapeutic agents, including cisplatin, doxorubicin BCRP and MRP2 upregulation can be suppressed by ATM and etoposide [40]. Higher expressions of NRF2 and inhibitors, indicating the role of ATM activation on MDR its target genes are associated with taxol resistance and formation in lung cancer chemotherapy [63]. anchorage-independent growth in MCF-7 and MDA- Post-translational regulation MB-231 mammospheres compared to adherent cells MDR1 is a phosphorylation substrate for a number [47]. Moreover, transport activities of several MRPs are of protein kinases, including protein kinase C (PKC) activated by γ-glutamylcysteine synthetase (γ-GCS, the and protein kinase A (PKA) [64]. PKA is shown to be rate-limiting enzyme for GSH de novo biosynthesis), activated by redox modifications through the formation of which can be induced by NRF2 [48]. intramolecular disulfide bonds which cause a subcellular Forkhead box O (FOXO) proteins, a family translocation, resulting in phosphorylation of established of transcription factors, are deregulated in several protein substrates [65]. PKC catalytic properties can be cancers including prostate, breast, glioblastoma, altered by redox mechanisms, which in turn influence rhabdomyosarcoma, and leukemia [49]. As inactivation the activity of MDR1 [66]. Activation of PKC has been of FOXOs has been determined to be a crucial step reported to increase the phosphorylation of MDR1 in carcinogenesis, increasing their activity could be a in multidrug-resistant cells [67] and decrease drug potential therapeutic strategy for cancer treatment [49, 50]. accumulation and sensitivity [68]. Conversely, treatment FOXOs are not only responsible for the initial therapeutic with PKC inhibitors has been shown to decrease the response to anticancer drugs, but also involved in the phosphorylation of MDR1, resulting in attenuated drug acquisition of drug resistance (Figure 4) [51, 52]. Under efflux activity and MDR1 drug binding [69]. continuous stress induced by anticancer drugs, FOXOs can elicit the expression of relevant genes for drug efflux and Epigenetic regulation antioxidant defense, such as MDR1, MRP2, Mn-SOD and The promoter region of MDR1 is highly GC- catalase [50, 53-55]. For instance, FOXO3 and FOXO1 rich and contains several CpG islands that are prone can induce MDR1 expression in adriamycin-resistant to be methylated for transcriptional silencing. Studies breast cancer cells and K562 leukemic cells [50, 54]. In have demonstrates that the methylation status of addition, the promoter region of the human MRP2 gene the MDR1 promoter is correlated with MDR1 gene contains four FOXO binding sites, and transcription of transcriptional activity [70-72]. The methylation is MRP2 gene is stimulated by overexpressed FOXO1 in catalyzed by DNA methyltransferases (DNMTs) and MCF-7 cells [53]. FOXO1 expression is significantly use of S-adenosylmethionine (SAM) as a methyl donor. upregulated in a paclitaxel resistant cells and further SAM is the first metabolite in the methionine cycle enhanced by exposure to paclitaxel [56]. Furthermore, catalyzed by S-adenosylmethionine synthetase (also FOXO1 overexpression has been frequently observed known as methionine adenosyltransferase, MAT). The in cancer tissue samples obtained from chemoresistant activities of MATs are profoundly correlated with redox www.impactjournals.com/oncotarget 42747 Oncotarget conditions, through the maintenance of a homotetrameric ALTERED DRUG METABOLISM conformation [73]. The methionine cycle is the primary source of cysteine, a precursor of GSH in the Besides increased rates of drug efflux, altered drug transsulfuration pathway. Intracellular GSH levels are metabolism is another important resistance mechanism, essential in the maintenance of methylated DNA. GSH including drug inactivation or deficient drug activation. depletion by hepatotoxin bromobenzene results in a The redox resetting induced by anticancer drugs may reduction of intracellular methionine pools and genome- hinder the therapeutic effects by such mechanisms. wide DNA hypomethylation [74]. Antioxidant systems can directly inhibit the antitumor activity of some anticancer agents, such as paclitaxel [75], bortezomib [76] and radiation therapy [77]. For