Current Drug Targets Celecoxib in Cancer Therapy and Prevention – Review

Table of contents :
Celecoxib in Cancer Therapy and Prevention – Review
Abstract: Background and Objectives
Conclusion:
Keywords:
1. INTRODUCTION
2. MOLECULAR MECHANISMS OF CELECOXIBBIOLOGICAL ACTIVITY
3. ADVERSE EFFECTS
4. CELECOXIB IN CLINICAL TRIALS
5. CELECOXIB IN COMBINATION WITH OTHERCHEMOTHERAPEUTICS
6. CELECOXIB AS A RADIOSENSITIZER
CONCLUSION
LIST OF ABBREVIATIONS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
AUTHOR CONTRIBUTION
REFERENCES

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Send Orders for Reprints to [email protected] Current Drug Targets, 2019, 20, 302-315

REVIEW ARTICLE ISSN: 1389-4501 eISSN: 1873-5592

Celecoxib in Cancer Therapy and Prevention – Review

Impact Factor: 3.112

BENTHAM SCIENCE

Natalia Tołoczko-Iwaniuk1, Dorota Dziemiańczyk-Pakieła2, Beata Klaudia Nowaszewska2, Katarzyna Celińska-Janowicz1 and Wojciech Miltyk1,* 1

Department of Pharmaceutical Analysis, Medical University of Bialystok, Mickiewicza 2D Street, 15-222 Białystok, Poland; 2Department of Maxillofacial and Plastic Surgery, Medical University of Bialystok, Skłodowskiej-Curie 24A, 15-404 Bialystok, Poland


ARTICLE HISTORY Received: March 20, 2018 Revised: June 04, 2018 Accepted: August 02, 2018 DOI: 10.2174/1389450119666180803121737

Abstract: Background and Objectives: It is generally accepted that inflammatory cells found in the tumor microenvironment are involved in the neoplastic process, promoting cell proliferation, survival, and migration. Therefore, administering anti-inflammatory medication in cancer therapy seems to be justified. A potential pathway associated with the aforementioned issue is cyclooxygenase-2 inhibition, particularly as the overexpression of this enzyme has been proven to occur in cancer tissues and is also associated with a poor prognosis in several types of human malignancies. Celecoxib, a COX-2 selective inhibitor, has been utilized for over 20 years, particularly as an anti-inflammatory, analgesic and antipyretic medication. However, to date, its antineoplastic properties have not been sufficiently investigated. In recent years, the number of research studies on the antineoplastic effects of celecoxib has increased considerably. The vast majority of publications refers to preclinical studies attempting to elucidate its mechanisms of action. Clinical trials concerning celecoxib have focused primarily on the treatment of cancers of the colon, breast, lung, prostate, stomach, head and neck, as well as premalignant lesions such as familial adenoma polyposis. In this review article authors attempt to summarise the latest research which has elucidated celecoxib use in the treatment and prevention of cancer. Conclusion: Both preclinical and clinical studies have demonstrated promising results of the role of celecoxib in the treatment and prevention of cancer – the best outcome was observed in colon, breast, prostate and head and neck cancers. However, more clinical trials providing real evidence-based clinical advances of celecoxib use are needed.

Keywords: Cancer, celecoxib, chemotherapy of cancer, combination therapy, COX-2, inflammation. 1. INTRODUCTION The relationship between inflammation and cancer development is not a new issue. It is generally acknowledged that inflammatory cells found in the tumor microenvironment are involved in the neoplastic process, promoting cell proliferation, survival, and migration. Moreover, tumor cells have adopted a number of signaling molecules such as selectins, chemokines and their receptors for promoting their own development. Therefore, these assumptions provide a foundation for using selected anti-inflammatory medications in cancer therapy. One of such potential treatment pathways is cyclooxygenase-2 (COX-2) inhibition, particularly as the overexpression of this enzyme has been proven to occur in cancer tissues and lymph node metastases. It has also been found to be associated with a poor prognosis in several types of human malignancies [1].

*Address correspondence to this author at the Department of Pharmaceutical Analysis, Department of Maxillofacial and Plastic Surgery, Medical University of Bialystok, Mickiewicza 2D street, 15-222 Białystok, Poland; Tel: +48 85 748 58 45; Fax: +48 85 748 57 65; E-mail: [email protected] 1873-5592/19 $58.00+.00

Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID), selective, noncompetitive inhibitor of COX-2 enzyme. It inhibits the prostaglandin cascade by preventing the substrate arachidonic acid from binding to the active site of COX-2 [2]. Metabolism of arachidonic acid via the COX pathway, with the synthesis of prostaglandins, influences numerous physiological activities in the human body. These factors, including prostaglandin E2 (PGE2), control not only the inflammatory process, but also regulate the constriction of blood vessels and smooth muscle, platelet aggregation, sensitization of neurons to pain, intracellular calcium regulation, cell division, apoptosis, which are essential to provide physiological homeostasis [3]. Celecoxib has been used for over 20 years, particularly as an anti-inflammatory, analgesic and antipyretic drug. However, the elucidation of the role of inflammation in carcinogenesis has afforded a new opportunity for its application. In the last few years, the number of research studies investigating the antineoplastic effects of celecoxib have significantly increased, but the vast majority of the published data regard preclinical studies. The majority of clinical trials concerning celecoxib have focused primarily on the treatment of cancers © 2019 Bentham Science Publishers

Celecoxib and Cancer

of the colon, breast, prostate, and lung which, collectively, constitute a significant number of all cancer deaths [3]. Another important issue of such research is the treatment of premalignant lesions such as familial adenoma polyposis, Barrett’s esophagus and oral leukoplakia [4]. Such studies are premised on the similarity between factors involved in carcinogenesis and those associated with the inflammatory process. Several mechanisms through which COX-2 supports carcinogenesis, including resistance to apoptosis, immunosuppression, promotion of angiogenesis, stimulation of proliferation and invasiveness have been reported in the literature. In spite of the generally accepted involvement of the pathways mentioned above, the exact process of explaining the toxicity of COX-2-inhibitors still seems to be unclear [5]. Despite the fact that some research indicates serious adverse effects of its use, such as cardiovascular events, an increased risk of thrombogenesis and renal physiology disruption [6-9], COX-2 inhibition is considered a valuable potential therapeutic target for various types of cancer [4]. In this review article, the authors attempt to summarise the latest research elucidating celecoxib use in the treatment and prevention of the most common types of cancer. 2. MOLECULAR MECHANISMS OF CELECOXIB BIOLOGICAL ACTIVITY Recent preclinical research concerning celecoxib in cancer treatment has focused principally on the evaluation of its efficacy as well as the elucidation of its anticancer mechanism of action. The majority of studies have explored COX2 activity and the downstream effects associated with its upregulation in cancer cells since COX-2 inhibition is believed to be the basis of anticancer activity of celecoxib. COX-2 is absent in most healthy cells; it is detected mainly in inflamed and neoplastic tissue. Some inflammation inducers or mutagenic factors such as bacterial lipopolysaccharides, cytokines, growth factors and other tumor promoters can cause rapid overexpression of this enzyme [10-12]. It has been proven that COX-2, as well as other pro-inflammatory enzymes, participates in the pathogenesis of cancer and its overexpression is associated with poorly differentiated and deeply invasive types of tumors [13, 14]. A great number of research studies have indicated that inhibiting COX-2 expression with celecoxib promotes apoptosis and significantly reduces cancer cell proliferation. Furthermore, it decreases the number and size of primary tumors and metastases in animal models, in a dose-dependent manner, without demonstrating toxicity [13, 15-19]. The possibility of controlling inflammation in tumor tissues by decreasing the levels of other inflammatory mediators such as TNF-α, iNOS, PGE2, VEGF, MMP-2, MMP-9 has also been confirmed [17, 2024]. However, inflammation is generally self-limiting (production of pro-inflammatory cytokines is usually followed by those with an anti-inflammatory effect). In cells which lose normal growth control, this process does not work. In such situations, inflammatory mediators stimulate cell proliferation, enroll inflammatory cells and increase the formation of reactive oxygen species, which results in DNA damage and impedes DNA repair. Such a dysfunction of programmed cell death and DNA repair mechanisms is characteristic of chronic inflammation and is associated with neoplastic transformation [10].

