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Huang Z, Huang L, Zhang C, Chen G, Mai H. Blocking β2-AR and Inhibiting COX-2: A Promising Approach to Suppress OSCC Development. Int Dent J 2025; 75:807-816. [PMID: 39043526 PMCID: PMC11976482 DOI: 10.1016/j.identj.2024.06.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 06/22/2024] [Accepted: 06/25/2024] [Indexed: 07/25/2024] Open
Abstract
OBJECTIVES β2-adrenergic receptor (β2-AR) and cyclooxygenase-2 (COX-2) are overexpressed in various malignant tumours including oral squamous cell carcinoma (OSCC), suggesting that they may contribute to the development of OSCC. This study aims to investigate the potential synergistic effect of β2-AR blockade and COX-2 inhibition on suppressing the development of OSCC. METHODS Effects of blocking β2-AR and inhibiting COX-2 on migration and invasion of OSCC cells were detected by wound-healing assay and transwell invasion assay. Western blot and enzyme-linked immunosorbent assay (ELISA) were used to detect the expression of genes related to the progression of OSCC. In vivo, OSCC xenograft models were established to evaluate the effect of combined treatment on survival time, tumour size, and submandibular lymph node metastasis. Immunohistochemistry, Western blot, and ELISA were used to detect the expression of invasion and metastasis relative genes. RESULTS In vitro, blocking β2-AR or inhibiting COX-2 alone could suppress invasion and metastasis of OSCC cells, and suppression with combined treatment was more significant. Expression of genes related to invasion and metastasis, including EGFR, TGF-β1, IL-1β, MMP2, and VEGFA, were downregulated significantly, especially in the combined treatment group. In vivo, the combined treatment could significantly prolong survival time in tumour-bearing mice and inhibit the growth of tumours. Furthermore, submandibular lymph node metastasis was less in the combined treatment group, and expression of the abovementioned genes was also downregulated. CONCLUSIONS The combination of β2-AR blockade and COX-2 inhibition can significantly suppress the development of OSCC via downregulating EGFR, TGF-β1, IL-1β, MMP2, and VEGFA. Findings suggest that the combined use of a β2-AR blocker and a COX-2 inhibitor could be a promising adjuvant therapy in OSCC. Both drugs are commonly prescribed, and their safety and efficacy are well established. Their use in adjuvants in OSCC should therefore be promoted in clinical practice.
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Affiliation(s)
- Zeliu Huang
- Department of Oral and Maxillofacial Surgery, College and Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, Guangxi, China; Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, Guangxi, China
| | - Laifeng Huang
- Department of Oral and Maxillofacial Surgery, College and Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, Guangxi, China; Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, Guangxi, China
| | - Chong Zhang
- Department of Oral and Maxillofacial Surgery, College and Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, Guangxi, China; Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, Guangxi, China
| | - Guosheng Chen
- Department of Oral and Maxillofacial Surgery, College and Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, Guangxi, China; Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, Guangxi, China
| | - Huaming Mai
- Department of Oral and Maxillofacial Surgery, College and Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, Guangxi, China; Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, Guangxi, China; Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, Guangxi, China.
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Wang M, Chen S, He X, Yuan Y, Wei X. Targeting inflammation as cancer therapy. J Hematol Oncol 2024; 17:13. [PMID: 38520006 PMCID: PMC10960486 DOI: 10.1186/s13045-024-01528-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 02/07/2024] [Indexed: 03/25/2024] Open
Abstract
Inflammation has accompanied human beings since the emergence of wounds and infections. In the past decades, numerous efforts have been undertaken to explore the potential role of inflammation in cancer, from tumor development, invasion, and metastasis to the resistance of tumors to treatment. Inflammation-targeted agents not only demonstrate the potential to suppress cancer development, but also to improve the efficacy of other therapeutic modalities. In this review, we describe the highly dynamic and complex inflammatory tumor microenvironment, with discussion on key inflammation mediators in cancer including inflammatory cells, inflammatory cytokines, and their downstream intracellular pathways. In addition, we especially address the role of inflammation in cancer development and highlight the action mechanisms of inflammation-targeted therapies in antitumor response. Finally, we summarize the results from both preclinical and clinical studies up to date to illustrate the translation potential of inflammation-targeted therapies.
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Affiliation(s)
- Manni Wang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No.17, Block3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Siyuan Chen
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No.17, Block3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Xuemei He
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No.17, Block3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yong Yuan
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No.17, Block3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China.
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Benjamin DJ, Haslam A, Prasad V. Cardiovascular/anti-inflammatory drugs repurposed for treating or preventing cancer: A systematic review and meta-analysis of randomized trials. Cancer Med 2024; 13:e7049. [PMID: 38491813 PMCID: PMC10943275 DOI: 10.1002/cam4.7049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 01/09/2024] [Accepted: 02/08/2024] [Indexed: 03/18/2024] Open
Abstract
BACKGROUND Due to encouraging pre-clinical data and supportive observational studies, there has been growing interest in applying cardiovascular drugs (including aspirin, angiotensin-converting enzyme [ACE] inhibitors, statins, and metformin) approved to treat diseases such as hypertension, hyperlipidemia, and diabetes mellitus to the field of oncology. Moreover, given growing costs with cancer care, these medications have offered a potentially more affordable avenue to treat or prevent recurrence of cancer. We sought to investigate the anti-cancer effects of drugs repurposed from cardiology or anti-inflammatories to treat cancer. We specifically evaluated the following drug classes: HMG-CoA reductase inhibitors (statins), cyclo-oxygenase inhibitors, aspirin, metformin, and both angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors. We also included non-steroidal anti-inflammatory drugs (NSAIDs) because they exert a similar mechanism to aspirin by blocking prostaglandins and reducing inflammation that is thought to promote the development of cancer. METHODS We performed a systematic literature review using PubMed and Web of Science with search terms including "aspirin," "NSAID," "statin" (including specific statin drug names), "metformin," "ACE inhibitors," and "ARBs" (including specific anti-hypertensive drug names) in combination with "cancer." Searches were limited to human studies published between 2000 and 2023. MAIN OUTCOMES AND MEASURES The number and percentage of studies reported positive results and pooled estimates of overall survival, progression-free survival, response, and disease-free survival. RESULTS We reviewed 3094 titles and included 67 randomized clinical trials. The most common drugs that were tested were metformin (n = 21; 30.9%), celecoxib (n = 20; 29.4%), and simvastatin (n = 8; 11.8%). There was only one study that tested cardiac glycosides and none that studied ACE inhibitors. The most common tumor types were non-small-cell lung cancer (n = 19; 27.9%); breast (n = 8; 20.6%), colorectal (n = 7; 10.3%), and hepatocellular (n = 6; 8.8%). Most studies were conducted in a phase II trial (n = 38; 55.9%). Most studies were tested in metastatic cancers (n = 49; 72.1%) and in the first-line setting (n = 36; 521.9%). Four studies (5.9%) were stopped early because of difficulty with accrual. The majority of studies did not demonstrate an improvement in either progression-free survival (86.1% of studies testing progression-free survival) or in overall survival (94.3% of studies testing overall survival). Progression-free survival was improved in five studies (7.4%), and overall survival was improved in three studies (4.4%). Overall survival was significantly worse in two studies (3.8% of studies testing overall survival), and progression-free survival was worse in one study (2.8% of studies testing progression-free survival). CONCLUSIONS AND RELEVANCE Despite promising pre-clinical and population-based data, cardiovascular drugs and anti-inflammatory medications have overall not demonstrated benefit in the treatment or preventing recurrence of cancer. These findings may help guide future potential clinical trials involving these medications when applied in oncology.
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Affiliation(s)
| | - Alyson Haslam
- Department of Epidemiology and BiostatisticsUniversity of CaliforniaSan FranciscoCaliforniaUnited States
| | - Vinay Prasad
- Department of Epidemiology and BiostatisticsUniversity of CaliforniaSan FranciscoCaliforniaUnited States
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Bąk U, Krupa A. Challenges and Opportunities for Celecoxib Repurposing. Pharm Res 2023; 40:2329-2345. [PMID: 37552383 PMCID: PMC10661717 DOI: 10.1007/s11095-023-03571-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 07/18/2023] [Indexed: 08/09/2023]
Abstract
Drug repositioning, also known as drug repurposing, reprofiling, or rediscovery, is considered to be one of the most promising strategies to accelerate the development of new original drug products. Multiple examples of successful rediscovery or therapeutic switching of old molecules that did not show clinical benefits or safety in initial trials encourage the following of the discovery of new therapeutic pathways for them. This review summarizes the efforts that have been made, mostly over the last decade, to identify new therapeutic targets for celecoxib. To achieve this goal, records gathered in MEDLINE PubMed and Scopus databases along with the registry of clinical trials by the US National Library of Medicine at the U.S. National Institutes of Health were explored. Since celecoxib is a non-steroidal anti-inflammatory drug that represents the class of selective COX-2 inhibitors (coxibs), its clinical potential in metronomic cancer therapy, the treatment of mental disorders, or infectious diseases has been discussed. In the end, the perspective of a formulator, facing various challenges related to unfavorable physicochemical properties of celecoxib upon the development of new oral dosage forms, long-acting injectables, and topical formulations, including the latest trends in the pharmaceutical technology, such as the application of mesoporous carriers, biodegradable microparticles, lipid-based nanosystems, or spanlastics, was presented.