example, buthionine sulphoximine (BSO) significantly increases paclitaxel cytotoxicity through ROS accumulation [75]. Figure 5: 5-FU resistance in cancer cells by TYMS oxidation. The fluoropyrimidines (5-FU) are broken down into three metabolites, fluorodeoxyuridine monophosphate (FdUMP), fluoro-deoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate (FUTP). The principal mechanism of action of 5-FU is the inhibition of thymidylate synthase (TYMS), but alternative pharmacodynamic pathways acting through incorporation of drug metabolites into DNA and RNA. TYMS can also be activated through direct oxidation that leads to 5-FU resistance. www.impactjournals.com/oncotarget 42748 Oncotarget Also, platinum drugs, which generate extremely high ROS cytotoxic chemotherapy drugs in a range of tumor cells. levels, can be inactivated by GSH [78]. Hypermethylation of the DNA promoter regions of the Alternatively, the cellular redox state is correlated drug targets results in cell resistance to anticancer drugs, with enzymic expression required for the conversion such as cisplatin and carboplatin [91, 92]. In addition, of antimetabolites, such as 5 fluorouracil (5-FU) and methylation of genes involved in apoptosis, including methotrexate, to their most active forms [79, 80]. the DNA mismatch repair (MMR) gene human mutL Capecitabine is a fluoropyrimidine prodrug that is homolog 1 (hMLH1), can occur in drug-resistant tumor converted into 5-FU by thymidinephosphorylase [81]. The models. This has led to the concept that the use of a DNA gene encoding thymidinephosphorylase can be inactivated demethylating agent such as 2′-deoxy-5-azacytidine by DNA methylation, thereby causing capecitabine in combination with anticancer drugs may reverse this resistance [82]. These epigenetic alterations have been resistance mechanism [93]. shown to be induced by H O , where DNMT1 binds more 2 2 tightly to chromatin after H O treatment and then alters INEFFECTIVE INDUCTION OF CELL 2 2 the methylation status of CpG regions [83]. As observed DEATH in the case of the topoisomerase inhibitor irinotecan, the inactivation by UDP glucuronosyl transferase 1 Following the action of an activated drug on its (UGT1A1) is induced by the redox-sensing NRF2-KEAP1 cellular target, the therapeutic outcome is then determined pathway [84]. Epigenetic silencing can also promote drug by the next key process; the response of cancer cells to activity, and the expression of UGT1A1 is reduced by drug treatment. Generally, oxidative stress causes by DNA methylation of the promoter. Therefore, in this case, anticancer drugs in turn leads to some cellular damage promoter methylation promotes irinotecan activity [85, (e.g., DNA damage) that is tightly coupled to the induction 86]. of cell death. Nevertheless, some intrinsic redox adaptive responses can be triggered to enable the cancer cells to ALTERATIONS IN THE DRUG TARGETS survive through inhibition of cell death and activation of cellular survival pathways, thus providing a mechanism of Drug response and resistance are also determined resistance to treatment with anticancer agents [7]. by alterations in the drug target, such as mutations or changes in expression level. The deregulated or prolonged Deregulation of apoptosis production of cellular oxidants has been linked to mutations (induced by oxidant-mediated DNA damage), as It is well known that resistance to apoptosis is a well as modification of gene expression [87]. Thus, target hallmark of cancer [94]. Thus, deregulation of apoptosis alteration is more likely to happen with anticancer drugs will protect cancer cells from cell death caused by drug- that induce high ROS levels. induced cellular damage. Cleavage of caspase-3 is known The fluoropyrimidine 5-FU is widely used to play a central role in apoptosis. Substantial evidence in the treatment of a variety of cancers, including reveals that the activity of caspase-3 is inhibited via colorectal, breast, and aerodigestive tract cancer redox modifications [95]. Caspase-3 has been found to [88]. It is converted intracellularly to three active be constitutively S-glutathionylated in human umbilical metabolites: fluorodeoxyuridinemonophosphate vein endothelial cells (HUVECs) [96]. Upon