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Nevertheless, the proliferation of particular cell lines lacking COX expression in vitro has also been proven to be inhibited by celecoxib. A significant number of studies attempting to explain this phenomenon have pointed to COX2-independent mechanisms such as cell cycle arrest, the induction of the mitochondrial pathway of apoptosis and necrosis [10, 25]. There are also some reports available in the recent literature which suggest that the aforementioned effects caused by celecoxib result from the induction, not inhibition of COX-2. According to published research conducted on human lung tumor cells, the proapoptotic mechanism of celecoxib commences with the upregulation of COX-2 and PPAR γ, which results in the nuclear translocation of PPARγ by de novo-synthesised prostaglandins dependent on COX- 2 (PGE2, PGD2, and 15d-PGJ2) [26]. Another potential anticancer effect of celecoxib is the inhibition of blood vessel development in cancerous tissue. Proper nourishment is essential for the uncontrolled growth of a primary tumor mass and spread of the metastatic colony. By inhibiting COX-2, celecoxib decreases levels of the vascular endothelial growth factor (VEGF) as well as the basic fibroblast growth factors, IL8 and TNF which have been recognized as powerful pro-angiogenic factors [10, 24]. A particularly important mechanism involved in metastasis formation is cross-communication between the levels of VEGF and matrix metalloproteinases [24]. The results of research conducted on various types of cancer cell lines and animal models prove that the celecoxib-induced reduction in VEGF and metalloproteinases (MMP-2, MMP-9) levels is associated with the inhibition of angiogenesis, lower microvascular density and a decrease in metastasis formation in lymph nodes as well as other organs [17, 23, 24, 27]. Interestingly, Xu et al. showed opposite results of their vivo study conducted on xenograft models of colorectal cancer. They found that celecoxib increased VEGF levels and that this process was independent of COX-2 activity but it was associated with the endoplasmic reticulum stress activation. The authors stated that the upregulation of VEGF could block celecoxib activity and be the cause of drug resistance [28]. One more potential anti-metastatic mechanism in which celecoxib affects cancer development is the suppression of the epithelial-to-mesenchymal transition (EMT), resulting in the upregulation of E-cadherin expression. It has been investigated whether selected COX-2 inhibitors (celecoxib, among others) influence gene expression of E-cadherin (CDH-1) in head and neck cancer cell lines, and downregulate transcription factors such as Slug, Snail SIP1, Twist and ZEB1, as well as cytoplasmic mediators (focal adhesion kinase, vimentin and β-catenin), cell adhesion molecules and surface receptors (AMFR and EGFR) [4, 29]. The aforementioned factors act as molecular switches which regulate the EMT signaling pathway. They recognize E-box DNA sequences in the promoter region of E-cadherin, enroll cofactors and histone deacetylases and thereby inhibit its expression [30]. In vivo research has confirmed such outcomes, pointing to the inhibition of oral cancer development in a murine xenograft model after celecoxib treatment compared to placebo [29]. Moreover, the comparison of results obtained in pre-clinical studies with the clinical status of patients with tongue cancer showed that low levels of CDH-1 closely correlated with the formation of lymph node metasta-

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sis in this type of cancer and celecoxib administration caused an increase of the levels of CDH-1 [4]. Interestingly, in similar research concerning epithelial-to-mesenchymal transition after celecoxib administration, conducted on lung cancer cells, quite opposite results were obtained. Wang et al. suggested that celecoxib, applied in clinically relevant concentrations, promoted epithelial-mesenchymal transition (EMT) in cancer tissues regardless of COX-2 status, and in this mechanism induced cell invasion and transformation into cells resistant to chemotherapy. This process was not observed when another COX-2 inhibitor (etodolac) was used [31]. A number of recent research studies have demonstrated that the immune system activation caused by celecoxib is also associated with an increase in the expression of tumor suppressors. Lönnroth et al. have demonstrated that the preoperative administration of NSAID to patients with colorectal cancer stimulates tumor infiltration by immune cells with the potential to kill cancer cells. Moreover, it appeared to decrease the expression of several genes responsible for growth, invasion, and metastasis (OCT4, SOX2 and BMP7 as well as some microRNAs), reported to act as tumor suppressors or oncomiRs [32, 33]. Schellhorn et al., using lung cancer cell lines and metastatic lung cancer cells obtained from patients, proved the upregulation of intercellular adhesion molecules (ICAM-1) after celecoxib application. Furthermore, they found that it led to increased cancer cell lysis by lymphokine-activated killer (LAK) cells (through the intercellular ICAM-1/LFA-1 crosslink). Such effects were not observed in non-tumor bronchial epithelial cells, used as controls, or following the administration of any other selective COX-2 inhibitor [34]. Another interesting potential link between inflammation and cancer development is the activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kB1), which is a specific component of the inflammatory response and is commonly detected in malignant tumors. Research conducted on colorectal cancer tissues has revealed the overexpression of NF-κB as well as high levels of proinflammatory enzymes and the aberrant nuclear localization of the activated cell survival transcription factor. Antiinflammatory drugs, including celecoxib, have been observed to significantly suppress NF-kappa B (and the inflammatory potential of the tumor). The suppression of the anti-inflammatory transcription factor PPAR-γ has also been observed [14]. Another potential mechanism through which celecoxib can inhibit cancer cells development is the inverse regulation of Notch1 gene. The family of Notch signaling factors play a significant role in a variety of developmental processes such as cell proliferation, differentiation, and self-destruction [13]. They also partly influence changes in the expression of Snail, a transcription factor which promotes the repression of the adhesion molecule E-cadherin and regulates the epithelial to mesenchymal transition (EMT) [35]. The expression of Notch signaling molecules differs between certain types of cancer cells. Particularly high mRNA expression of Notch1 have been discovered in gastric cancer and it correlated with deep invasion and high TNM staging. The mRNA levels of Notch2, Notch3, Jagged1, and N2IC have also been found to be high in this type of malignancy [13].

