Curr Pain Headache Rep (2014) 18:384 DOI 10.1007/s11916-013-0384-1
CANCER PAIN (DA MARCUS, SECTION EDITOR)
Cancer-Induced Oxidative Stress and Pain Mina G. Nashed & Matthew D. Balenko & Gurmit Singh
Published online: 1 December 2013 # Springer Science+Business Media New York 2013
Abstract Cancer pain is a well-documented and prevalent healthcare problem, with current treatment strategies often failing to achieve acceptable efficacy. One of the major difficulties in treating cancer pain owes to the complex interplay between the cancer microenvironment, cancer therapy, and the body’s own responses to these biochemical changes. A better understanding of the molecular pathways of nociception that are activated during cancer progression and treatment is necessary for better pain management and increased quality of life. This article reviews the current research that implicates oxidative stress as an important target for attenuating cancer pain. Sources of oxidative stress are first established, followed by a discussion of the various pathways that are affected by oxidative stress and that ultimately cause cancer pain.
Keywords Cancer . Pain . Chemotherapy . Radiotherapy . Oxidative stress . Reactive oxygen species . Free radicals . Nitric oxide . Glutathione . System xc . Glutamate . NMDA . Inflammation . Cytokines
This article is part of the Topical Collection on Cancer Pain. M. G. Nashed : M. D. Balenko Department of Pathology & Molecular Medicine, McMaster University, Lab 4 N48 Health Sciences Building, McMaster University, 1280 Main St W, Hamilton, ON L8S 4 L8, Canada M. G. Nashed e-mail:
[email protected] M. D. Balenko e-mail:
[email protected] G. Singh (*) Department of Pathology and Molecular Medicine, McMaster University, 2102 Michael G DeGroote Centre for Learning and Discovery, 1280 Main St. W., Hamilton, ON L8S 4K1, Canada e-mail:
[email protected]
Introduction Chronic pain is associated with many forms of cancer, and can lead to a rapid decline in the quality of life for cancer patients. This is particularly true in the case of metastatic bone disease, which is the most prevalent type of metastasis for prostate, breast, and lung cancers [1, 2]. Cancer pain is a welldocumented public health problem, and although under active investigation, remains costly to treat and treatment is often ineffective [3]. Up to 15 % of nearly 7 million patients exhibiting pain do not achieve acceptable relief with conventional pain management [4, 5]. The current strategy to manage pain, established by the World Health Organization (WHO) and recently updated with the EAPC (European Association for Palliative Care) recommendations, involves a three-step ladder, beginning with non-steroidal anti-inflammatory drugs (NSAIDs), followed by weak opioids, and finally escalating to the use of strong opioids for more persistent and severe pain [3, 6, 7]. As illustrated by recent findings on metastatic bone disease, it has been suggested that cancer pain may involve a separate pain state [8, 9••]. For example, studies using murine pain models have shown that noxious or painful stimuli cause changes in presynaptic glutamate release and postsynaptic αAmino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated responses in the anterior cingulate cortex (ACC) [10–12]. In contrast, bone cancer pain does not affect AMPAR activity, but causes a decrease in the level of N-Methyl-D-aspartate receptors (NMDARs) at the protein level, leading to impaired long-term depression (LTD) in the ACC, which may contribute to impaired depression of descending facilitatory pain fibers [9••]. A better understanding of the underlying mechanisms involved in cancer-specific pain is an essential and logical step in elucidating novel treatment targets, and offering pain management strategies that are more effective. Evidence presented by others, and complimented by findings from our group, suggest that oxidative stress may be an
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The excessive proliferative state of cancer cells is considered to be a fundamental property of this particular pathology [13]. In order to fuel an energetically expensive state, cancer cells alter their existing metabolic pathways to increase nutrient delivery [14]. The main consequence of rapid cellular division is an increase in harmful metabolic byproducts, such as excessive production of reactive oxygen species (ROS) [15]. This results in an oxidatively hostile environment inside the cell. Additionally, some cancers, such as melanoma, have