tumor (FdUMP), fluorodeoxyuridinetriphosphate (FdUTP) and necrosis factor α (TNFα) stimulation, de-glutathionylation fluorouridine triphosphate(FUTP) (Figure 5).These active of caspase-3 occurs mediated by glutaredoxin (Grx). metabolites disrupt RNA synthesis and the function of Knockdown of Grx notably inhibit TNFα-induced thymidylate synthase (TYMS). TYMS plays a crucial cell death owing to attenuated caspase-3 cleavage, role in catalyzing deoxyuridylate (dUMP) to thymidylate concomitant with enhanced caspase-3 S-glutathionylation (dTMP), which provides the sole intracellular de novo [96]. Mutations of key S-glutathionylation sites of source of dTMP [89]. Human TYMS protein can caspase-3 (C163S, C184S, and C220S) enhance cleavage specifically bind to its own TYMS mRNA and functions compared with wild-type caspase-3 [97]. Furthermore, as a translational repressor. The RNA binding activity is S-glutathionylated caspase-3 inhibits its cleavage by determined by its redox state. In the presence of reducing caspase-8 in vitro (Figure 6) [97]. In addition, caspase-3 agents, the RNA binding activity of TYMS protein is can also be S-nitrosylated at Cys163 [98]. Upon the first significantly enhanced. In contrast, treatment of TYMS apoptosis signal (Fas) ligation, de-nitrosylated caspase-3 protein with the oxidizing agent diamide inhibits RNA leads to caspase-3 activation (Figure 6) [99]. Collectively, binding [90]. These results demonstrate that the oxidation the higher ROS levels in drug-resistant cells may of TYMS, resulting in loss of translational repressor contribute to their escape from apoptosis by caspase-3 function, could lead to 5-FU resistance in cancer cells. S-glutathionylation and S-nitrosylation. Drug target changes through epigenetic events Upon Fas ligand (FasL) binding, Fas interacts have also been shown to be involved in resistance to www.impactjournals.com/oncotarget 42749 Oncotarget with Fas-associated protein with death domain (FADD) produce excessive cellular damage and even lead to cell and procaspase 8 or 10, to form an active death death, thus attenuating the drug resistance activity of inducing signaling complex (DISC) [100]. The FADD cancer cells [106]. On the other hand, autophagy has a and procaspase-8 interaction can be inhibited by Flice role in maintaining cancer cell survival during conditions inhibitory protein (FLIP) through competitive binding of stress and might mediate resistance to anticancer to FADD [100, 101]. Intriguingly, the activity of FLIP therapies [107, 108]. For example, co-administration is shown to be enhanced by S-nitrosylation [102]. Loss of cisplatin and an autophagy inhibitor chloroquine of S-nitrosylation increases FLIP degradation, which in significantly suppress tumor survival whereas cisplatin turn facilitates DISC complex formation, and results in monotherapy fails to show anticancer activity in nude activation of the downstream apoptosis cascade (Figure 6) mice xenografts using EC109/CDDP cells [109]. Another [102]. FLIP have been shown to be involved in cisplatin- study demonstrated that in chronic lymphocytic leukemia resistance to bladder cancer cells [103]. Also, fibroblast (CLL), autophagy was induced by multiple stimuli and growth factor receptor 4 (FGFR4) has been indicated to be acted as a mechanism of resistance against flavopiridol, an an inducer of chemoresistance in colorectal cancer through endoplasmic reticulum (ER)-stress-mediating agent [110]. regulation of FLIP expression [104]. Thus, inhibition of Redox resetting has been shown to regulate FLIP may be a promising therapeutic strategy in numerous autophagy at multiple levels. To start with, high drug-resistant cancer scenarios [105]. Taken together, cellular ROS accumulation has been widely proven these studies described herein highlight that apoptosis to induce autophagy [111]. In response to ER stress is deregulated at multiple layers via redox-associated induced by tunicamycin, but not thapsigargin, NADPH mechanisms. oxidase 4 (Nox4)-mediated production of H O leads 2 2 to cytoprotective autophagy in HUVEC cells [112]. Treatment with either the antioxidant N-acetyl-L-cysteine Activation of autophagy (NAC) or catalase hinder the conversion of LC3-I to LC3-II