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A similar aspect of the anticancer potential of celecoxib was evaluated by Saito et al. Having 53 samples of gastric cancer tissue, they revealed that celecoxib significantly upregulated miR-29c activity and downregulated the expression of oncogene Mcl-1 associated with it. The low activity of miR-29c was characteristic of gastric cancer tissue in comparison to the healthy gastric mucosa. Furthermore, it was associated with rapid disease progression and was more pronounced in advanced gastric cancers than in early-stage tumors. The activation of miR-29c by celecoxib suppressed Mcl-1 and, in effect, induced apoptosis of gastric cancer cells [36]. Another important target for cancer therapy utilizing celecoxib (particularly gastric and head and neck cancers) is the induction of apoptosis and autophagy through the PI3K/Akt signaling pathway. It is one of several pathways whose activation may lead to the transcription of genes involved in cellular invasion and proliferation, such as cyclin D1 production. Research concerning this issue has revealed decreased levels of cyclin D1 and pAkt proteins, increased caspase-8 and -9 mRNA expression, while procaspase-8 and -9 protein expression was found to be reduced relative to the time- and dose-dependent manner after celecoxib treatment [37, 38]. A number of research studies have focused on the impact of celecoxib on the cell cycle in cancer cells. The majority of them indicate that the cell cycle is arrested after celecoxib administration at G0/G1 checkpoint (resting phase /apoptosis), with a significantly decreased number of cells in S phase (DNA replication). Such an effect may be partly mediated through the STAT3 pathway (involved in cell cycle blockade) as the authors have proven the significant downregulation of genes downstream of STAT3 (Survivin, Mcl-1, Bcl-2 and Cyclin D1) after exposure to celecoxib [22, 39]. It can also be associated with the induction of p53, which is involved, inter alia, in several different aspects of cell cycle arrest and apoptosis and celecoxib has been proven to affect p53 via multiple molecular mechanisms [40-42]. On the other hand, Katkoori et al. showed that the inhibition of cancer cell proliferation by celecoxib was independent of normal levels of native p53. When p53 expression was inhibited using siRNA, the inhibitory effects on the growth of prostate cancer cell lines usually exerted by celecoxib did not change significantly [43]. The role of autophagy in celecoxib-induced apoptosis has also been the focus of research. It has been investigated whether it has protective or destructive activity. The results of a study by Zhu and co-authors indicate that despite the fact that celecoxib induces apoptosis, it also activates JNK (c-jun-N-terminal kinase) -mediated autophagy, which exerts cytoprotective effects in prostate cancer cells. The authors state that the blockade of autophagy via the JNK-mediated pathway is required to enhance apoptosis and constitutes a potential promising strategy in prostate cancer therapy [44]. The results of another study regarding the impact of celecoxib on prostate cancer have revealed one more potential way of its activity. It has been found to suppress the androgen receptor (AR), crucial in the development of this type of cancer. Two probable signaling pathways through which it downregulates this receptor have been suggested. The first

Celecoxib and Cancer

one concerns downregulating the prostaglandin receptor EP2 and cellular transcription factor CREB (EP2/CREB pathway) [45]. The second one regards EGF and amphiregulin (AREG) induction, which causes EGFR and ErbB2 activation. In addition, the downregulation of ErbB3 is closely associated with castration-resistant prostate cancer. The authors emphasize that this significant crosstalk between the COX-2-ErbB family receptor network and androgen receptor (AR)-EGFR signaling pathways indicates that inflammation plays a central role in prostate cancer development [46]. The results of another study show that the effectiveness of celecoxib therapy depends on collagen density of tissue. An increase in tumor size and metastasis occurrence has been observed in breast tumors with high collagen density (PyMT/Col1a1tm1jae), which express higher levels of COX-2 and PGE2. Celecoxib administration decreased the expression levels of COX-2, PGE2, and Ki-67 as well as inhibited macrophage and neutrophil recruitment and led to a reduction in overall collagen deposition. Tumors with low collagen density (PyMT) demonstrated the minimal effect after such treatment. These findings suggest that COX-2 inhibition may be an effective therapeutic target for patients with dense breast tissue and early-stage breast cancer [47]. 3. ADVERSE EFFECTS The most commonly reported adverse effect of celecoxib is the increased frequency of cardiovascular disorders following its long-term use. COX-2 inhibition has been indicated as the molecular mechanism underlying such complications. Celecoxib causes a reduction in the physiological formation of COX-2-dependent prostanoids, such as PGE2, which have vasodilatory properties as well as the overproduction of leukotriene B4 and thromboxane A2 (TXA2) with the vasoconstrictive and proaggregatory activity [48-50]. However, the mechanism independent of the COX isozyme, leading to an increased risk of thrombotic complications, has also been suggested [51]. It has been proven that COX-2 expression is higher in blood vessel walls or the heart muscle and its inhibition may cause damage to the arterial wall, induce arterial blood clotting and, as a result, lead to myocardial infarction, stroke, and death due to cardiovascular causes [50]. Some studies have demonstrated the increased frequency of such disorders after prolonged celecoxib treatment compared with the control group, pointing also to a higher risk of hypertension in participants with pre-existing cardiovascular risk factors [52, 53]. However, the results of other studies have not confirmed the higher frequency of such complications. They have provided no evidence of significant differences in toxicity or adverse events in the treatment with or without celecoxib [54-56] and in comparison with a number of other widely used traditional NSAIDs (diclofenac and ibuprofen) [57]. The cardiovascular risk of COX-2 inhibitors appears heterogeneous. It may increase with celecoxib treatment prolongation, after the application of a higher individual drug dose and may also vary according to the patient’s individual cardiovascular risk. Therefore, it’s important to identify patients at an increased risk for cardiovascular damage [50, 58, 59]. Another adverse effect of celecoxib therapy reported in the literature is renal dysfunction. It is more characteristic of

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COX-1 inhibitors while COX-2 inhibitors, including celecoxib, should theoretically have a less significant impact on renal hemodynamics. Case-control cohort studies as well as meta-analyses available in the literature have demonstrated that the association between COX-2-selective NSAIDs treatment and the risk of acute kidney injury does not reach statistical significance [60] and nonselective NSAIDs, rather than COX-2 inhibitors, are responsible for such a dysfunction [61, 62]. On the other hand, some studies have indicated that the risk of renal impairment among users of celecoxib remains unclear since the results of the latest research have revealed a statistically significantly increased risk of such impairment irrespective of COX-2 selectivity [63]. Future randomized trials are needed to elucidate these findings. However, patients at the greatest risk of renal injury (those with pre-existing renal impairment, heart failure, liver dysfunction, those taking diuretics and/or ACE inhibitors, and the elderly) should be monitored for any signs of potential renal injuries shortly after commencing therapy including these agents [64]. To minimize the adverse effects of celecoxib use and to improve its effectiveness, some new forms of administration of the drug have been investigated. The development of nanotechnology in recent years has presented an opportunity to create nanoparticles delivering celecoxib directly to cancer cells, without affecting the entire organism [10]. In the case of colon cancer, colon-specific prodrugs have been designed - SG1C and SG5C (N-succinylglutam-1 or 5yl celecoxib) which transfer the drug directly to the tumor. They are stable in the small intestinal contents and then release celecoxib in the cecal contents. As a result, lower systemic absorption of celecoxib has been observed, with the plasma concentration of the drug at a far lower level compared with oral administration, as well as an increase in the therapeutic concentration of the drug at the target site [65]. Another advantage of using nanoparticles is the possibility of administering a few agents simultaneously in cancer treatment. Such multiple therapy generally decreases the development of drug resistance in cancer cells. However, this approach is normally limited by the increased toxicity and different bioavailability of drugs administered jointly. Using nanoparticles which release drugs at an optimal ratio for maximal synergistic killing efficacy at a single location appears to be a preferred way to resolve this problem. It has been adapted for the treatment of melanoma by formulating CelePlum-777, a nanoliposomal-based agent containing Celecoxib and Plumbagin. The traditional approach of the combined application of both agents was not possible because of poor bioavailability and toxicological complications. The results of research involving the use of CelePlum777 appear promising – it has inhibited xenograft melanoma tumor growth by up to 72% without apparent toxicity and has been more effective at killing melanoma than individual agents applied alone [66]. A similar method has been described in the multiple therapy of glioblastoma. The authors used biodegradable poly-lactide-co-glycolide (PLGA)microspheres (a mean diameter 10-20 µm) containing celecoxib, etoposide, and elacridar. The drugs were encapsulated by an oil/water emulsification solvent evaporation method. The effectiveness of such drug forms was evaluated in a rat