distinct ways of creating an oxidative environment outside the cell. In healthy melanocytes, melanosomes scavenge ROS created by intracellular metabolism and electromagnetic radiation. In melanoma, the melanosomes become dysfunctional and reverses their role to become a potent distributor of free radical species, such as hydrogen peroxide [16]. This increase in ROS enhances the proliferative ability, evasion of apoptosis, and metastatic potential of cancer cells through autocrine signaling [17, 18]. Several cancer cell lines have also been shown to produce excessive amounts of hydrogen peroxide, including MCF-7 breast cancer [19], HCT-15 colon cancer, SK-Ov-3 ovarian cancer, and Lan-1 neuroblastoma cells [20]. The amounts of ROS production from these cell lines were found to be comparable to ROS-producing polymorphonuclear leukocytes (PMNs) of the immune system [20, 21]. Although the mechanism is not well understood, increases in hydrogen peroxide reportedly has a cascading effect on cancer-associated fibroblasts, leading them to dramatically increase their own ROS production. In vitro results have shown that this often results in deleterious effects such as DNA damage and apoptosis in surrounding tissues [19, 22]. These findings suggest that many cancers increase ROS
Fig. 1 Schematic illustrating the relationship between cancer cells, cancer therapy-induced oxidative stress (OS), and cancer pain. Cancer cells release oxidants, such as free radicals, both inside the cell and in the cellular microenvironment. Therapy contributes to the oxidative environment of cancer. To combat this oxidative environment, cancer cells activate system xc, which exchanges glutamate for cystine at a 1:1 ratio. Cystine is converted to cysteine by thioredoxin reductase 1 (TRR1), ultimately producing the antioxidant glutathione (GSH). The excessive glutamate released in the process acts peripherally on group 1 metabotropic glutamate receptors (mGluRs) to facilitate peripheral sensitization. Glutamate acts centrally on ionotropic glutamate receptors, such as N-
methyl-D-aspartate receptor (NMDAR), to facilitate central sensitization. The oxidative environment of the cancer activates the immune system through upregulation of cytokines and macrophages. Cox-2 enzymes in macrophages are further activated by oxidants, and in turn upregulate inflammatory responses. Additionally, cytokines are able to act directly on primary sensory afferent neurons to increase sodium (Na+) permeability and sensitize capsaicin receptors (TRPV1). Both of these effects facilitate peripheral sensitization. Finally, oxidant synthesis is involved in activating brain regions that are responsible for nociceptive processing, such as the rostral ventrolateral medulla (RVM), which relays pain signals from other brain regions down to the descending facilitatory pathway
important contributor to cancer pain, the source of which may be targeted in future pharmacological interventions. In this article, we review the current literature pertaining to cancerinduced oxidative stress and chronic pain. We first examine the sources of oxidative stress; namely cancer cells and cancer therapeutics. We then consider the impact of oxidative stress on glutamatergic pathways of nociception, as well as inflammatory and central pathways that lead to sensitization and hyperalgesia (findings summarized in Fig. 1).
Cancer and Oxidative Stress
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in vitro, both inside the cells and in the cancer microenvironment. Evidence from controlled in vivo experiments is lacking. However, there is clinical evidence suggesting that chronic lymphocytic leukemia cells, which are readily extracted from patients, express an increase in ROS production when compared to non-cancerous lymphocytes [23]. Similarly, increased ROS production was found in multiple B-cell lines from patients with Epstein-Barr-associated Burkett’s lymphoma [24]. Together, these results suggest that malignant cells do enter a pro-oxidative state in vivo. The external microenvironment surrounding cancer cells can also be altered indirectly by the immune system. In the presence of cancer cells, lymphocytes are activated and consequently produce inflammatory conditions, which are often accompanied by an increase in ROS [13, 25]. Nearly all clinically induced tumors are also infiltrated by activated macrophages [26]. These tumor-associated macrophages (TAMs) have been found to express both proinflammatory M1 [27] and anti-inflammatory M2 cytokine profiles [28], with an initial response skewed towards an M1 phenotype [29]. Although M1 macrophages have properties associated with tumor destruction, they contribute excessive amounts of ROS and reactive nitrogen species (RNS) to the surrounding microenvironment. This consequence of macrophage activation may contribute to tumor progression, and a high TAM activity correlates with poor patient prognosis [26, 30]. Furthermore, recent evidence has emphasized the role that tumor-associated neutrophils can play in tumorigenesis and ROS production. The phagolysosomes of neutrophils contain enzymes such as NADPH oxidases, which act to reduce oxygen and convert superoxide radical species into hydrogen peroxide [31]. Therefore, it is evident that the oxidative microenvironment surrounding tumor cells is highly associated with increased oxidative stress and hydrogen peroxide, whether this oxidative stress results either directly from the cancer cells or indirectly by immune system activation.