which is a key step in autophagy induction, Autophagy plays paradoxical roles in acquired thereby decreasing the formation of LC3-II positive resistance to anticancer drugs. On one hand, cytotoxic autophagosomes, and reducing starvation-induced protein drug treatment triggers persistent autophagy, which will Figure 6: ROS-induced deregulation of apoptosis. S-nitrosylation of FLIP inhibits the interaction between procaspase-8 and FADD, leading to inactivation of caspase-8. S-glutathionylation and S-nitrosylation of caspase-3 inhibit cleavage to the active form. The high ROS level in drug-resistant cells may contribute to escape from apoptosis by S-nitrosylation of FLIP, as well as S-glutathionylation and S-nitrosylation of caspase-3. www.impactjournals.com/oncotarget 42750 Oncotarget degradation [113]. The activity of Atg4, which has been pancreatic carcinoma [129]. APE-1 can be activated by shown to be involved in the processing of LC3, has also nontoxic levels of ROS that promote translocation into the 2+ been proved to be sensitive to H O [113]. However, nucleus (Figure 4) [130]. ROS production following Ca 2 2 antioxidant activity is also essential for autophagy mobilization via purinergic receptors-induced extracellular induction. For example, overexpression of catalase ATP stimulation is responsible for the localization of APE- increases LC3-II levels in both HCT116 cells and H460 1 [131]. Furthermore APE-1 phosphorylation by PKC cells with low levels of endogenous catalase [114, 115]. after an oxidative challenge has been shown to increase Inhibition or knockdown of catalase attenuates LC3-II the activity of the APE-1 redox domain [132]. accumulation in HCT116, H1299 as well as WI38 cells In addition, the activities of other DNA-repair [114, 115]. Due to the paradoxical roles autophagy plays proteins such as Ku, ATM, and human replication protein in cancers, a better understanding of how redox regulation A (RPA) have been also reported to be altered by the distinguishes between the survival-supporting and death- redox resetting. In the nonhomologous end joining promoting roles of autophagy is necessary [116]. (NHEJ) double-strand DNA repair pathway, Ku DNA binding is lower in an oxidizing environment, although the mechanism is not clear [133]. Ku is a heterodimer that DNA damage repair encircles broken DNA ends during repair and can recruit the DNA-PK catalytic subunit (DNA-PKcs) [134]. The The anticancer activity of most chemotherapy duration of binding of Ku to the DNA is needed to improve drugs relies on the induction of DNA damage in rapidly recruitment of DNA-PKcs to the DNA-PK complex [135]. cycling tumor cells with inadequate DNA repair [117]. Ku is inactivated during oxidative stress in glucose-6- The cellular response to DNA damage is either repair or phosphate dehydrogenase (G6PD) null mutant Chinese cell death. Therefore, the DNA damage repair capacity of hamster ovary cells [136]. ATM is subsequently activated cancer cells has a significant influence on the efficacy of through oxidation at specific cysteine residues [61]. DNA-damaging drugs. Evidence also shows that ATM can promote an antioxidant The redox environment is capable of directly response via regulation of the pentose phosphate modulating DNA repair. One of the initial pieces of pathway—one of the primary sources of NADPH [137]. evidence is that both an increase in 8-oxoguanine (8-oxoG) An additional example of a DNA repair pathway protein and a reduction in DNA repair occurs in vitro following involved in oxidative stress is human RPA. RPA is a treatment with cadmium [118]. This is subsequently shown DNA-binding protein involved in replication, repair, and to be due to cysteine modification of 8-oxoguanine DNA recombination. In an oxidizing environment, the cysteines glycosylase 1 (OGG1) [119]. Furthermore, an interaction in the zinc-finger motif of the p70 subunit form disulfide between OGG1 and poly (ADP-ribose) polymerase 1 bonds that impair its DNA binding [138]. (PARP-1), a sensor of DNA damage involved in DNA It has been established that the detection of MMR repair, has recently been described [120]. This interaction is associated with resistance to many, but not all, DNA- is enhanced by oxidative stress