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Affiliation(s)
- Urszula Bąk
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Cracow, Poland
| | - Anna Krupa
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Cracow, Poland.
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Chan SHY, Khatib Y, Webley S, Layton D, Salek S. Identification of cardiotoxicity related to non-small cell lung cancer (NSCLC) treatments: A systematic review. Front Pharmacol 2023; 14:1137983. [PMID: 37383708 PMCID: PMC10294714 DOI: 10.3389/fphar.2023.1137983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 03/27/2023] [Indexed: 06/30/2023] Open
Abstract
Introduction: In the last few decades, there has been a rapid development in cancer therapies and improved detection strategies, hence the death rates caused by cancer have decreased. However, it has been reported that cardiovascular disease has become the second leading cause of long-term morbidity and fatality among cancer survivors. Cardiotoxicity from anticancer drugs affects the heart's function and structure and can occur during any stage of the cancer treatments, which leads to the development of cardiovascular disease. Objectives: To investigate the association between anticancer drugs for non-small cell lung cancer (NSCLC) and cardiotoxicity as to whether: different classes of anticancer drugs demonstrate different cardiotoxicity potentials; different dosages of the same drug in initial treatment affect the degree of cardiotoxicity; and accumulated dosage and/or duration of treatments affect the degree of cardiotoxicity. Methods: This systematic review included studies involving patients over 18 years old with NSCLC and excluded studies in which patients' treatments involve radiotherapy only. Electronic databases and registers including Cochrane Library, National Cancer Institute (NCI) Database, PubMed, Scopus, Web of Science, ClinicalTrials.gov and the European Union Clinical Trials Register were systematically searched from the earliest available date up until November 2020. A full version protocol of this systematic review (CRD42020191760) had been published on PROSPERO. Results: A total of 1785 records were identified using specific search terms through the databases and registers; 74 eligible studies were included for data extraction. Based on data extracted from the included studies, anticancer drugs for NSCLC that are associated with cardiovascular events include bevacizumab, carboplatin, cisplatin, crizotinib, docetaxel, erlotinib, gemcitabine and paclitaxel. Hypertension was the most reported cardiotoxicity as 30 studies documented this cardiovascular adverse event. Other reported treatment-related cardiotoxicities include arrhythmias, atrial fibrillation, bradycardia, cardiac arrest, cardiac failure, coronary artery disease, heart failure, ischemia, left ventricular dysfunction, myocardial infarction, palpitations, and tachycardia. Conclusion: The findings of this systematic review have provided a better understanding of the possible association between cardiotoxicities and anticancer drugs for NSCLC. Whilst variation is observed across different drug classes, the lack of information available on cardiac monitoring can result in underestimation of this association. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020191760, identifier PROSPERO CRD42020191760.
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Affiliation(s)
- Stefanie Ho Yi Chan
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom
| | - Yasmin Khatib
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom
| | - Sherael Webley
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom
| | - Deborah Layton
- IQVIA UK, London, United Kingdom
- PEPI Consultancy Limited, Southampton, United Kingdom
- University of Keele, Keele, United Kingdom
| | - Sam Salek
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom
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Li L, Zhang Y, Qin L. Effect of celecoxib plus standard chemotherapy on cancer prognosis: A systematic review and meta-analysis. Eur J Clin Invest 2023; 53:e13973. [PMID: 36807298 DOI: 10.1111/eci.13973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 01/31/2023] [Accepted: 02/09/2023] [Indexed: 02/20/2023]
Abstract
BACKGROUND Inflammation is closely related to cancer prognosis. The effect of celecoxib, a nonsteroidal anti-inflammatory drug, on the prognosis of patients with cancer remains uncertain. To assess the association between celecoxib plus standard chemotherapy and cancer prognosis, we conducted a systematic review and meta-analysis of published studies. METHODS PubMed, EMBASE, and the Cochrane Library were searched from inception until July 2022 for randomized controlled trials reporting the prognosis of patients with cancer treated with celecoxib plus standard chemotherapy. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Meta-analysis was performed using Review Manager software version 5.4. The following search terms were used in the databases: ((((celecoxib)) AND ((((((((cancer) OR (carcinoma)) OR (sarcoma)) OR (neoplasms)) OR (tumor)) OR (tumour)) OR (tumors)) OR (tumours))) AND ((survival) OR (mortality))) AND (((Clinical Trials, Randomized) OR (Trials, Randomized Clinical)) OR (Controlled Clinical Trials, Randomized)). RESULTS Overall, 13 randomized controlled trials, including 8957 patients with cancer, were included in the analysis. Compared to conventional chemotherapy alone, 1-year OS and 1-year PFS rates were not significantly improved with celecoxib adjuvant therapy (OS: p = .38; PFS: p = .65). In addition, no differences were observed between the celecoxib and placebo groups in 3-year overall (p = .98), 3-year progression-free (p = .40), 5-year overall (p = .59), or 5-year progression-free (p = .56) survival rates. An increase in the risk ratio of leukopenia (p = .02) and thrombocytopenia (p = .05) was also observed, suggesting that celecoxib promotes hematologic toxicity. No increased risk of cardiovascular (p = .96) and gastrointestinal (p = .10-.91) events was observed. CONCLUSIONS The addition of celecoxib to standard chemotherapy did not improve OS or PFS rates of patients with cancer. Additionally, celecoxib can increase hematologic toxicity without increasing the risk of gastrointestinal or cardiovascular reactions. Further randomized controlled trials are necessary to clarify its effects and applications.
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Affiliation(s)
- Liangyu Li
- Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Yingrui Zhang
- Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Lizheng Qin
- Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
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Mitrіaіeva NA, Grebinyk LV, Bilozor NV, Starenkyі VP. The content of VEGF, COX-2 and PGE-2 in the blood serum of patients with non-small cell lung cancer with different schemes of conformal radiotherapy in the dynamics of treatment. УКРАЇНСЬКИЙ РАДІОЛОГІЧНИЙ ТА ОНКОЛОГІЧНИЙ ЖУРНАЛ 2022. [DOI: 10.46879/ukroj.3.2022.33-40] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background. Overcoming radioresistance is an important problem in radiation oncology. Therefore, the development of new approaches to modeling the radiosensitivity of tumors in cancer patients becomes relevant and important. Cyclooxygenase-2 (COX-2) inhibitors are new agents for radiomodification in various radiation therapy schemes, the use of which slows down angiogenesis by suppressing the activity of the COX-2 enzyme.
Purpose. To determine the content of indicators of radioresistance: vascular endothelial growth factor (VEGF), COX-2, prostaglandin E-2 (PGE-2) in the blood serum of patients with non-small cell lung cancer (NSCLC) and changes in their levels with different schemes of radiation therapy (RT).
Materials and methods. 36 patients with NSCLC were examined and treated, who were divided into four groups: RT (the first group – 16 patients), RT with the COX-2 inhibitor – ranselex (the second group – 9 patients), RT with ranselex and cisplatin (the third group – 5 patients ) and RT with cisplatin (fourth group – 6 patients). The patients received a course of radiation treatment using a Clinac 600C linear accelerator. The classical fractionation mode was used, the total focal doses were 60–66 Gy. Cisplatin was prescribed at 30 mg/m2 per week up to a total dose (SD) of 200 mg, the COX-2 inhibitor Rancelex® at a dose of 100 mg per day (active substance – celecoxib). The levels of VEGF, COX-2, and PGE-2 in the blood serum of patients with NSCLC were determined by enzyme-linked immunosorbent assay (ELISA) before and after treatment.
Results. The level of the angiogenesis marker VEGF after treatment in the group with RT decreases by 1.46 times, in the group with the combined action of RT and ranselex – 2.4 times, in the group with the combined action of PT, ranselex and cisplatin – by 3.7 times, and in the group with the combined effect of RT and cisplatin, it decreases by 1.1 times. The greatest decrease in the level of VEGF is observed with RT in combination with ranselex and cisplatin, which indicates a more effective enhancement of the antiangiogenic effect.
Conclusions. It has been proven that with various schemes of RT using the COX-2 inhibitor – ranselex and cisplatin in patients with NSCLC, there is a decrease in the radioresistance markers PGE-2 and COX-2, the angiogenesis marker – VEGF, which indicates that the effect of radiomodification on the angiogenesis process is most pronounced in the combined actions of RT and both radio modifiers. The use of COX-2 inhibitors as radiosensitizers in combination with RT provides a new opportunity to increase tumor radiosensitivity.