Cancer Therapy and Oxidative Stress A discussion regarding the generation of oxidative stress in cancer patients would be incomplete without carefully considering the role of cancer therapies. Many chemotherapeutics have been reported to cause oxidative stress, either as a side effect or as a mechanism of action in targeting cancer cells. ROS are known to be elevated in the cancer cell microenvironment through various mechanisms, which include increased basal metabolism of cancer cells, mitochondrial dysfunction, and oncogene activity, among others [32•]. It has been proposed that this increase in ROS, which would be cytotoxic to normal cells, serves to promote tumorigenesis by promoting some of the hallmarks of cancer recently outlined by Hanahan and Weinberg [13, 32•]. However, while
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the initial carcinogenic microenvironment associated with cancer seems to be highly oxidative, solid tumors grow in an increasingly hypoxic environment [33]. Antioxidants are rendered inept in this low-oxygen environment, which likely triggers the repression of antioxidant enzymes that is observed in most animal and human cancers [34, 35]. Some chemotherapeutic drugs are designed to target this characteristic by inducing oxidative stress in cancer cells. As an example, the chemotherapeutic antibiotic bleomycin acts by breaking DNA strands, thereby increasing oxidative stress through the production of reactive oxygen intermediates and further depletion of the antioxidant glutathione (GSH) [36]. Some chemotherapeutic agents, particularly the anthracyclines, create oxidative stress as a byproduct in nontargeted tissues [37]. For example, in cardiac muscle, doxorubicin (DOX), a commonly used anthracycline, diverts electrons from their normal pathway in the electron transport system (ETS) to out-of-sequence electron acceptors, leading to the formation of superoxide radicals, and ultimately cardiotoxicity [38]. While anthracyclines are associated with the highest level of oxidative stress, other agents such as platinum coordination complexes, alkylating agents, epipodophyllotoxins, and camptothecins have also been reported to generate high levels of oxidative stress [39].
Antioxidants with Chemotherapy Although several chemotherapeutics exploit the induction of oxidative stress as a cancer fighting mechanism, the free radicals produced in this process often lead to serious side effects, such as cardiotoxicity, nephrotoxicity, and peripheral neuropathy [40]. Recent studies have investigated the efficacy of co-administrating antioxidants with highly oxidative chemotherapies, such as DOX, in an effort to prevent oxidative damage to nontargeted tissue. For example, grape seed proanthocyanidins, a dietary antioxidant supplement, has been shown to ameliorate DOX-induced myocardial oxidative stress in tumor-bearing mice [41]. Perhaps more significantly, the same study revealed that grape seed proanthocyanidins enhanced the anti-tumor activity of DOX. A recent systematic review of randomized, controlled trials with human subjects suggests that antioxidant supplements may result in increased patient survival time and/or increased tumor response [42]. However, the use of antioxidants in conjunction with chemotherapy has been a point of contention. It is possible that antioxidant supplementation may reduce the efficacy of some chemotherapeutics that reply on oxidative stress as a mechanism of action [43]. Therefore, larger studies are warranted to conclusively determine whether or not antioxidant supplements interfere with some of the pro-oxidant mechanisms of chemotherapeutics. As an alternative strategy to directly targeting the oxidative stress produced by some therapeutics,
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it may be advantageous to target downstream pathways that are activated by free radicals. In most cases, the free radicals produced by cancer cells and cancer therapeutics do not directly activate nociceptive pathways, but rather act on other molecular targets. Therefore, pharmacologically modulating these targets may alleviate pain without interfering with the pro-oxidant mechanism of some therapeutics (see later discussion on system xc for an example of one of these pathways). In addition to chemotherapy-induced oxidative stress, there is also evidence that ionizing radiation during clinical radiotherapy may lead to increased oxidative stress [44, 45]. However, it should be noted that no consensus exists as to the role of radiotherapy in inducing oxidative stress, and some studies actually report a reduction in oxidative stress following radiotherapy [46]. There is mounting evidence in the literature suggesting a relationship between cancer therapies and increased oxidative stress. This increase in oxidative stress may be an inadvertent side effect of some chemotherapeutics, or in fact the very mechanism by which they act. In either case, new strategies must be developed to counteract the damage caused by excessive free radical formation, while maintaining maximal effectiveness of cancer therapeutics that take advantage of cancer’s sensitivity to oxidative stress.