and can stimulate damaging anticancer agents, such as monofunctional PARP-1 activity [120]. Oxidative stress also causes the alkylating agents, cisplatin, and the antimetabolite translocation of the Y-box binding protein (YB-1) to the 6-thioguanine [139]. Alkylating agents, including the nucleus, where it has a stable interaction with nei-like 2 chloroethylnitrosoureas (carmustine [BCNU], lomustine, protein (NEIL2) and increases NEIL2 activity in the base and fotemustine), temozolomide, and procarbazine, are excision repair (BER) pathway [121]. A further example of commonly used for the treatment of malignant brain redox regulation of DNA damage repair is the interaction tumors [140]. These agents add alkyl groups to DNA between oxidized XRCC1 (x-ray cross-complementing causing DNA damage and apoptosis [141]. Resistance group 1) and DNA polymerase b (Pol b) which is enhanced to alkylating agents through direct DNA repair by O6- due to the formation of a disulfide bond [122]. methylguanine methyltransferase (MGMT) remains a Apurinic-apyrimidinic endonuclease 1 (APE- significant barrier to successful treatments of patients with 1) is a versatile protein that has both DNA repair and malignant glioma [142, 143]. The relative expressions of transcriptional regulatory functions by facilitating MGMT in tumor cells may determine the response to transcription factors binding to DNA [123, 124]. alkylating agents [141]. Moreover, promoter methylation Overexpression of APE-1 has been found in can silence MGMT expression in gliomas [144]. Recent several cancers and are correlated with the tumor studies showed that oxidative damage induced the radiosensitivity [125]. For example, APE-1 contributes formation of a large complex containing the DNMTs to radioresistance [126] and alkylating agent resistance and polycomb repressive complex 4 (PRC4) members, [127] in human glioma cells, as well as also promotes which could lead to MGMT promoter methylation [145]. resistance to radiation combined with chemotherapy in Early clinical studies showed that glioma patients with medulloblastoma, primitive neuroectodermal tumors methylated MGMT promoters had a survival benefit and pediatric ependymomas [128]. Knockdown of APE- treated with radiotherapy [146]. 1 dramatically sensitizes cancer cells to radiotherapy in www.impactjournals.com/oncotarget 42751 Oncotarget also reported to be effective for relapsed or refractory TARGETING REDOX ALTERATIONS IN multiple myeloma in a clinical study [159]. CANCER THERAPY CONCLUSIONS In general, cancer cells exhibit higher levels of ROS than normal cells that facilitate tumorigenesis and tumor Due to significant advances in the research arena progression. Therefore, the treatment of antioxidants can in the last few decades, cancer drug resistance is now suppress cancer initiation or progression. A number of realized to be more complicated than originally conceived. studies suggest that antioxidants could diminish cancer The emergence of drug resistance is the result of dynamic initiation by suppressing DNA damage and genomic battles between cancer cells and chemotherapeutic instability. For example, ATM-deficiency-accelerated agents. Although new anticancer drugs will continue to transgenic murine lymphomagenesis is suppressible be developed, it is anticipated that novel drug-resistance by NAC [147]. Another study has also claimed that mechanisms will follow. Therefore, deciphering the NAC slowed tumor progression in a p53-dependent intrinsic mechanisms of drug resistance induction may be mouse lymphomagenesis model, seemingly by reducing an effective strategy to solve this significant problem in genomic instability [148]. Furthermore, a recent study has cancer therapy. also observed that NAC and vitamin C have significant Redox resetting, which usually occurs in anticancer antitumorigenic effects in vivo. But in stark contrast to drug treatment, is a protective response from tumor cells earlier studies, they found that the effect of NAC and that can buffer drug-induced stresses and damage by vitamin C highly relied on hypoxia-inducible factor 1 rebuilding redox homeostasis and activating multiple (HIF-1) rather than on reduction of genomic instability redox signaling