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model. It was found to be an efficient method for the treatment of glioblastoma although the simultaneous drug delivery did not improve the therapeutic outcome [67]. 4. CELECOXIB IN CLINICAL TRIALS Pre-clinical studies have produced highly promising outcomes concerning the anticarcinogenic potential of celecoxib - they have indicated the inhibition of implanted cancer cell growth, a reduction in angiogenesis and the suppression of solid tumor metastases. The results differed according to cancer type, but the majority of tumors responded well to celecoxib administration, with the lowest efficacy reported in lung cancer cells. In general, clinical trials conducted in recent years evaluating the potential role of celecoxib in both prevention and treatment of diverse types of cancer proved the reasonability of its use. 4.1. Colorectal Cancer The largest number of trials have focused on colorectal cancer. The initial ones, conducted several years ago, gave inconsistent results. A great number of them reported a good response to celecoxib treatment, resulting in a reduction of colorectal adenoma recurrence or longer disease-free survival. On the other hand, some failed to show any improvements in the effectiveness of such treatment, prevention or reduction in chemotherapy-induced toxicity [68-70]. Moreover, some authors have indicated that it could increase the risk of gastrointestinal bleeding and of serious cardiovascular events [69, 71]. The results of familial adenomatous polyposis treatment with celecoxib were generally considered promising, which resulted in the U.S. Food and Drug Administration approval for such therapy. It appeared to be a good method for delaying surgery in specific cases of primary adenomas as well as a way of secondary prevention after prophylactic surgery [72]. The most recent trials concerning the prevention and treatment of colorectal cancer have reported satisfactory outcomes. A phase II trial combining celecoxib and preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (stage II or III) was published by Wang LW et al. Patients were treated with celecoxib (400 mg/day), radiotherapy of 44 Gy in 22 fractions, oral tegafur-uracil and folinate. Fifty-three participants completed the treatment with a good response – T or N downstaging was found in 81%, while sphincter preservation in the case of low-positioned tumors was acquired in 77% of the participants. Patients with tumors expressing high levels of COX-2 had shorter diseasefree survival and the overall survival following treatment than those with low-level expression. Therefore, more intensified adjuvant therapy may be considered for tumors with high levels of COX-2 [54]. Wang Y et al. reported a metaanalysis of randomized trials concerning the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on preventing the secondary occurrence of colorectal adenoma. A number of databases had been searched for suitable randomized, double-blind, placebo-controlled trials, published before March 2014, of which nine articles with 8521 subjects, qualified for analysis. The analysis indicated that celecoxib inclusion in the treatment was associated with a significant decrease in adenoma recurrence at 1 and 3 years of follow-

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up and may be effective in the early prevention of adenoma recurrence [73]. Another network meta-analysis of randomized controlled trials concerning the similar treatment of recurrent colorectal adenoma also showed good results. Twenty eligible trials comprising 12,625 participants were included in the meta-analysis conducted between January 2008 and September 2016. The authors of the paper stated that treatment with celecoxib 400 mg/day, low-dose aspirin and calcium was associated with a reduction in colorectal adenoma recurrence, and celecoxib was far more effective than the other investigated medications [74]. 4.2. Breast Cancer Initial clinical trials concerning celecoxib as a treatment method in breast cancer related to chemoprevention, neoadjuvant, adjuvant and metastatic treatment settings and the majority of them focused on the combined treatment with some other chemotherapeutic agents (e.g. trastuzumab, 5fluorouracil, epirubicin, cyclophosphamide or the aromatase inhibitor - exemestane). Despite the fact that some of the results showed a good clinical and pathological response, with longer time to progression achieved and no side effects from the additional administration of celecoxib, epidemiological evidence for the efficacy of this therapy is conflicting [75, 76]. The results of clinical trials conducted in recent years are similar. A trial concerning the efficacy of oral metronomic chemotherapy with cyclophosphamide (50 mg daily) and celecoxib (400 mg - 200 mg twice a day) in advanced breast cancer patients, conducted by Perroud and co-workers, indicated that such therapy was safe and showed a therapeutic effect in advanced breast cancer patients. The overall clinical benefit rate was 46.7%. Progression-free survival at 24 weeks was 40% and the 1-year overall survival rate was 46.7%. Adverse effects were evaluated as mild and the patients' quality of life showed no changes during the response period [77]. The same authors published the results of another trial (a single-arm, mono-institutional, nonrandomised, phase II, two-step clinical trial) concerning metronomic chemotherapy of advanced mammary tumors but that study focused on the co-administration of celecoxib with cyclophosphamide (cyclophosphamide 50 mg daily and celecoxib 200 mg twice a day). Qualified participants completed ≤4 chemotherapy schemes and had good performance status prior to trial commencement. Only twenty patients were enrolled. The proposed treatment was found to be effective, had a low toxicity profile and excellent tolerability. Furthermore, clinical outcomes showed prolonged disease stabilization and partial remission in 10/20 and 1/20 patients, respectively [56]. In another single-center, double-blind phase II study, involving thirty-seven breast cancer patients, presented by Brandão et al., the authors attempted to evaluate gene expression in fresh-frozen pre-surgical biopsies prior to treatment with celecoxib 400mg (or placebo), in comparison to surgical excision specimens (following pharmacotherapy). The study results indicated that short-term celecoxib use in primary breast cancer induced transcriptional programs supporting anti-tumor activity. The impact on proliferation-associated genes was evaluated by a reduction in Ki-67 positive cells - the difference between treatment groups in Ki-67 levels was statistically significant.