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Ye SY, Li JY, Li TH, Song YX, Sun JX, Chen XW, Zhao JH, Li Y, Wu ZH, Gao P, Huang XZ. The Efficacy and Safety of Celecoxib in Addition to Standard Cancer Therapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Curr Oncol 2022; 29:6137-6153. [PMID: 36135051 PMCID: PMC9497539 DOI: 10.3390/curroncol29090482] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 08/20/2022] [Accepted: 08/23/2022] [Indexed: 12/02/2022] Open
Abstract
The purpose of this meta-analysis was to evaluate the efficacy and safety of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, in addition to standard anticancer therapy. Randomized controlled trials (RCTs) that evaluated the efficacy and safety of celecoxib-combined cancer therapy were systematically searched in PubMed and Embase databases. The endpoints were overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), objective response rate (ORR), disease control rate (DCR), pathological complete response (pCR), and adverse events (AEs). The results of 30 RCTs containing 9655 patients showed limited benefits in celecoxib-combined cancer therapy. However, celecoxib-combined palliative therapy prolonged PFS in epidermal growth factor receptor (EGFR) wild-type patients (HR = 0.57, 95%CI = 0.35–0.94). Moreover, despite a slight increase in thrombocytopenia (RR = 1.35, 95%CI = 1.08–1.69), there was no increase in other toxicities. Celecoxib combined with adjuvant therapy indicated a better OS (HR = 0.850, 95%CI = 0.725–0.996). Furthermore, celecoxib plus neoadjuvant therapy improved the ORR in standard cancer therapy, especially neoadjuvant therapy (overall: RR = 1.13, 95%CI = 1.03–1.23; neoadjuvant therapy: RR = 1.25, 95%CI = 1.09–1.44), but not pCR. Our study indicated that adding celecoxib to palliative therapy prolongs the PFS of EGFR wild-type patients, with good safety profiles. Celecoxib combined with adjuvant therapy prolongs OS, and celecoxib plus neoadjuvant therapy improves the ORR. Thus, celecoxib-combined cancer therapy may be a promising therapy strategy.
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Affiliation(s)
- Shi-Yu Ye
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang 110002, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang 110122, China
- Institute of Health Sciences, China Medical University, Shenyang 110122, China
| | - Jia-Yi Li
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang 110002, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang 110122, China
- Institute of Health Sciences, China Medical University, Shenyang 110122, China
| | - Teng-Hui Li
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang 110002, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang 110122, China
- Institute of Health Sciences, China Medical University, Shenyang 110122, China
| | - Yong-Xi Song
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang 110002, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang 110122, China
- Institute of Health Sciences, China Medical University, Shenyang 110122, China
| | - Jing-Xu Sun
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang 110002, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang 110122, China
- Institute of Health Sciences, China Medical University, Shenyang 110122, China
| | - Xiao-Wan Chen
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang 110002, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang 110122, China
- Institute of Health Sciences, China Medical University, Shenyang 110122, China
| | - Jun-Hua Zhao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang 110002, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang 110122, China
- Institute of Health Sciences, China Medical University, Shenyang 110122, China
| | - Yuan Li
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang 110002, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang 110122, China
- Institute of Health Sciences, China Medical University, Shenyang 110122, China
| | - Zhong-Hua Wu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang 110002, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang 110122, China
- Institute of Health Sciences, China Medical University, Shenyang 110122, China
| | - Peng Gao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang 110002, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang 110122, China
- Institute of Health Sciences, China Medical University, Shenyang 110122, China
- Correspondence: (P.G.); (X.-Z.H.); Tel.: +86-24-83283556 (P.G. & X.-Z.H.)
| | - Xuan-Zhang Huang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N. Nanjing Street, Shenyang 110002, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang 110122, China
- Institute of Health Sciences, China Medical University, Shenyang 110122, China
- Correspondence: (P.G.); (X.-Z.H.); Tel.: +86-24-83283556 (P.G. & X.-Z.H.)
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Circulating Tumour Cells (CTCs) in NSCLC: From Prognosis to Therapy Design. Pharmaceutics 2021; 13:pharmaceutics13111879. [PMID: 34834295 PMCID: PMC8619417 DOI: 10.3390/pharmaceutics13111879] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/27/2021] [Accepted: 10/30/2021] [Indexed: 02/08/2023] Open
Abstract
Designing optimal (neo)adjuvant therapy is a crucial aspect of the treatment of non-small-cell lung carcinoma (NSCLC). Standard methods of chemotherapy, radiotherapy, and immunotherapy represent effective strategies for treatment. However, in some cases with high metastatic activity and high levels of circulating tumour cells (CTCs), the efficacy of standard treatment methods is insufficient and results in treatment failure and reduced patient survival. CTCs are seen not only as an isolated phenomenon but also a key inherent part of the formation of metastasis and a key factor in cancer death. This review discusses the impact of NSCLC therapy strategies based on a meta-analysis of clinical studies. In addition, possible therapeutic strategies for repression when standard methods fail, such as the administration of low-toxicity natural anticancer agents targeting these phenomena (curcumin and flavonoids), are also discussed. These strategies are presented in the context of key mechanisms of tumour biology with a strong influence on CTC spread and metastasis (mechanisms related to tumour-associated and -infiltrating cells, epithelial–mesenchymal transition, and migration of cancer cells).
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The Efficacy of Celecoxib During Chemoradiation in Locally Advanced Head and Neck Carcinoma; A Phase 2 Randomized Placebo-Controlled Clinical Trial. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2021. [DOI: 10.5812/ijcm.103653] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: Cyclo-oxygenase-2 (COX-2), an enzyme induced in pathological states, mediates the production of prostaglandins. Celecoxib as a selective COX-2 inhibitor may affect the outcome of treatments in several cancer types. Objectives: We conducted a randomized controlled double-blind clinical trial to evaluate the toxicity and efficacy of celecoxib administered concurrently with chemoradiation in locally advanced head and neck carcinomas. Methods: Patients with locally advanced head and neck carcinoma referred for definitive chemoradiation were eligible to enter the study. Celecoxib (100mg, qid, oral) or placebo was administered all over the chemoradiation period. Results: Totally, 122 patients were enrolled. Patients in the celecoxib group had a longer median time to onset of grade 2 mucositis (56 days vs. 28 days, P < 0.001) and a lower rate of grade 3 mucositis (1.6% vs. 21.3%, P = 0.001). The 4-year progression-free survival was significantly higher in the celecoxib group (P = 0.0013). Conclusions: This study revealed that utilizing celecoxib may lead to better tumor local control and delayed and reduced mucosal side effects of chemoradiation.
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Xu YQ, Long X, Han M, Huang MQ, Lu JF, Sun XD, Han W. Clinical benefit of COX-2 inhibitors in the adjuvant chemotherapy of advanced non-small cell lung cancer: A systematic review and meta-analysis. World J Clin Cases 2021; 9:581-601. [PMID: 33553396 PMCID: PMC7829738 DOI: 10.12998/wjcc.v9.i3.581] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 10/17/2020] [Accepted: 11/09/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Lung cancer is a major cause of death among patients, and non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers in many countries.
AIM To evaluate the clinical benefit (CB) of COX-2 inhibitors in patients with advanced NSCLC using systematic review.
METHODS We searched the six electronic databases up until December 9, 2019 for studies that examined the efficacy and safety of the addition of COX-2 inhibitors to chemotherapy for NSCLC. Overall survival (OS), progression free survival (PFS), 1-year survival rate (SR), overall response rate (ORR), CB, complete response (CR), partial response (PR), stable disease (SD), and toxicities were measured with more than one outcome as their endpoints. Fixed and random effects models were used to calculate risk estimates in a meta-analysis. Potential publication bias was calculated using Egger’s linear regression test. Data analysis was performed using R software.
RESULTS The COX-2 inhibitors combined with chemotherapy were not found to be more effective than chemotherapy alone in OS, progression free survival, 1-year SR, CB, CR, and SD. However, there was a difference in overall response rate for patients with advanced NSCLC. In a subgroup analysis, significantly increased ORR results were found for celecoxib, rofecoxib, first-line treatment, and PR. For adverse events, the increase in COX-2 inhibitor was positively correlated with the increase in grade 3 and 4 toxicity of leukopenia, thrombocytopenia, and cardiovascular events.
CONCLUSION COX-2 inhibitor combined with chemotherapy increased the total effective rate of advanced NSCLC with the possible increased risk of blood toxicity and cardiovascular events and had no effect on survival index.
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Affiliation(s)
- Yu-Qiong Xu
- Department of Emergency Medicine, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen 518000, Guangdong Province, China
| | - Xiang Long
- Department of Respiratory and Critical Care Medicine, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Ming Han
- Department of Emergency Medicine, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen 518000, Guangdong Province, China
| | - Ming-Qiang Huang
- Department of Emergency Medicine, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen 518000, Guangdong Province, China
| | - Jia-Fa Lu
- Department of Emergency Medicine, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen 518000, Guangdong Province, China
| | - Xue-Dong Sun
- Department of Emergency Medicine, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen 518000, Guangdong Province, China
| | - Wei Han
- Department of Emergency Medicine, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen 518000, Guangdong Province, China
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Yoshida Y, Kaneko M, Narukawa M. Impact of Advantage in Tumor Response on the Correlation Between Progression-Free Survival and Overall Survival: Meta-Analysis of Clinical Trials in Patients with Advanced Non-Small Cell Lung Cancer. Pharmaceut Med 2021; 35:81-92. [PMID: 33483892 DOI: 10.1007/s40290-021-00383-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/11/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Progression-free survival (PFS) has not been validated as a surrogate endpoint for overall survival (OS) in patients with advanced non-small cell lung cancer. OBJECTIVE This study aimed to investigate an impact of advantage in tumor response on the correlation between PFS and OS in advanced non-small cell lung cancer. METHODS Based on a literature search, we identified randomized controlled trials of first-line therapy for advanced non-small cell lung cancer. The impact of absolute difference in objective response rate between treatment arms on the correlation between hazard ratios (HRs) for PFS and OS was evaluated based on Spearman rank correlation coefficients. RESULTS Sixty trials with a total of 29,134 patients were identified. The HR for PFS showed a relatively higher correlation with HR for OS (rs = 0.75) when the trials were limited to those that demonstrated a larger advantage in objective response rate, compared with the case for trials that demonstrated a smaller advantage (rs = 0.66). This tendency was also observed in the subgroup analysis stratified by the types of treatment agents (non-targeted, anti-angiogenic, and immunotherapy) except for the group of epidermal growth factor receptor-targeted agents. CONCLUSIONS The magnitude of advantage in tumor response was suggested to contribute to a better prediction of OS-HR based on PFS-HR in clinical trials in patients with advanced non-small cell lung cancer.