Oxidative Stress and Glutamate: A Pain Pathway Cancer cells circumvent the consequences of oxidative stress by increasing antioxidant production. GSH is one of the main cellular antioxidants and is critical in maintaining safe levels of intracellular ROS [47]. The upregulation of GSH levels can be achieved through the antiporter system xc. System xc is a heterodimeric membrane transporter composed of a light chain (xCT), and a heavy chain (4F2hc). The heavy chain is involved in localizing the antiporter to the membrane, while xCT is responsible for amino acid transport [48]. xCT, when active, exchanges intracellular glutamate for extracellular cystine at a 1:1 ratio in a Na+-independent manner [49]. Once inside the cell, cystine is readily reduced by thioredoxin reductase 1 (TRR1) to cysteine, the rate-limiting substrate of GSH synthesis [50]. Additionally, cystine and cysteine form a powerful redox pair. System xc-related pathways are pivotal to antioxidant production and aid in minimizing oxidative damage. This system of ROS mitigation has been found to be directly inducible by oxidative stress [51] and remains highly conserved in breast [49, 52, 53], pancreatic [54, 55], lung [52, 53], ovarian [52, 55], colon [52], liver [55], and prostate cancers [56], as well as cancers of the central nervous system (CNS) [52, 55, 57]. Using animal models, work from our laboratory has shown that the oxidative stress-induced activation of system xc leads to pain behaviors. Furthermore, blocking this transporter with known inhibitors, such as
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sulfasalazine, attenuates pain responses in vivo [58••]. We are currently investigating the effects of oxidative stress on breast cancer cells and their glutamatergic responses. Glutamate is the most abundant excitatory neurotransmitter in the CNS, and mediates fast excitatory transmission through NMDA and AMPA receptors in the brain. Importantly, the glutamate by-product of system xc, which is released into the cancer microenvironment, has been linked to bone remodelling [59], neuronal excitotoxicity [57], and pain [60]. The specific mechanisms involved in pain modulation and nociceptive transmission are not well understood, and are undoubtedly complex. It is, however, evident that glutamate dysregulation and activation of certain metabotropic glutamate receptors (mGluRs) play a key role in neuropathic and inflammatory pain. In rats, a model of neuropathic pain (sciatic nerve section) was shown to upregulate metabotropic glutamate receptor 5 (mGluR5; a group I mGluR) in several regions of the spinal cord [61]. Additionally, agonist-induced activation of peripheral group I mGluRs (which include mGluR1 and mGluR5) have been shown to stimulate glutamate release and spontaneous pronociceptive effects in rats [62, 63], as well as induce thermal hyperalgesia in mice [64], whereas antagonism of these receptors attenuates chemicallyinduced pain [63, 64] and even reduces cancer-induced bone pain [65•]. Although the cellular mechanisms of modulating mGluR nociception are unclear, activation of a phospholipase C (PLC) cascade has been implicated as a potential mechanism [66]. More recently, the focus has shifted to activation of other downstream kinases, particularly the extracellular signal-regulated kinase (ERK) [67]. At the brain level, glutamate plays a key role in activitydependent central sensitization following painful stimuli, as highlighted by the finding that antagonists of ionotropic glutamate receptors (iGluRs) in the brain (i.e., NMDA and AMAP receptors) decrease nociceptive transmission [68]. However, due to psychotomimetic effects and amnesia, the use of NMDA antagonists to target chronic pain is limited, and iGluRs are considered poor targets for pain treatment [69]. Therefore, the literature clearly indicates a connection between cancer-induced oxidative stress and increased activity of system xc. This leads to increased glutamate secretion, which is highly implicated in peripheral and central nociceptive pain pathways. Further research is required to delineate the specific mechanisms of glutamate-induced pain, as well as identifying therapeutic targets at the level of glutamate output and glutamate receptors.