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Conversely, cleaved caspase-3 and CD34 expression did not differ significantly between treatment and control groups. Therefore, further clinical testing is needed to explore the possibility of using COX-2 inhibition as a treatment strategy in primary breast cancer [78]. 4.3. Lung Cancer Despite the availability of a variety of treatment methods in this type of malignancy, celecoxib has not been included in any standard therapeutic procedures and its potential anticarcinogenic mechanism is still a matter of debate. Previous preclinical and clinical studies produced inconsistent results in the efficacy of lung cancer treatment with celecoxib. The majority of them concerned palliative treatment. Some of them demonstrated positive outcomes of the combined celecoxib and radiotherapy treatment [79-81]. Recent trials evaluating the advantages of using celecoxib in the treatment of lung cancer have shed more light on the issue. Its beneficial influence depends on the advancement of the disease and the type of medication with which celecoxib is co-administrated. The majority of them suggest that its use does not produce any benefits or provides only a marginal improvement in cancer therapy. Koch et al. presented the results of a double-blind, placebo-controlled multicenter phase III trial at 13 centers in Sweden, involving 316 patients with advanced non-small cell lung cancer (stage IIIB-IV). The participants received celecoxib 400mg twice a day or placebo in addition to standard palliative chemotherapy. The study did not reveal any differences in survival rates between treatment groups. Marginal, although not statistically significant, differences in the overall quality of life and pain were found in the celecoxib group. No increased incidence of cardiovascular events was observed in the celecoxib group [82]. Similar outcomes were demonstrated by Edelman and co-workers, who also evaluated the benefits of such treatment in advanced non-small cell lung cancer (stage IIIB or IV). The study included 322 patients whose tissues showed high COX-2 expression. The participants received standard palliative chemotherapy with the addition of celecoxib (400mg twice per day) or placebo. No significant differences dependent on COX -2 activity were observed between the groups, demonstrating no advantage for COX-2 inhibition in lung cancer treatment [83]. Karen et al. evaluated the combined therapy of celecoxib and erlotinib in patients with stage IIIB/IV non-small cell lung cancer 107 patients whose disease progressed following at least one line of therapy or refused standard chemotherapy. The participants were randomised to receive erlotinib/celecoxib versus erlotinib/placebo. The study demonstrated that combining erlotinib with celecoxib did not improve outcomes in a random population, but selection based on elevated baseline PGEM led to an increase in progression-free survival. Therefore, patients with EGFR wild-type status may benefit from such a combination. Adverse events were similar in both arms [84]. 4.4. Prostate Cancer Outcomes of clinical trials regarding prostate cancer treatment with celecoxib were also ambiguous. All recent publications have focused on combined therapy. However, the majority of them indicate that such therapy may provide

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some advantages, but further investigations are required to elucidate the issue [85, 86]. Newest reports suggest different conclusions. Mason et al. conducted a study concerning the treatment of locally advanced or metastatic prostate cancer. Standard therapy was implemented in each case (Zoledronic acid, hormone therapy and radiotherapy if needed) and combined with celecoxib administration (400 mg, twice a day) for 1 year. A total of 1,245 men were randomly assigned. The collected data showed no convincing evidence of improved survival after celecoxib use [87]. Similar results were reported by James and co-authors, who conducted an international randomised controlled trial, involving 2114 participants with nonmetastatic prostate cancer. The patients were treated using multi-arm, multi-stage methods to evaluate the introduction of 1 or 2 of three agents (docetaxel, zoledronic acid and celecoxib - 400mg twice daily) to standard hormone therapy. The outcomes did not show sufficient effectiveness of combining hormone therapy with celecoxib. Furthermore, the Independent Data Monitoring Committee recommended stopping accrual to this arm as well as ending ongoing treatment [55]. The same effects of celecoxib use were indicated by Kattan et al. in their phase II, open label, multinational prospective trial, evaluating the efficacy of docetaxel (25mg/m(2)) in combination with celecoxib (200mg twice daily) and zoledronic acid (4mg). Twenty two patients with castration-resistant prostate cancer were included in the study. The authors found that the combination of Docetaxel, Celecoxib and Zoledronic acid did not improve overall survival and failed to offer an acceptable biological response [88]. In contrast, Jeong et al. obtained marginally different outcomes from the combined therapy of prostate cancer using celecoxib. They implemented oral metronomic chemotherapy consisting of cyclophosphamide (50 mg daily), dexamethasone (1 mg daily) and celecoxib (200 mg twice a day) in 60 patients with metastatic castration-resistant prostate cancer and found the treatment to be safe, well-tolerated and displaying a promising activity against prostate cancer, although there were no significant differences in the time to PSA progression (TTPSA) between the pre- and postdocetaxel groups [89]. 4.5. Gastric Cancer Only several animal and clinical studies have reported the anticarcinogenic potential of celecoxib in gastric cancer. Previous studies have mainly focused on the chemoprophylactic effect, while its chemotherapeutic potential is still to be confirmed. The authors of published reports have emphasised the cardiovascular risk that celecoxib use potentially increases [90, 91]. The authors of recent studies evaluating the efficacy of celecoxib use in combination with other drugs have obtained conflicting data. Han et al. reported the results of their study in which they examined the effects of combining celecoxib with standard chemotherapy (FOLFOX4) in patients with gastric cancer. The clinical benefits of its use were not assessed. It was only serum VEGF and COX-2 levels, which were assumed to be associated with a poor prognosis, that were investigated. Eighty patients who had undergone laparoscopic radical surgery qualified for the study. The re-

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sults showed no significant differences in serum VEGF and COX-2 levels between the groups prior to chemotherapy, while after 6 cycles of chemotherapy, there was a greater decrease in serum VEGF and COX-2 levels in the combination group compared to the FOLFOX4 group. The authors concluded that the obtained outcomes may indicate a potential therapeutic value through the inhibition of tumor angiogenesis and prevention of recurrence or metastasis [92]. Wong and co-authors conducted a different study. They examined co-therapy consisting of celecoxib administration and anti-H. pylori treatment. 1024 participants aged 35-64 years with a H. pylori infection and advanced gastric lesions were enrolled in the study. They received anti-H. pylori treatment for 7 days, and celecoxib or placebo for 24 months. The results revealed that both celecoxib and H. pylori eradication therapies used independently had beneficial effects on the regression of advanced gastric lesions, but no advantages were seen for the simultaneous treatment [93]. 4.6. Head and Neck Cancer Preclinical studies conducted on animal models have generated a considerable interest in the potential use of COX-2 inhibitors in the chemotherapy of head and neck cancer [94]. Chemoprevention of this type of cancer has also been considered an interesting issue, since it usually develops from dysplastic or premalignant lesions [95]. Recent preclinical studies have delivered promising results. They have demonstrated a positive impact on patient survival, particularly in combined therapy, with minimal toxicity of such treatment [37, 96]. The majority of studies concerned palliative chemotherapy, since the standard treatment method for this type of cancer is surgery followed by radiotherapy. Patil et al. reported significantly increased progressionfree survival and overall survival after oral metronomic chemotherapy (celecoxib, methotrexate and cisplatin) in patients with head and neck cancers requiring palliative chemotherapy. They conducted a randomised phase II trial including 110 patients [97]. Similar results concerning the use of erlotinib instead of cisplatin in palliative metronomic chemotherapy were obtained from a prospective observational study involving 15 patients. Therapy (celecoxib, methotrexate and erlotinib) was continued until the disease progressed or intolerable side-effects occurred. The best, post-MCT response was complete remission in two patients and partial remission in seven patients. Disease stabilisation was observed in four patients, and disease progression in two patients. For a median follow-up of 181 days, there were only three deaths [98]. Opposite effects were observed after similar treatment of oral cancer patients with an early failure (within 1-month of adjuvant radiotherapy or within 6 months of chemoradiation) and/or platinum-insensitive failure - patients received oral methotrexate in combination with celecoxib. Chemotherapy was administered until either the disease progressed or until intolerable side effects appeared. The follow-up was continued until the patients’ death. The results demonstrated that the metronomic combination of methotrexate and celecoxib failed to improve treatment efficacy, as the proportion of patients surviving at 6 months was only 26.4% [99]. The chemopreventive potential of celecoxib has also been evaluated in clinical research, involving patients with precancerous lesions (oral leukoplakia). The