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Affiliation(s)
- Yosuke Yoshida
- Department of Clinical Medicine (Pharmaceutical Medicine), Graduate School of Pharmaceutical Sciences, Kitasato University, Shirokane 5-9-1, Minato-ku, Tokyo, 108-8641, Japan. .,MSD K.K., a subsidiary of Merck & Co., Inc, Kenilworth, NJ, USA.
| | - Masayuki Kaneko
- Department of Clinical Medicine (Pharmaceutical Medicine), Graduate School of Pharmaceutical Sciences, Kitasato University, Shirokane 5-9-1, Minato-ku, Tokyo, 108-8641, Japan
| | - Mamoru Narukawa
- Department of Clinical Medicine (Pharmaceutical Medicine), Graduate School of Pharmaceutical Sciences, Kitasato University, Shirokane 5-9-1, Minato-ku, Tokyo, 108-8641, Japan
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Yang J, Wang X, Gao Y, Fang C, Ye F, Huang B, Li L. Inhibition of PI3K-AKT Signaling Blocks PGE 2-Induced COX-2 Expression in Lung Adenocarcinoma. Onco Targets Ther 2020; 13:8197-8208. [PMID: 32904445 PMCID: PMC7455753 DOI: 10.2147/ott.s263977] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 07/24/2020] [Indexed: 12/22/2022] Open
Abstract
Purpose Cyclooxygenase-2 (COX-2) and its enzymatic product prostaglandin E2 (PGE2) possess tumor-promoting activity, and COX-2 is considered as a candidate for targeted cancer therapy. However, several randomized clinical trials using COX-2 inhibitors to treat advanced lung cancer have failed to improve survival indices. To employ a more effective therapeutic strategy to inhibit the COX-2-PGE2 axis in tumors, it is necessary to revisit the mechanism underlying the protumor effect of COX-2-PGE2. Patients and Methods Immunohistochemistry was used to predict the expression and prognostic value of COX-2 in lung adenocarcinoma samples. The mRNAs or proteins expression of COX-2, pAKT1/2/3, pErk1/2 and pCREB were detected after different treatments by qPCR or Western blot. The impacts of PGE2 and some inhibitors on cell proliferation and migration ability were verified by CCK-8 and transwell assays, respectively. Results In this study, we first confirmed that COX-2 expression in tumor specimens is associated with the pathological stage of the disease. Next, using lung adenocarcinoma cell lines, we found that exogenous PGE2 induces the expression of COX-2 at the mRNA and protein levels. Moreover, downregulation of COX-2 expression restrained PGE2-induced cancer cell proliferation and migration. Mechanistic analysis revealed that PGE2 stimulation activates the PKA-CREB and PI3K-AKT pathways. Downregulation of CREB expression abrogated PGE2-induced COX-2 expression. Moreover, inhibition of PI3K-AKT signaling suppressed the activation of CREB and PGE2-induced COX-2 expression. Specific inhibitors for PI3K and AKT suppressed COX-2 mRNA expression in ex vivo cultures of tumor specimens with PGE2. Conclusion Simultaneous targeting of COX-2 and PI3K-AKT effectively suppressed PGE2-induced cell proliferation and migration and both acted in a synergistic manner. Targeting the COX-2-PGE2 positive feedback loop may be therapeutically beneficial to lung adenocarcinoma.
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Affiliation(s)
- Jianjian Yang
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Xue Wang
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Yi Gao
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Can Fang
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Fan Ye
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Bing Huang
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Lequn Li
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
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Tołoczko-Iwaniuk N, Dziemiańczyk-Pakieła D, Nowaszewska BK, Celińska-Janowicz K, Miltyk W. Celecoxib in Cancer Therapy and Prevention - Review. Curr Drug Targets 2020; 20:302-315. [PMID: 30073924 DOI: 10.2174/1389450119666180803121737] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 06/04/2018] [Accepted: 08/02/2018] [Indexed: 12/13/2022]
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.
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Affiliation(s)
- Natalia Tołoczko-Iwaniuk
- Department of Pharmaceutical Analysis, Medical University of Bialystok, Mickiewicza 2D Street, 15-222 Bialystok, Poland
| | - Dorota Dziemiańczyk-Pakieła
- Department of Maxillofacial and Plastic Surgery, Medical University of Bialystok, Skłodowskiej-Curie 24A, 15-404 Bialystok, Poland
| | - Beata Klaudia Nowaszewska
- Department of Maxillofacial and Plastic Surgery, Medical University of Bialystok, Skłodowskiej-Curie 24A, 15-404 Bialystok, Poland
| | - Katarzyna Celińska-Janowicz
- Department of Pharmaceutical Analysis, Medical University of Bialystok, Mickiewicza 2D Street, 15-222 Bialystok, Poland
| | - Wojciech Miltyk
- Department of Pharmaceutical Analysis, Medical University of Bialystok, Mickiewicza 2D Street, 15-222 Bialystok, Poland
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Rescifina A, Surdo E, Cardile V, Avola R, Eleonora Graziano AC, Stancanelli R, Tommasini S, Pistarà V, Ventura CA. Gemcitabine anticancer activity enhancement by water soluble celecoxib/sulfobutyl ether-β-cyclodextrin inclusion complex. Carbohydr Polym 2019; 206:792-800. [PMID: 30553385 DOI: 10.1016/j.carbpol.2018.11.060] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 11/18/2018] [Accepted: 11/18/2018] [Indexed: 12/12/2022]
Abstract
We investigated the complexation of celecoxib (CCB) into sulfobuthyl-ether-β-cyclodextrin (SBE-β-CD) for the realization of an inhalable dry-powder formulation containing gemcitabine (GEM) for lung anticancer therapy. Complexation increased the water solubility of CCB (0.003 mg/mL and 0.834 mg/mL for CCB free and complexed, respectively) and produced a quantitative dissolution of the drug within 15 min. The CCB/SBE-β-CD inclusion complex showed a high stability constant (8131 M-1) not influenced by the presence of GEM in solution. Two-dimensional NMR experiments and computational studies demonstrated that the pyrazole ring of CCB penetrates deeper into SBE-β-CD from the secondary rim. The aromatic rings are positioned at the edge of the cavity, establishing hydrogen bonds with the SBE-β-CD that stabilized the complex. CCB showed limited cytotoxic activity on A549 cell lines. Complexation significantly increased activity passing from 30% to 45% cell mortality. Moreover, CCB/SBE-β-CD strongly improved the cytotoxicity of GEM, observing about 60% of cell mortality for the combined formulation.
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Affiliation(s)
- Antonio Rescifina
- Department of Drug Sciences, University of Catania, V.le A. Doria, 6 - 95125 Catania, Italy.
| | - Emanuela Surdo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le F. Stagno D'Alcontrés, 31 - 98166 Messina, Italy.
| | - Venera Cardile
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia, 97 - 95125 Catania, Italy.
| | - Rosanna Avola
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia, 97 - 95125 Catania, Italy.
| | | | - Rosanna Stancanelli
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le F. Stagno D'Alcontrés, 31 - 98166 Messina, Italy.
| | - Silvana Tommasini
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le F. Stagno D'Alcontrés, 31 - 98166 Messina, Italy.
| | - Venerando Pistarà
- Department of Drug Sciences, University of Catania, V.le A. Doria, 6 - 95125 Catania, Italy.
| | - Cinzia Anna Ventura
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le F. Stagno D'Alcontrés, 31 - 98166 Messina, Italy.
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Hamy AS, Tury S, Wang X, Gao J, Pierga JY, Giacchetti S, Brain E, Pistilli B, Marty M, Espié M, Benchimol G, Laas E, Laé M, Asselain B, Aouchiche B, Edelman M, Reyal F. Celecoxib With Neoadjuvant Chemotherapy for Breast Cancer Might Worsen Outcomes Differentially by COX-2 Expression and ER Status: Exploratory Analysis of the REMAGUS02 Trial. J Clin Oncol 2019; 37:624-635. [PMID: 30702971 DOI: 10.1200/jco.18.00636] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
PURPOSE The overexpression of cyclooxygenase 2 (COX-2) gene, also known as prostaglandin-endoperoxide synthase 2 ( PTGS2), occurs in breast cancer, but whether it affects response to anticox drugs remains unclear. We investigated the relationships between PTGS2 expression, celecoxib use during neoadjuvant chemotherapy (NAC), and both event-free survival (EFS) and overall survival (OS). MATERIALS AND METHODS We analyzed a cohort of 156 patients with human epidermal growth factor receptor 2 -negative breast cancer from the REMAGUS02 (ISRCTN Registry No. 10059974) trial with pretreatment PTGS2 expression data. Patients were treated by sequential NAC (epirubicin plus cyclophosphamide followed by docetaxel with or without celecoxib). Experimental validation was performed on breast cancer cell lines. The Cancer and Leukemia Group B (CALGB) 30801 ( ClinicalTrials.gov identifier: NCT01041781) trial that tested chemotherapy with or without celecoxib in patients with lung cancer served as an independent validation cohort. RESULTS After 94.5 months of follow-up, EFS was significantly lower in the celecoxib group (hazard ratio [HR], 1.7; 95% CI, 1 to 2.88; P = .046). A significant interaction between PTGS2 expression and celecoxib use was detected ( Pinteraction = .01). In the PTGS2-low group (n = 100), EFS was lower in the celecoxib arm (HR, 3.01; 95% CI, 1.45 to 6.24; P = .002) than in the standard treatment arm. Celecoxib use was an independent predictor of poor EFS, distant relapse-free survival, and OS. Celecoxib in addition to docetaxel enhanced cell viability in PTGS2-low cell lines but not in PTGS2-high cell lines. In CALGB 30801, a trend toward poorer progression-free survival was observed in the patients with low urinary metabolite of prostaglandin E2 who received celecoxib (HR = 1.57; 95% CI, 0.87 to 2.84; P = .13). CONCLUSION Celecoxib use during chemotherapy adversely affected survival in patients with breast cancer, and the effect was more marked in PTGS2-low and/or estrogen receptor-negative tumors. COX-2 inhibitors should preferably be avoided during docetaxel use in patients with breast cancer who are undergoing NAC.