Inflammatory and Central Pathways of Nociceptive Sensitization Inflammation is an important aspect of peripheral sensitization leading to hyperalgesia. It is well-established that oxidative
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stress contributes vitally to such inflammatory pathways. Antioxidants as well as free radical scavengers have been found to have immunoregulatory affects, which act to reduce inflammation and implicate these molecules in inflammatory states [70–72]. Although the relationship between oxidative stress and the immune response is complex, one example that highlights this relationship is provided by Matsuzawa et al., who show that ROS can be a key factor in the innate immune response through the activation of various mitogen-activated protein kinases (MAPKs) [73]. MAPKs are essential in directing cellular responses to a wide array of stimuli and for the production of proinflammatory cytokines such as interleukin-1, 6 (IL-1, IL-6) and tumor necrosis factor alpha (TNF-α) [71, 74]. These findings correlate with mounting evidence that ROS and oxidative stress can upregulate other proinflammatory cytokines such as IL-1β and IL-18, as well as nuclear factor kappa-B (NF-κB), which act to create an inflammatory phenotype [75, 76]. The actions of ROS are not confined to cytokine production. A reduction in macrophage activation has also been observed when intracellular ROS levels are reduced, implicating ROS in macrophage phagocytic activity [77]. In nociceptive pathways, the activation of cytokines and the immune system are essential to peripheral sensitization, both directly and indirectly. The proinflammatory cytokine TNF-α, for example, is involved in the maintenance of neuropathic pain, and has been shown to directly enhance Na+ levels in primary afferent neurons of the dorsal root ganglion (DRG), leading to possible voltage-gated ion channeldependent allodynia [78]. In addition to the direct nociceptive action of inflammatory molecules on peripheral neurons, several pathways of oxidative stress-induced pain exist. Cyclooxygenase (COX) enzymes, particularly the inducible COX-2 enzyme involved in inflammation, are important targets for pharmacological pain control. Non-steroidal antiinflammatory drugs (NSAIDs), such as aspirin and ibuprofen, exert their analgesic effects by inhibiting these enzymes. Using a mouse macrophage cell line, Salvemini et al. illustrated that COX enzymes, which are involved in the production of proinflammatory prostaglandins, are activated by the free radical nitric oxide (NO) [79], a result that has since been confirmed by other groups [80, 81]. Although the specific mechanism remains to be defined, it has been shown that NO and peroxynitrite (PN), which is produced from NO and superoxide (SO), are able to activate COX-2 by serving as a substrate for the enzyme’s peroxidase activities [82]. In addition to activating the enzyme, NO has also been shown to maintain prolonged COX-2 gene expression [83]. Another pathway under active investigation involves the capsaicin receptor (TRPV1), which is associated with inflammatory pain. This nociceptive receptor responds to heat and acidic conditions commonly associated with an inflamed environment. It has also been reported that IL-1β and TNF- α are able
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to sensitize and increase TRPV1-mediated calcium channels in DRG neurons [84, 85]. Similar to COX enzymes, TRPV1 activity is regulated by oxidative stress as it produces NO [86], and is also sensitized by the oxidative modulation of specific cysteine residues [87]. In addition to peripheral inflammatory pathways, free radicals may be involved more directly in central mechanisms of nociception. The rostral ventrolateral medulla (RVM) is a relay center in the brain involved in relaying pain signals from other brain regions, such as the ACC, to the spinal cord through the descending facilitatory pathway [88, 89], a process that is crucial to central sensitization. The activity of the RVM has been shown to be dependent upon the synthesis of NO, as well as activation of NMDARs [90]. It is evident that in addition to the previously discussed impact of oxidative stress on nociceptive glutamatergic signaling, oxidative stress is also involved in multiple inflammatory pathways. These pathways are critical in the development of peripheral and central sensitization, which are required for the development of chronic pain that is often associated with cancer.
Conclusion The existing literature clearly implicates oxidative stress induced by cancer cells and cancer therapies in the progression and maintenance of chronic pain. Continued research will help to elucidate the specific molecular mechanisms involved in both cancer-induced oxidative stress and oxidative stressinduced pain. Cancer cells as well as cancer therapies contribute to the typical oxidative environment observed in cancer. Additionally, mounting evidence suggests that oxidative stress can trigger and maintain pain pathways through activation of glutamatergic signaling and inflammatory pathways, as well as by directly affecting nociceptive centers in the brain. However, few studies have directly investigated the oxidative environment of cancers in the context of cancer pain, which is critical in gaining a better understanding of their complex biological relationship and the development of new targets for cancer pain therapies. In addition, recent results suggest that cancer pain may be a biologically unique pain state compared to inflammatory and neuropathic pain. Therefore, results from pain studies cannot always be extrapolated to cancer-specific pain, and future studies should focus on delineating pain pathways that are specific to cancer. Clinically, the need for novel therapy is highlighted by evidence that the typical methods of managing pain are often ineffective for cancer patients, leading to decreased quality of life. Targeting the consequences of oxidative stress, such as the increased glutamate output by cancer cells through system xc, may prove to be a useful new strategy in managing cancer pain.
384, Page 6 of 8 Compliance with Ethics Guidelines Conflict of Interest Dr. Mina G. Nashed and Dr. Matthew D. Balenko both declare that they have no conflicts of interest relevant to this article. Dr. Gurmit Singh reports receiving a research grant from the Canadian Breast Cancer Foundation. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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