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results of monotherapy with celecoxib provided no evidence of such treatment reducing the risk of oral cancer more than placebo [100]. Distinctly different outcomes were obtained after the combined therapy of celecoxib/erlotinib. A phase I study, involving 12 patients with oral leukoplakia or carcinoma in situ, showed the overall histological response rate in 63% of participants after therapy consisting of erlotinib 3+3 design at 50, 75, and 100mg daily and celecoxib 400mg twice daily. Complete response was observed in 43%, partial response - 14%, disease stabilisation- 29% and disease progression in 14% cases, with the mean of 25.4 months to progression to higher-grade dysplasia or carcinoma. Despite the erlotinib-related rash, which was the main limitation to dose escalation, the therapy was well tolerated [101]. 5. CELECOXIB IN COMBINATION WITH OTHER CHEMOTHERAPEUTICS Combined therapy may provide a therapeutic advantage resulting from a different mechanism of action, in the hope of achieving synergy. The authors of this review quote the results of research concerning multiple-agent treatment consisting of celecoxib and several commonly used chemotherapeutics. 5.1. Cisplatin Cisplatin is a chemotherapeutic drug widely used in the treatment of several types of cancer (including gastric, testicular, ovarian, cervical, breast, bladder, head and neck, oesophageal and lung cancers). It interferes with DNA replication and affects the fastest proliferating cells, which in theory are carcinogenic [102]. It has been successfully used with other chemotherapeutics in combined therapy. Studies investigating its simultaneous administration with celecoxib have produced diverse results. Some research has proven that such therapy significantly decreases cell proliferation and induces apoptosis [8, 103]. It would be particularly important in cisplatin-resistant cells as the overexpression of cyclooxygenase-2 has been found in these types of cells. Xu et al., on the basis of their in vitro research regarding the issue, suggested that cyclooxygenase-2 may be involved in the development of P-glycoprotein-mediated drug resistance and celecoxib application, through the inhibition of this enzyme, may enhance the cytotoxic effect of chemotherapeutic agents. They demonstrated that the celecoxib-induced apoptosis of drug-resistant gastric cancer cells led to increased p53 expression, decreased Bcl-2/Bax ratio and up-regulation of caspase-3 level [103]. In their subsequent study, the authors confirmed similar activity of celecoxib in vivo on the xenograft mouse model. Furthermore, following the coadministration of cisplatin and celecoxib, Ki67 and PCNA levels were significantly lower when compared with those of cisplatin treatment alone [8]. Another study concerning the benefits of using celecoxib in cisplatin-resistant cells showed different results. During the evaluation of cell viability of oesophageal cisplatin-resistant cell lines exposed to carboplatin alone or the combination of carboplatin and celecoxib, the authors found that celecoxib antagonized the cytotoxic effect of carboplatin and inhibited carboplatin-induced apoptosis by reducing intracellular carboplatin accumulation. Celecoxib notably increased the IC50 of carboplatin, suppressed carboplatin-induced caspase-3 activity and cleavage

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of PARP (Poly ADP ribose polymerase, involved in DNA repair). Moreover, combined exposure to both drugs did not cause significant changes in the protein expression of CTR1 (playing a key role in the cellular transport of antineoplastic drugs containing platinum ions) [104]. Chen and co-authors showed similar results. They demonstrated that combined treatment did not elicit greater antitumor activity than cisplatin or celecoxib monotherapy. In their research conducted on a gastric cancer xenograft model, they also found that celecoxib antagonized cisplatin-induced cytotoxicity and apoptosis, decreased whole-cell cisplatin accumulation and DNA platination. The authors suggested a COX-2independent mechanism, as indomethancin and nimesulide exerted no effect [105]. 5.2. 5-fluorouracil 5-fluorouracil is a commonly used chemotherapeutic, anti-metabolite, administered systemically in several types of cancer such as breast, colorectal, oesophageal, stomach, pancreatic, head and neck cancers [106]. However, drugresistance in cancer cells greatly limits its efficacy. A few potential mechanisms of this process in some cancer cell lines have been described in the literature, such as p53 function loss, NF-kappaB over-expression or the BNIP3 gene silencing [107, 108]. The results of some research also indicates higher cyclooxygenase 2 (COX-2) expression. Rahman and co-authors observed this effect in chemoresistant colorectal cancer cells and tumor xenografts. The authors showed that major tumor regression was achieved in examined xenografts after chemotherapy consisting of 5-fluorouracil in combination with celecoxib and this effect correlated with COX-2 expression. A synergistic effect with 5-FU was found only with celecoxib but not aspirin [109]. The potential of celecoxib to reduce resistance to 5-FU chemotherapy in cancer cells has also been reported by Zhang et al. in the results of their two research studies. In both, conducted on hypoxic gastric cancer cell lines and gastric cancer xenografts, the authors demonstrated that treatment with the 5-FU/celecoxib combination resulted in a significantly higher inhibition rate than in cells treated with each drug individually. Moreover, cells which received the combined treatment and after celecoxib administration showed lower expression levels of HIF-2α, ABCG2 and Oct-4 in comparison to 5-FU-treated cells and to controls [110, 111]. Another effect of the simultaneous use of celecoxib and 5fluorouracil has been described by Sung et al. The authors observed enhanced inhibition of cell proliferation when both drugs were combined, which was positively correlated with an increase in reactive oxygen species (ROS) production. Furthermore, increased survival time was observed in an orthotopic mouse model compared to treatment with either agent alone. The authors indicated that AKT pathway inhibition and increased ROS production may be a key mechanism in this combination therapy [112]. The described findings point to a potential benefit of combining COX-2 inhibitors with 5-fluorouracil and suggest that it can be a potential method of reducing chemotherapy resistance and enhancing the effectiveness of chemotherapy treatment. 5.3. Cetuximab Cetuximab is a chimeric (mouse/human) monoclonal antibody, an inhibitor of the epidermal growth factor recep-