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Affiliation(s)
| | - Sandrine Tury
- 1 Institut Curie, Université Paris Descartes, Paris, France
| | - Xiaofei Wang
- 2 Alliance Statistics and Data Center, Durham, NC
| | - Junheng Gao
- 2 Alliance Statistics and Data Center, Durham, NC
| | | | - Sylvie Giacchetti
- 3 Hôpital Saint Louis (APHP), Université Paris Diderot, Paris, France
| | - Etienne Brain
- 1 Institut Curie, Université Paris Descartes, Paris, France
| | | | - Michel Marty
- 3 Hôpital Saint Louis (APHP), Université Paris Diderot, Paris, France
| | - Marc Espié
- 3 Hôpital Saint Louis (APHP), Université Paris Diderot, Paris, France
| | | | - Enora Laas
- 1 Institut Curie, Université Paris Descartes, Paris, France
| | - Marick Laé
- 1 Institut Curie, Université Paris Descartes, Paris, France
| | | | | | | | - Fabien Reyal
- 1 Institut Curie, Université Paris Descartes, Paris, France
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Martinez-Marti A, Navarro A, Felip E. COX-2 inhibitors in NSCLC: never-ending story or misplaced? Transl Lung Cancer Res 2018; 7:S191-S194. [PMID: 30393598 DOI: 10.21037/tlcr.2018.04.17] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Alex Martinez-Marti
- Medical Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Alejandro Navarro
- Medical Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Enriqueta Felip
- Medical Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
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Ikeda M, Ochibe T, Tohkin M. Possible Causes of Failing to Meet Primary Endpoints: A Systematic Review of Randomized Controlled Phase 3 Clinical Trials in Patients With Non-Small Cell Lung Cancer. Ther Innov Regul Sci 2018; 53:324-331. [PMID: 30089401 DOI: 10.1177/2168479018791135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related mortality worldwide and represents a huge unmet medical need. Despite the favorable results of phase 2 clinical trials, many phase 3 clinical trials fail to meet primary endpoints. Therefore, we investigated the causes of failure to meet primary endpoints in phase 3 clinical trials. METHODS We performed a systematic review of phase 3 clinical trials in patients with NSCLC. The results of phase 3 clinical trials collected from the survey were categorized as "negative" (failed to meet the primary endpoint) or "positive" (met the primary endpoint). RESULTS Of a total of 106 trials collected from this survey, 40 positive trials (38%) and 66 negative trials (62%) were identified. The majority of the primary endpoints were overall survival (OS) or progression-free survival (PFS) (94%). More trials using OS as the primary endpoint were negative (42 of 56 trials), and more trials using PFS as the primary endpoint were positive (24 of 44 trials). The median OS in the control arm in negative trials was significantly longer than the pretrial estimate ( P < .001), whereas the median PFS in the control arm in positive trials was relatively consistent with the pretrial estimate. CONCLUSIONS Our findings suggest that the selection of the primary endpoint and the pretrial estimate can potentially impact the results of phase 3 clinical trials in patients with NSCLC and are critical success factors when planning phase 3 clinical trials.
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Affiliation(s)
- Mitsugu Ikeda
- 1 Department of Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
| | - Tatsuya Ochibe
- 1 Department of Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
| | - Masahiro Tohkin
- 1 Department of Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
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Yi L, Zhang W, Zhang H, Shen J, Zou J, Luo P, Zhang J. Systematic review and meta-analysis of the benefit of celecoxib in treating advanced non-small-cell lung cancer. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:2455-2466. [PMID: 30122902 PMCID: PMC6086108 DOI: 10.2147/dddt.s169627] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Background The clinical benefit of a selective cyclooxygenase-2 inhibitor, celecoxib, combined with anticancer therapy in advanced non-small-cell lung cancer (NSCLC) remains unclear. A meta-analysis was performed to address the efficacy and safety of celecoxib in patients with advanced NSCLC. Materials and methods Three databases, including PubMed, EMBASE, and the Cochrane Library, were systematically searched for available literature until March 1, 2018. Data on tumor response rates, one-year survival, overall survival, progression-free survival, and toxicities were extracted from the included randomized clinical trials. Subgroup analysis was carried out according to the line of treatment. Review Manager 5.3 software was applied to conduct the meta-analysis. Results A total of 7 randomized controlled trials involving 1,559 patients with advanced NSCLC were enrolled for analysis. The pooled overall response rate (ORR) of celecoxib added to systemic therapy was not significantly improved (risk ratio [RR] =1.14, 95% CI =0.96–1.35, P=0.13). Additionally, no differences were observed between the celecoxib and placebo groups regarding 1-year survival (RR =0.99, 95% CI =0.88–1.12, P=0.91). Subgroup analysis showed that adding celecoxib to the first-line treatment significantly improved the ORR (RR =1.21, 95% CI =1.01–1.44, P=0.04) and partial response rate (RR =1.26, 95% CI =1.01–1.58, P=0.04). The aggregated Kaplan–Meier analysis found no significant difference between celecoxib and placebo regarding the 5-year overall survival (median, 12.9 vs 12.5 months, P=0.553) and 5-year progression-free survival (median, 7.4 vs 7.2 months, P=0.641). The increased RR of leukopenia (RR =1.25, 95% CI =1.03–1.50) and thrombocytopenia (RR =1.39, 95% CI =1.11–1.75) indicated that celecoxib increased hematologic toxicities (grade ≥III). However, celecoxib did not increase the related risks of thrombosis or embolism (RR =1.26, 95% CI =0.66–2.39) and cardiac ischemia (RR =1.16, 95% CI =0.39–3.44). Conclusion Celecoxib had no benefit on survival indices for advanced NSCLC but improved the ORR of first-line treatment. Additionally, celecoxib increased the rate of hematologic toxicities without increasing the risk of cardiovascular events.
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Affiliation(s)
- Lilan Yi
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China, ;
| | - Wei Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China, ;
| | - Hongman Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China, ;
| | - Jie Shen
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China, ;
| | - Jingwen Zou
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China, ;
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China, ;
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China, ;
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Dai P, Li J, Ma XP, Huang J, Meng JJ, Gong P. Efficacy and safety of COX-2 inhibitors for advanced non-small-cell lung cancer with chemotherapy: a meta-analysis. Onco Targets Ther 2018; 11:721-730. [PMID: 29440919 PMCID: PMC5804138 DOI: 10.2147/ott.s148670] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Background The study of cyclooxygenase-2 (COX-2) inhibitors is now mired in controversy. We performed a meta-analysis to assess the efficacy and safety profile of COX-2 inhibitors in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods A literature search of PubMed, EMBASE, the Cochrane Central databases, and ClinicalTrials.gov, up until March 26, 2017, identified relevant randomized controlled trials. Data analysis was performed using Stata 12.0. Results Six eligible trials (1,794 patients) were selected from the 407 studies that were identified initially. A significant difference, favoring COX-2 inhibitors plus chemotherapy over chemotherapy alone, was observed in the overall response rate (relative risk [RR] =1.25, 95% confidence interval [CI]: 1.06-1.48). Further, we conducted two subgroup analyses according to the type of COX-2 inhibitors (celecoxib, rofecoxib, or apricoxib) and treatment line (first or second chemotherapy). The first-line treatment includes: NP (changchun red bean + cisplatin or carboplatin), GP (double fluorine cytidine + cisplatin or carboplatin), or TP (paclitaxel + cisplatin or carboplatin, docetaxel + cisplatin or carboplatin). The second-line treatment includes two internationally recognized compounds, one is docetaxel and the other is the pemetrexed, both of which are individually selected. In subgroup analysis, significantly increased overall response rate (ORR) results were found for rofecoxib plus chemotherapy (RR =1.56, 95% CI: 1.08-2.25) and COX-2 inhibitor given with first-line chemotherapy (RR =1.27, 95% CI: 1.07-1.50). However, there was no difference between COX-2 inhibitors plus chemotherapy and chemotherapy alone in overall survival (hazard ratio [HR] =1.04, 95% CI: 0.91-1.18), progression-free survival (HR =0.97, 95% CI: 0.86-1.10), and 1-year survival rate (RR =1.03, 95% CI: 0.89-1.20). Toxicity did not differ significantly between COX-2 inhibitors plus chemotherapy and chemotherapy alone with the exception of leukopenia (RR =1.21, 95% CI: 1.03-1.42), thrombocytopenia (RR =1.32, 95% CI: 1.04-1.67), and cardiovascular events (RR =2.39, 95% CI: 1.06-5.42). The results of the Egger's test indicated no significant difference in primary outcomes. Conclusion COX-2 inhibitors improved ORR of advanced NSCLC with chemotherapy, but had no effect on survival indices. Moreover, COX-2 inhibitors may lead to higher rates of hematologic toxicities and cardiovascular events.