pathways, thereby leading to drug in a MYC-dependent lymphoma model [149]. However, resistance. The versatility of redox signaling is such that it other studies showed that supplementation with vitamin can affect almost every cell and involve multiple signaling E significantly increased the risk of prostate cancer processes. Thus it is anticipated that redox signaling will [150] and taking b-carotene, vitamin A or E supplements continue to be an important stimulator in the development increased the incidence of lung cancer [151]. A recent of drug resistance with new therapeutic agents. Therefore, study showing that NAC promotes melanoma progression it is essential to reveal and understand the molecular supports these findings [152]. Likewise, a study showed mechanisms underlying redox resetting-induced drug that NAC increased melanoma metastasis in vivo through resistance. the small guanosine triphosphatase (GTPase) RHOA Despite the universality of redox resetting in activation [153]. chemotherapeutic treatments, different agents for distinct Based on the intrinsic oxidative stress of cancer cancer types, patients with individual variations, and cells, further ROS inductions have been shown to be genetic heterogeneity in tumors may lead to inequable efficient in preferentially killing malignant cells, with situations. Therefore, only when we have screened and some showing promise in clinical studies. However, identified enough usable drug-resistant biomarkers related upregulated antioxidant capacity has been found in some to redox resetting, will it be feasible to overcome drug cancer cells, especially those in advanced stages. This resistance by monitoring and regulating the process of redox adaptation enables the cancer cells to survive under redox resetting. The use of modern genomic, proteomic increased oxidative stress, and provides a mechanism and other omics techniques has dramatically promoted of drug resistance. For example, elevated levels and the ability to identify novel genes and signaling networks activity of catalase are found in multidrug resistant HL-60 involved in tumor responsiveness to drug treatment. leukaemia cells [154]. Upregulation of HMOX1, SOD1 Moreover, high-throughput techniques combined with and GSH are found to be associated with arsenic trioxide bioinformatics approaches has allowed the identification resistance [155]. Also, several studies suggest that the of genotypes and molecular signatures also aided the resistance to doxorubicin, paclitaxel or platinum-based interrogation of clinical samples, facilitating the prediction drugs, which induce intracellular ROS production, is of drug responses to certain drugs. These will provide correlated with increased antioxidant capacity [156, 157]. abundant data that can be used to identify potential For those cancer cells that have adapted to higher predictive biomarkers for patient stratification. level of oxidative stress by increasing their antioxidant capacity, simply ROS-generating agents treatment might not be effective. It is possible to combine ROS-generating Abbreviations drugs with compounds that restrain the cellular antioxidant capacity. For example, a combination of arsenic trioxide ROS : Reactive oxygen species and 2-Me, a SOD inhibitor, shows significantly enhanced ABC : the ATP-binding cassette cytotoxic activity in primary chronic lymphocytic MDR : multidrug resistance leukaemia (CLL) cells [158]. A combination of arsenic MRP : MDR-associated protein trioxide and ascorbic acid, mediating GSH depletion, are www.impactjournals.com/oncotarget 42752 Oncotarget BCRP : breast cancer resistance protein approach? Nature reviews Drug discovery. 2009; 8:579- NRF2: Nuclear factor-erythroid 2 related factor 2 591. ARE : antioxidant response element 8. Traverso N, Ricciarelli R, Nitti M, Marengo B, Furfaro FOXO : Forkhead box O AL, Pronzato MA, Marinari UM and Domenicotti C. Role ATM: Ataxia telangiectasia mutated of glutathione in cancer progression and chemoresistance. DNMTs : DNA methyltransferases Oxidative medicine and cellular longevity. 2013; 5-FU: 5 fluorouracil 2013:972913. 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Published: Apr 5, 2016

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