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tor (EGFR). It is used in the treatment of EGFR-expressing metastatic colorectal cancer, metastatic non-small cell lung cancer and head and neck cancer [113]. The results of two studies evaluating the inhibitory potency of the EGFR pathway obtained by co-administration of cetuximab and celecoxib showed promising results. Such a combination was found to significantly suppress the proliferation, migration, and invasion of oral squamous cell carcinoma cells, downregulate PEG2 production and VEGF expression in vitro as well as inhibit tumor growth in vivo, in comparison to the treatment with either medication alone. Furthermore, simultaneous therapy with both agents induced apoptosis and increased caspase-3 and caspase-8 activity, reduced the expression of p-EGFR, p-PI3K and p-Akt in cancer cells, which may contribute to the inhibition of tumor growth [114]. Research concerning chemotherapy in colorectal cancer has produced similar results. The authors have suggested that combining cetuximab with celecoxib improves the efficacy of the former to induce apoptosis and to inhibit cancer cell proliferation. Moreover, such therapy was more efficient than either treatment alone in reducing tumor volume in a mouse xenograft model. The authors are of the opinion that the described effects are related to the impairment of EGFRRAS-FOXM1-β-catenin signaling axis [115]. In conclusion, the combination of cetuximab and celecoxib may constitute a potential cancer therapy, but further research and clinical trials are needed. 5.4. Tyrosine Kinase Inhibitors Tyrosine kinases and its improper activation play a major role in the process of carcinogenesis based on pathological intracellular signal transduction, cell growth regulation , differentiation, adhesion, motility, death, and others. Thus, the use of drugs which block or attenuate this enzyme activity provides a possibility in cancer therapy [116]. Selected tyrosine kinase inhibitors may be used in combined treatment to improve its anti-cancer effects or may play a role in decreasing toxicity and resistance to treatment. There are reports in the recent literature regarding the combined administration of celecoxib and tyrosine kinase inhibitors. A chemotherapeutic strategy combining erlotinib – an epidermal growth factor receptor and tyrosine kinase inhibitor with celecoxib used in the treatment of head and neck cancer has significantly inhibited cancer cell growth and arrested cell cycle at G1. The effect was more pronounced than when either agent was used alone. An in vivo study examining tissue samples collected from participants confirmed this results. Furthermore, it demonstrated the downregulation of EGFR, pERK and pS6 levels after the proposed therapy, which correlated with clinical treatment outcomes - the overall pathological response rate reached 71%. The authors suggested that the described effects were associated with the modulation of EGFR and mTOR signaling pathways [117]. Combining imatinib, another tyrosine kinase inhibitor, with celecoxib has also been found to be effective. An in vitro study with colon cancer cell lines demonstrated that the combined therapy improved the anticancer activity of each component – it significantly reduced cell viability and increased caspase-3 enzyme activity. Decreased COX-2 gene expression was found in celecoxib and combined therapy groups, while an increase in caspase-3 gene expression was observed in

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imatinib and in cells treated with both drugs. The authors stated that caspase-3 and COX-2 dependent molecular targets seemed to be involved in mediating the antiproliferative effects of the combination of both medications [118]. Valverde et al. also presented the results of in vitro research exploring the issue of whether the simultaneous administration of tyrosine kinase inhibitor, targeting EGFR/ VEGF, and cyclooxygenase-2 inhibitor may improve the treatment of patients with metastatic colorectal cancer. The combined treatment of celecoxib and AEE788 was used in the study. Besides the effects achieved by the administration of the mentioned medications separately (such as inhibition of cell proliferation, induction of apoptosis and G1 cell cycle arrest, downregulation of VEGF production by cancer cells and reduction of cell migration), the authors found that the combined AEE788/celecoxib treatment prevented β-catenin nuclear accumulation in tumor cells, reduced the expression of stem cell markers Oct 3/4, Nanog, Sox-2 and Snail in cancer cells and promoted the diminution of the cancer stem cells subpopulation [119]. 5.5. Other Drugs Fewer research results concerning the combined therapy of celecoxib with chemotherapeutics other than those previously mentioned have been reported lately in the literature. Maji with co-authors described beneficial outcomes of the simultaneous use of celecoxib and Sabutoclax, which significantly inhibited the growth of oral squamous cell carcinoma in vitro and also notably reduced tumor growth in vivo (OSCC mouse model). The authors suggested that this effect may be connected with knocking down Mcl-1 (one of the apoptotic Bcl-2 family proteins) which is responsible for resistance to cell death [120]. Another medication which also showed good results in combination with celecoxib in head and neck cancer treatment was methotrexate. Vijay et al. presented the results of a retrospective analysis of patients who received palliative metronomic chemotherapy consisting of methotrexate and celecoxib, with satisfactory outcomes, similar to those seen in head and neck cancers [121]. The usefulness of celecoxib has also been proven in cotreatment with paclitaxel in paclitaxel-resistant oral cancer cells. The results of a study by Janakiraman et al., both in vitro and in vivo, showed that specific inhibition of COX-2 by celecoxib promoted apoptosis through the activation of caspase-3 and cleavage of HuR (its high level was involved in paclitaxel-resistance) [122]. Other beneficial properties of celecoxib in combined therapy were reported by Kumar et al. In co-administration with tamoxifen, it suppressed VEGF gene expression, which appears to be important as tamoxifen in monotherapy increases VEGF levels in patients, promoting new blood vessel formation and thereby limiting its efficacy. The results of this in vitro study, besides the downregulation of VEGF level, also demonstrated decreased expression of Src (a family of kinases responsible for tumor progression and metastasis) as well as a significant increase in reactive oxygen species levels. Notably stronger effects were observed after combined treatment than therapy with tamoxifen alone. The authors concluded that the proposed therapy allowed for a reduction in dosage of both drugs and it may be a potential candidate for the treatment of breast tumors expressing high VEGF levels [123].

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The combined administration of celecoxib and other selected chemotherapeutics has produced promising outcomes in anti-carcinogenic, apoptotic and anti-metastatic studies. It appears particularly significant in the colorectal, head and neck and breast cancers. However, this issue needs a further evaluation in clinical trials. 6. CELECOXIB AS A RADIOSENSITIZER The issue of a potential radiosensitizing effect of celecoxib on several types of cancer has been raised in the literature lately. In most cases, mechanisms associated with COX2 inhibition have been considered a potential factor responsible for this effect since the increased activity of this enzyme has resulted in tumor resistance to radiotherapy [124]. The authors of such papers have attempted to elucidate molecular mechanisms mediating this process. Zhang et al. have suggested that it is related to COX-2 activity. In their research conducted on nasopharyngeal carcinoma xenograft models, they showed that celecoxib enhanced radiation cytotoxicity in cancer cells which expressed high levels of COX2 (C666-1 and CNE-1) but not in CNE-2 cells, which expressed low levels of this enzyme. Furthermore, they indicated a correlation between radiosensitivity of celecoxib and the induction of apoptosis. Combining celecoxib administration (25 mg/kg) and radiation (6 Gy) treatment significantly reduced tumor volume. Moreover, celecoxib enhanced radiation-induced cell cycle arrest in the G2-M phase [125]. Similar outcomes have been observed by Yusup and co-authors, who have also stated that tumor response to radiotherapy is connected with COX-2 activity. They presented the results of a study in which the effect of celecoxib was examined on oesophageal squamous cell carcinoma (ESCC). Celecoxib enhanced the antitumor effects of radiotherapy and chemotherapy (5-FU) by the inhibition of both cell invasion and migration activity [126]. Another study confirming the correlation between COX-2 inhibition and an improved response to radiotherapy was conducted by Han et al. on lung cancer cells (A549). The authors demonstrated that irradiation as a single method caused only marginal suppression of cell proliferation in comparison to the combined treatment with celecoxib and X-ray radiation [127]. The inhibition of the tumor cell population with an increase in apoptosis during simultaneous radiotherapy (12 to 18 fractions of 3.0 Gy daily or every second day) and celecoxib administration (100 mg/ kg/day) has also been proven in the treatment of FaDu (hypopharyngeal) squamous cell carcinoma in nude mice [128]. Another mechanism of the radiosensitizing potential of celecoxib has been described by Xu with co-authors, in their research conducted on three different cell lines - HeLa (human cervical cancer), A549 (human lung cancer), and HCT116 cells (human colorectal cancer). They found that celecoxib enhanced the radiosensitivity of HeLa, A549 and HCT116 cell lines. COX-2 expression was undetected in HCT116 cells but celecoxib significantly increased BCCIP gene expression in this type of cancer. The fact that, after blocking this gene, the radiosensitivity of HCT116 cells induced by celecoxib was abrogated suggests that BCCIP may be a radiosensitivity-related gene in colorectal cancer. Moreover, the combination of celecoxib and radiotherapy induced far more γ-H2AX foci formation, higher levels of radiation injury-related proteins phosphorylation, G2/M ar-