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Affiliation(s)
- Ping Dai
- Department of Oncology, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, People's Republic of China
| | - Jing Li
- Department of Oncology, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, People's Republic of China
| | - Xiao-Ping Ma
- Department of Oncology, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, People's Republic of China
| | - Jian Huang
- Department of Oncology, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, People's Republic of China
| | - Juan-Juan Meng
- Department of Oncology, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, People's Republic of China
| | - Ping Gong
- Department of Oncology, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, People's Republic of China
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Gulyas M, Mattsson JSM, Lindgren A, Ek L, Lamberg Lundström K, Behndig A, Holmberg E, Micke P, Bergman B. COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer. Acta Oncol 2018; 57:244-250. [PMID: 29140138 DOI: 10.1080/0284186x.2017.1400685] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
AIM Inhibition of cyclooxygenase-2 (COX-2) is proposed as a treatment option in several cancer types. However, in non-small cell lung cancer (NSCLC), phase III trials have failed to demonstrate a benefit of adding COX-2 inhibitors to standard chemotherapy. The aim of this study was to analyze COX-2 expression in tumor and stromal cells as predictive biomarker for COX-2 inhibition. METHODS In a multicenter phase III trial, 316 patients with advanced NSCLC were randomized to receive celecoxib (400 mg b.i.d.) or placebo up to one year in addition to a two-drug platinum-based chemotherapy combination. In a subset of 122 patients, archived tumor tissue was available for immunohistochemical analysis of COX-2 expression in tumor and stromal cells. For each compartment, COX-2 expression was graded as high or low, based on a product score of extension and intensity of positively stained cells. RESULTS An updated analysis of all 316 patients included in the original trial, and of the 122 patients with available tumor tissue, showed no survival differences between the celecoxib and placebo arms (HR 1.01; 95% CI 0.81-1.27 and HR 1.12; 95% CI 0.78-1.61, respectively). High COX-2 scores in tumor (n = 71) or stromal cells (n = 55) was not associated with a superior survival outcome with celecoxib vs. placebo (HR =0.96, 95% CI 0.60-1.54; and HR =1.51; 95% CI 0.86-2.66), and no significant interaction effect between COX-2 score in tumor or stromal cells and celecoxib effect on survival was detected (p = .48 and .25, respectively). CONCLUSIONS In this subgroup analysis of patients with advanced NSCLC treated within the context of a randomized trial, we could not detect any interaction effect of COX-2 expression in tumor or stromal cells and the outcome of celecoxib treatment in addition to standard chemotherapy.
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Affiliation(s)
- Miklos Gulyas
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | | | - Andrea Lindgren
- Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, Allergy Centre, Linkoping, Sweden
| | - Lars Ek
- Pulmonary Medicine, Skane University Hospital, Lund, Sweden
| | | | - Annelie Behndig
- Pulmonary Medicine, Norrland University Hospital, Umeå, Sweden
| | - Erik Holmberg
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Patrick Micke
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Bengt Bergman
- Department of Respiratory Medicine, Institute of medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
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Takhar H, Singhal N, Mislang A, Kumar R, Kim L, Selva-Nayagam S, Pittman K, Karapetis C, Borg M, Olver IN, Brown MP. Phase II study of celecoxib with docetaxel chemoradiotherapy followed by consolidation chemotherapy docetaxel plus cisplatin with maintenance celecoxib in inoperable stage III nonsmall cell lung cancer. Asia Pac J Clin Oncol 2017; 14:91-100. [DOI: 10.1111/ajco.12749] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Accepted: 06/22/2017] [Indexed: 10/19/2022]
Affiliation(s)
- Harminder Takhar
- Cancer Clinical Trials Unit; Royal Adelaide Hospital; Adelaide South Australia Australia
| | - Nimit Singhal
- Cancer Clinical Trials Unit; Royal Adelaide Hospital; Adelaide South Australia Australia
| | - Anna Mislang
- Cancer Clinical Trials Unit; Royal Adelaide Hospital; Adelaide South Australia Australia
| | - Raj Kumar
- Department of Medical Oncology; Flinders Medical Centre and Flinders University; Adelaide South Australia Australia
| | - Laurence Kim
- Cancer Clinical Trials Unit; Royal Adelaide Hospital; Adelaide South Australia Australia
| | - Sid Selva-Nayagam
- Cancer Clinical Trials Unit; Royal Adelaide Hospital; Adelaide South Australia Australia
| | - Ken Pittman
- Department of Medical Oncology; The Queen Elizabeth Hospital; Woodville South Australia Australia
| | - Chris Karapetis
- Department of Medical Oncology; Flinders Medical Centre and Flinders University; Adelaide South Australia Australia
| | - Martin Borg
- Adelaide Radiotherapy Centre; Adelaide South Australia Australia
| | - Ian N. Olver
- Sansom Institute; University of South Australia; Adelaide South Australia Australia
| | - Michael P. Brown
- Cancer Clinical Trials Unit; Royal Adelaide Hospital; Adelaide South Australia Australia
- Sansom Institute; University of South Australia; Adelaide South Australia Australia
- Centre for Cancer Biology; SA Pathology and University of South Australia; Adelaide South Australia Australia
- Discipline of Medicine; University of Adelaide; Adelaide South Australia Australia
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Role of Cyclooxygenase-2 on Intermittent Hypoxia-Induced Lung Tumor Malignancy in a Mouse Model of Sleep Apnea. Sci Rep 2017; 7:44693. [PMID: 28300223 PMCID: PMC5353645 DOI: 10.1038/srep44693] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 02/13/2017] [Indexed: 12/15/2022] Open
Abstract
An adverse role for obstructive sleep apnea (OSA) in cancer epidemiology and outcomes has recently emerged from clinical and animal studies. In animals, intermittent hypoxia (IH) mimicking OSA promotes tumor malignancy both directly and via host immune alterations. We hypothesized that IH could potentiate cancer aggressiveness through activation of the cyclooxygenase-2 (COX-2) pathway and the concomitant increases in prostaglandin E2 (PGE2). The contribution of the COX-2 in IH-induced enhanced tumor malignancy was assessed using celecoxib as a COX-2 specific inhibitor in a murine model of OSA bearing Lewis lung carcinoma (LLC1) tumors. Exposures to IH accelerated tumor progression with a tumor associated macrophages (TAMs) shift towards a pro-tumoral M2 phenotype. Treatment with celecoxib prevented IH-induced adverse tumor outcomes by inhibiting IH-induced M2 polarization of TAMs. Furthermore, TAMs isolated from IH-exposed mice treated with celecoxib reduced the proliferation of LLC1 naïve cells, while the opposite occurred with placebo-treated IH-exposed mice. Finally, in vitro IH exposures of murine macrophages and LLC1 cells showed that both cell types increased PGE2 release in response to IH. These results suggest a crucial role for the COX-2 signaling pathway in the IH-exacerbated malignant processes, and designate macrophages and lung adenocarcinoma cells, as potential sources of PGE2.
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25
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Zhou YY, Hu ZG, Zeng FJ, Han J. Clinical Profile of Cyclooxygenase-2 Inhibitors in Treating Non-Small Cell Lung Cancer: A Meta-Analysis of Nine Randomized Clinical Trials. PLoS One 2016; 11:e0151939. [PMID: 27007231 PMCID: PMC4805232 DOI: 10.1371/journal.pone.0151939] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 03/07/2016] [Indexed: 01/27/2023] Open
Abstract
Background Evidence on the benefits of combining cyclooxygenase-2 inhibitor (COX-2) in treating non-small cell lung cancer (NSCLC) is still controversial. We investigated the efficacy and safety profile of cyclooxygenase-2 inhibitors in treating NSCLC. Methods The first meta-analysis of eligible studies was performed to assess the effect of COX-2 inhibitors for patients with NSCLC on the overall response rate (ORR), overall survival (OS), progression-free survival (PFS), one-year survival, and toxicities. The fixed-effects model was used to calculate the pooled RR and HR and between-study heterogeneity was assessed. Subgroup analyses were conducted according to the type of COX-2 inhibitors, treatment pattern, and treatment line. Results Nine randomized clinical trials, comprising 1679 patents with NSCLC, were included in the final meta-analysis. The pooled ORR of patients who have NSCLC with COX-2 inhibitors was significantly higher than that without COX-2 inhibitors. In subgroup analysis, significantly increased ORR results were found on celecoxib (RR = 1.29, 95% CI: 1.09, 1.51), rofecoxib (RR = 1.61, 95% CI: 1.14, 2.28), chemotherapy (RR = 1.40, 95% CI: 1.20, 1.63), and first-line treatment (RR = 1.39, 95% CI: 1.19, 1.63). However, COX-2 inhibitors had no effect on the one-year survival, OS, and PFS. Increased RR of leucopenia (RR = 1.21, 95% CI: 1.01, 1.45) and thrombocytopenia (RR = 1.36, 95% CI: 1.06, 1.76) suggested that COX-2 inhibitors increased hematologic toxicities (grade ≥ 3) of chemotherapy Conclusions COX-2 inhibitors increased ORR of advanced NSCLC and had no impact on survival indices, but it may increase the risk of hematologic toxicities associated with chemotherapy.
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Affiliation(s)
- Yuan Yuan Zhou
- Department of Respiratory medicine, The first College of Clinical Medicine science, Three Gorges University, Yichang, 443003, People’s Republic of China
| | - Zhi Gang Hu
- Department of Respiratory medicine, The first College of Clinical Medicine science, Three Gorges University, Yichang, 443003, People’s Republic of China
| | - Fan Jun Zeng
- Department of Respiratory medicine, The first College of Clinical Medicine science, Three Gorges University, Yichang, 443003, People’s Republic of China
- * E-mail:
| | - Jiao Han
- Department of Respiratory medicine, The first College of Clinical Medicine science, Three Gorges University, Yichang, 443003, People’s Republic of China
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26
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Fiteni F, Anota A, Westeel V, Bonnetain F. Methodology of health-related quality of life analysis in phase III advanced non-small-cell lung cancer clinical trials: a critical review. BMC Cancer 2016; 16:122. [PMID: 26892541 PMCID: PMC4758022 DOI: 10.1186/s12885-016-2152-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 02/09/2016] [Indexed: 12/31/2022] Open
Abstract
Background Health-related quality of life (HRQoL) is recognized as a component endpoint for cancer therapy approvals. The aim of this review was to evaluate the methodology of HRQoL analysis and reporting in phase III clinical trials of first-line chemotherapy in advanced non-small cell lung cancers (NSCLC). Methods A search in MEDLINE databases identified phase III clinical trials in first-line chemotherapy for advanced NSCLC, published between January 2008 to December 2014. Two authors independently extracted information using predefined data abstraction forms. Results A total of 55 phase III advanced NSCLC trials were identified. HRQoL was declared as an endpoint in 27 studies (49 %). Among these 27 studies, The EORTC questionnaire Quality of Life Questionnaire C30 was used in 13 (48 %) of the studies and The Functional Assessment of Cancer Therapy-General was used in 12 (44 %) trials. The targeted dimensions of HRQoL, the minimal clinically important difference and the statistical approaches for dealing with missing data were clearly specified in 13 (48.1 %), 9 (33.3 %) and 5 (18.5 %) studies, respectively. The most frequent statistical methods for HRQoL analysis were: the mean change from baseline (33.3 %), the linear mixed model for repeated measures (22.2 %) and time to HRQoL score deterioration (18.5 %). For each targeted dimension, the results for each group, the estimated effect size and its precision were clearly reported in 4 studies (14.8 %), not clearly reported in 11 studies (40.7 %) and not reported at all in 12 studies (44.4 %). Conclusions This review demonstrated the weakness and the heterogeneity of the measurement, analysis, and reporting of HRQoL in phase III advanced NSCLC trials. Precise and uniform recommendations are needed to compare HRQoL results across publications and to provide understandable messages for patients and clinicians.
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Affiliation(s)
- Frédéric Fiteni
- Methodology and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France. .,EA 3181 University of Franche-Comté, Besançon, France. .,Department of Medical Oncology, University Hospital of Besançon, Besançon, France.
| | - Amélie Anota
- Methodology and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France. .,EA 3181 University of Franche-Comté, Besançon, France. .,The French National Platform Quality of Life and Cancer, Besançon, France.
| | - Virginie Westeel
- Chest disease Department, University Hospital of Besançon, Besançon, France.
| | - Franck Bonnetain
- Methodology and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France. .,EA 3181 University of Franche-Comté, Besançon, France. .,The French National Platform Quality of Life and Cancer, Besançon, France. .,EORTC QOL Group, Brussels, Belgium.
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Yokouchi H, Kanazawa K. Revisiting the role of COX-2 inhibitor for non-small cell lung cancer. Transl Lung Cancer Res 2015; 4:660-4. [PMID: 26629442 DOI: 10.3978/j.issn.2218-6751.2015.04.03] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Accumulating preclinical and clinical studies have shown that cyclooxygenase-2 (COX-2) inhibitor has some efficacy for non-small cell lung cancer (NSCLC). However, two phase III clinical trials using COX-2 inhibitor in combination with platinum-based chemotherapy showed no survival benefit for "unselected" patients with advanced NSCLC. Thus, exploratory analyses of the association between biomarker and clinical outcome of NSCLC patients treated with COX-2 inhibitors have been warranted. A report by Edelman recently published in the Journal of Clinical Oncology demonstrated the results of a prospective randomized trial using a combination of chemotherapy (docetaxel or pemetrexed) and either COX-2 inhibitor or a placebo for patients with advanced NSCLC. The remarkable point of this study was that it adopted the eligible criteria requiring decreased urinary levels of prostaglandin E metabolite (PGE-M) after administration of COX-2 inhibitor in a run-in period, as a possible predictive marker for the COX-2 inhibitor. The primary endpoint was progression-free survival (PFS). However, no improvement in PFS was observed between the patients treated with COX-2 inhibitor and those with placebo. A number of efforts from various investigators, including this report, have failed to demonstrate the meaningful clinical effect of COX-2 inhibitor for NSCLC. Is COX-2 inhibitor useless anymore? Here, we address the "difficult" character of this COX-2 inhibitor from various viewpoints and discuss potential future strategy using this drug.
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Affiliation(s)
- Hiroshi Yokouchi
- Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan
| | - Kenya Kanazawa
- Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan
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28
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Hou LC, Huang F, Xu HB. Does celecoxib improve the efficacy of chemotherapy for advanced non-small cell lung cancer? Br J Clin Pharmacol 2015; 81:23-32. [PMID: 26331772 DOI: 10.1111/bcp.12757] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Revised: 08/19/2015] [Accepted: 08/26/2015] [Indexed: 12/21/2022] Open
Abstract
AIMS Clinical trials have reported conflicting results about whether celecoxib plus chemotherapy improves outcomes over chemotherapy alone in patients with advanced non-small cell lung cancer. METHODS We performed a meta-analysis comparing the primary and secondary endpoints of treatment with celecoxib plus chemotherapy vs. chemotherapy alone in patients with advanced non-small cell lung cancer. RESULTS Six eligible trials (1181 patients) were selected from the 206 studies that were identified initially. A significant difference, favouring celecoxib plus chemotherapy over chemotherapy alone, was observed in the overall response rate [odds ratio (OR) 1.34; 95% confidence interval (CI) 1.08, 1.67; P = 0.009). However, there was no difference in the 1-year survival rate (OR 1.08; 95% CI 0.86, 1.35; P = 0.512), clinical benefit (OR 1.05; 95% CI 1.88, 1.25; P = 0.613), complete response (OR 0.77; 95% CI 0.39, 1.51; P = 0.446) or partial response (OR 1.22; 95% CI 0.92, 1.63; P = 0.163). Toxicity did not differ significantly with the exception of the occurrence of leucopenia and thrombocytopenia. CONCLUSIONS Celecoxib plus chemotherapy appeared to improve the overall response rate compared with chemotherapy alone in the treatment of patients with advanced non-small cell lung cancer. Further prospective randomized controlled trials are now needed.
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Affiliation(s)
- Leng-Chen Hou
- Department of Anesthesia, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Fang Huang
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Hong-Bin Xu
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
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29
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Hiller JG, Parat MO, Ben-Eliyahu S. The Role of Perioperative Pharmacological Adjuncts in Cancer Outcomes: Beta-Adrenergic Receptor Antagonists, NSAIDs and Anti-fibrinolytics. CURRENT ANESTHESIOLOGY REPORTS 2015. [DOI: 10.1007/s40140-015-0113-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Saxena A, Becker D, Preeshagul I, Lee K, Katz E, Levy B. Therapeutic Effects of Repurposed Therapies in Non-Small Cell Lung Cancer: What Is Old Is New Again. Oncologist 2015; 20:934-45. [PMID: 26156329 DOI: 10.1634/theoncologist.2015-0064] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Accepted: 04/17/2015] [Indexed: 02/07/2023] Open
Abstract
The recent emergence of targeted and immunotherapeutic agents has dramatically changed the management for patients with non-small cell lung cancer (NSCLC). Despite these advances, lung cancer is not exempt from the challenges facing oncology drug development, including the huge financial cost and the time required for drug implementation. Repositioning noncancer therapies with potential antineoplastic properties into new therapeutic niches is an alternative treatment strategy offering the possibility of saving money and time and improving outcomes. The goal of such a strategy is to deliver an effective drug with a favorable toxicity profile at a reduced cost. Preclinical models and observational data have demonstrated promising activity for many of these agents, and they are now being studied in prospective trials. We review the relevant published data regarding the therapeutic effects of metformin, statins, nonsteroidal anti-inflammatory drugs, β-blockers, and itraconazole in NSCLC, with a focus on the putative mechanisms of action and clinical data. As these drugs are increasingly being tested in clinical trials, we aim to highlight the salient challenges and future strategies to optimize this approach.