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rest, apoptosis, and p53 and p21 expression, and lower levels of Cyclin B1 in HCT116 cells in comparison with those in cells treated with irradiation alone. Such changes have not been observed in BCCIP-silenced HCT116 cells [129]. The radiosensitizing effect of celecoxib used in combined therapy with another anti-chemotherapeutic drug - Hydroxystaurosporine (UCN-01) has been investigated by Kim et al. in human lung cancer cell lines. UCN-01 is a Chk1-specific inhibitor which has demonstrated a promising chemo- and radiosensitizing activity, although with severe side effects. The results of this study indicated that the synergistic application of both drugs induced cytotoxicity and radiosensitizing effects in lung cancer cell lines. Furthermore, it inhibited IR-induced G(2)/M arrest and increased the G(2) to mitotic transition [130]. A different potential model of enhancing radiosensitivity by celecoxib, including another chemotherapeutic, was proposed by Pal and co-authors. Based on the assumption that the amplification of PI3K-Akt pathway promotes radioresistance, they examined the effect of combined therapy with celecoxib and BI-69A11, a small molecule inhibitor of Akt, followed by irradiation. The authors suggested that the combination of both drugs inhibited the phosphorylation of ataxia telangiectasia mutated (ATM) kinase and DNA-PK responsible for ionizing radiation (IR)induced double-strand break (DSB) repair. Moreover, it impaired IR-induced G2/M cell cycle arrest and reduced IRinduced activation of Akt and downstream targets of ATM [131]. Similar results were obtained by Sun et al. as well as Fu and co-authors (using lung cancer cells and head and neck cancer cells, respectively). Both studies regarded the combined therapy consisting of celecoxib, erlotinib and radiation. The results showed more effective inhibition of tumor growth following the aforementioned treatment in comparison to single-agent therapy. The authors also indicated the inhibition of the PI3K/AKT signalling pathway as a possible mechanism underlying this process [132, 133]. Moreover, Sun et al. demonstrated that the antitumor effect was associated with the inhibition of cell colony formation and the induction of G0/G1 phase arrest, as well as the reduction of S phase [132]. In addition, Fu and co-authors described enhanced inhibition of several pro-survival proteins (including p-ERK1/2, p-EGFR, p-AKT, p-STAT3, COX-2 and PGE-2) following the combined treatment in comparison to single-agent therapy [133]. The results of the cited research confirmed the radiosensitizing potential of celecoxib, in mechanisms dependent and independent of COX-2 activity. These observations may have important therapeutic implications and need to be thoroughly examined in future clinical trials. CONCLUSION Both preclinical and clinical studies have demonstrated promising results of the role of celecoxib in the treatment and prevention of cancer. Therapeutic effects described in the present paper differed according to the type and stage of cancer – the best outcome was observed in colon, breast, prostate and head and neck cancers. Precancerous lesions such as familial adenoma polyposis as well as tumors qualified for palliative therapy appear to be targeted for such treatment, particularly in combination with other chemotherapeutics and radiotherapy. However, more clinical

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trials providing real evidence-based clinical advances of celecoxib use are needed. LIST OF ABBREVIATIONS iNOS MMP-2 MMP-9 PPARγ PGD2 15d-PGJ2 EMT CDH-1 SIP1 ZEB1 AMFR E-box DNA ICAM LAK LFA-1

= = = = = = = = = = = = = = =

NF-kB

=

JNK AR PyMT PLGA CRT PSA TTPSA

= = = = = = =

FOLFOX4

=

PCNA IC50 PARP CTR1 HIF 1α ABCG2

= = = = = =

Oct 4 5-FU ROS AKT PI3K

= = = = =

Inducible nitric oxide synthase Matrix metalloproteinases 2 Matrix metalloproteinases 9 Peroxisome proliferator-activated receptor γ Prostaglandin D2 15-Deoxy-Delta-12,14-prostaglandin J2 Epithelial-to-mesenchymal transition Cadherin-1 Smad interacting protein 1 Zinc Finger E-Box Binding Homeobox 1, Autocrine motility factor receptor Enhancer box DNA Intercellular adhesion molecules Lymphokine-activated killer Crosslink- lymphocyte function-associated molecule-1 Nuclear factor of kappa light polypeptide gene enhancer in B-cells jun-N-terminal kinase Androgen receptor Polyoma middle T oncogene Poly-lactide-co-glycolide Chemoradiotherapy Prostate-specific antigen Time to prostate-specific antigen progression Chemotherapy regimen: FOL– Folinic acid (leucovorin), F – Fluorouracil (5-FU), OX – Oxaliplatin (Eloxatin) Proliferating cell nuclear antigen Half maximal inhibitory concentration Poly ADP ribose polymerase High affinity copper uptake protein 1 Hypoxia-inducible factor 1 alpha ATP-binding cassette sub-family G member 2 Octamer-binding transcription factor 4 5-fluorouracil Reactive oxygen species Protein kinase B Phosphatidylinositol-4,5-bisphosphate 3kinase

EGFR-RASFOXM1β-catenin = Signaling axis: epidermal growth factor receptor-ras protein- Forkhead box protein M1-β-catenin signaling axis pERK = Cytokine-mediated phosphorylation of Erk mTOR = Signaling pathways: mammalian target of rapamycin signaling pathway Oct ¾ = Octamer 3/4 OSCC = Oral squamous cell carcinoma HuR = Hu-antigen R ESCC = Esophageal squamous cell carcinoma UCN-01 = Hydroxystaurosporine

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Chk1 ATM IR DSB

= = = =

Checkpoint kinases 1 Ataxia telangiectasia mutated Ionizing radiation Double-strand break

CONSENT FOR PUBLICATION

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[16]

[17]

Not applicable. CONFLICT OF INTEREST

[18]

The authors declare no conflict of interest, financial or otherwise.

[19]

ACKNOWLEDGEMENTS The authors would like to thank Ms. J. MacDonald for the professional language revision of the manuscript.

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AUTHOR CONTRIBUTION Natalia Tołoczko-Iwaniuk, Dorota DziemiańczykPakieła, Katarzyna Celińska-Janowicz and Beata Klaudia Nowaszewska searched and analyzed the literature. Natalia Tołoczko-Iwaniuk and Wojciech Miltyk wrote the paper. All authors read and approved the final manuscript. REFERENCES [1] [2]

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