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Affiliation(s)
- Ashish Saxena
- Memorial Sloan Kettering Cancer Center, New York, New York, USA; St. Luke's Roosevelt Hospital, Mount Sinai Health System, New York, New York, USA; Mount Sinai Beth Israel Hospital, New York, New York, USA; Mount Sinai Hospital, Mount Sinai Health System, New York, New York, USA
| | - Daniel Becker
- Memorial Sloan Kettering Cancer Center, New York, New York, USA; St. Luke's Roosevelt Hospital, Mount Sinai Health System, New York, New York, USA; Mount Sinai Beth Israel Hospital, New York, New York, USA; Mount Sinai Hospital, Mount Sinai Health System, New York, New York, USA
| | - Isabel Preeshagul
- Memorial Sloan Kettering Cancer Center, New York, New York, USA; St. Luke's Roosevelt Hospital, Mount Sinai Health System, New York, New York, USA; Mount Sinai Beth Israel Hospital, New York, New York, USA; Mount Sinai Hospital, Mount Sinai Health System, New York, New York, USA
| | - Karen Lee
- Memorial Sloan Kettering Cancer Center, New York, New York, USA; St. Luke's Roosevelt Hospital, Mount Sinai Health System, New York, New York, USA; Mount Sinai Beth Israel Hospital, New York, New York, USA; Mount Sinai Hospital, Mount Sinai Health System, New York, New York, USA
| | - Elena Katz
- Memorial Sloan Kettering Cancer Center, New York, New York, USA; St. Luke's Roosevelt Hospital, Mount Sinai Health System, New York, New York, USA; Mount Sinai Beth Israel Hospital, New York, New York, USA; Mount Sinai Hospital, Mount Sinai Health System, New York, New York, USA
| | - Benjamin Levy
- Memorial Sloan Kettering Cancer Center, New York, New York, USA; St. Luke's Roosevelt Hospital, Mount Sinai Health System, New York, New York, USA; Mount Sinai Beth Israel Hospital, New York, New York, USA; Mount Sinai Hospital, Mount Sinai Health System, New York, New York, USA
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HIĽOVSKÁ LUCIA, JENDŽELOVSKÝ RASTISLAV, FEDOROČKO PETER. Potency of non-steroidal anti-inflammatory drugs in chemotherapy. Mol Clin Oncol 2015; 3:3-12. [PMID: 25469262 PMCID: PMC4251142 DOI: 10.3892/mco.2014.446] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Accepted: 10/01/2014] [Indexed: 12/19/2022] Open
Abstract
Cancer cell resistance, particularly multidrug resistance (MDR), is the leading cause of chemotherapy failure. A number of mechanisms involved in the development of MDR have been described, including the overexpression of ATP-dependent membrane-bound transport proteins. The enhanced expression of these proteins, referred to as ATP-binding cassette (ABC) transporters, results in an increased cellular efflux of the cytotoxic drug, thereby reducing its intracellular concentration to an ineffective level. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently consumed drugs worldwide. NSAIDs are mainly used to treat pain, fever and inflammation. Numerous studies suggest that NSAIDs also show promise as anticancer drugs. NSAIDs have been shown to reduce cancer cell proliferation, motility, angiogenesis and invasiveness. In addition to these effects, NSAIDs have been shown to induce apoptosis in a wide variety of cancer types. Moreover, several studies have indicated that NSAIDs may sensitise cancer cells to the antiproliferative effects of cytotoxic drugs by modulating ABC transporter activity. Therefore, combining specific NSAIDs with chemotherapeutic drugs may have clinical applications. Such treatments may allow for the use of a lower dose of cytotoxic drugs and may also enhance the effectiveness of therapy. The objective of this review was to discuss the possible role of NSAIDs in the modulation of antitumour drug cytotoxicity. We particularly emphasised on the use of COX-2 inhibitors in combination with chemotherapy and the molecular and cellular mechanisms underlying the alterations in outcome that occur in response to this combination therapy.
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Affiliation(s)
- LUCIA HIĽOVSKÁ
- Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University in Košice, 040 01 Košice, Slovakia
| | - RASTISLAV JENDŽELOVSKÝ
- Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University in Košice, 040 01 Košice, Slovakia
| | - PETER FEDOROČKO
- Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University in Košice, 040 01 Košice, Slovakia
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ZHANG HONG, LI ZHIHONG, WANG KAIZHONG, REN PING. Combined treatment of XIAP-targeting shRNA and celecoxib synergistically inhibits the tumor growth of non-small cell lung cancer cells in vitro and in vivo. Oncol Rep 2014; 33:1079-88. [DOI: 10.3892/or.2014.3678] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Accepted: 07/16/2014] [Indexed: 11/05/2022] Open
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Prognostic impact of COX-2 in non-small cell lung cancer: a comprehensive compartment-specific evaluation of tumor and stromal cell expression. Cancer Lett 2014; 356:837-45. [PMID: 25449785 DOI: 10.1016/j.canlet.2014.10.032] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 10/24/2014] [Accepted: 10/29/2014] [Indexed: 12/22/2022]
Abstract
Cyclooxygenase-2 (COX-2) is an enzyme that has been extensively investigated as a prognostic marker in cancer. In non-small cell lung cancer (NSCLC) previous results regarding the prognostic impact of COX-2 expression are inconsistent. Therefore we evaluated the association between transcript levels and overall survival in nine publicly available gene expression data sets (total n = 1337) and determined in situ compartment-specific tumor and stromal cell protein expression in two independent cohorts (n = 616). Gene expression did not show any correlation with clinical parameters or with overall survival. Protein expression in tumor and stromal cells did not correlate with any clinical parameter or with overall survival in one of the analyzed cohorts, while a significant association of high stromal expression with longer survival was observed in both univariate and multivariate analysis in the other cohort. Stromal expression of COX-2 has not been separately evaluated in NSCLC previously and may be a subject of further investigation, whereas the presented findings from this comprehensive compartment specific evaluation clearly reject the hypothesis of COX-2 tumor cell expression having a prognostic value in NSCLC.
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Chen J, Shen P, Zhang XC, Zhao MD, Zhang XG, Yang L. Efficacy and safety profile of celecoxib for treating advanced cancers: a meta-analysis of 11 randomized clinical trials. Clin Ther 2014; 36:1253-63. [PMID: 25016505 DOI: 10.1016/j.clinthera.2014.06.015] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 05/31/2014] [Accepted: 06/12/2014] [Indexed: 01/27/2023]
Abstract
PURPOSE Evidence on the benefits of combining celecoxib, a cyclooxygenase-2 inhibitor, in treating advanced cancer is still controversial. This study aimed to establish the efficacy and safety profile of celecoxib in treating advanced cancers. METHODS The PubMed, Embase, and Cochrane databases and abstracts from the American Society of Clinical Oncology and European Society for Medical Oncology were searched for reports dated up to January 31, 2014, to find relevant randomized clinical trials. The outcomes included overall response rate (ORR), 1-year mortality, progression-free survival, overall survival, and toxicities. Fixed-effects meta-analytical models were used when indicated, and between-study heterogeneity was assessed. Subgroup analysis was conducted according to cancer type, treatment pattern, and treatment line. FINDINGS A total of 11 randomized clinical trials consisting of 2570 patients with advanced cancer were included in the final meta-analysis. Addition of celecoxib to the treatment regimen significantly increased the ORR (pooled risk ratio [RR] = 1.20; 95% CI, 1.06-1.36; P = 0.005) but had no effect on 1-year mortality (RR = 1.02; 95% CI, 0.92-1.13; P = 0.68). Subgroup analysis found that the ORR results were significant with non-small cell lung cancer (RR = 1.29; 95% CI, 1.08-1.54; P = 0.005), colorectal cancer (RR = 1.32; 95% CI, 1.02-1.72; P = 0.037), chemotherapy treatment (RR = 1.22; 95% CI, 1.07-1.39; P = 0.003), and first-line treatment (RR = 1.22; 95% CI, 1.07-1.38; P = 0.003). However, celecoxib increased the risk of cardiovascular events (RR = 1.78; 95% CI, 1.30-2.43; P < 0.001) and anemia (RR = 1.88; 95% CI, 0.95-3.74; P = 0.071). IMPLICATIONS Celecoxib is beneficial in the treatment of advanced cancers but with increased risk of cardiovascular events. Benefit versus harm needs to be carefully considered when celecoxib is recommended in patients with advanced cancers.
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Affiliation(s)
- Jian Chen
- Department of Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, P.R. China
| | - Peng Shen
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, P.R. China
| | - Xiao-chen Zhang
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, P.R. China
| | - Meng-dan Zhao
- Department of Pharmacy, Women's Hospital, College of Medicine, Zhejiang University, Hangzhou, P.R. China
| | - Xing-guo Zhang
- Department of Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, P.R. China.
| | - Liu Yang
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, P.R. China.
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Yokouchi H, Kanazawa K, Ishida T, Oizumi S, Shinagawa N, Sukoh N, Harada M, Ogura S, Munakata M, Dosaka-Akita H, Isobe H, Nishimura M. Cyclooxygenase-2 inhibitors for non-small-cell lung cancer: A phase II trial and literature review. Mol Clin Oncol 2014; 2:744-750. [PMID: 25054040 DOI: 10.3892/mco.2014.319] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 05/13/2014] [Indexed: 11/06/2022] Open
Abstract
Several preclinical and clinical studies have demonstrated that cyclooxygenase-2 (COX-2) inhibitors are efficient for the treatment of non-small-cell lung cancer (NSCLC). However, two recent phase III clinical trials using COX-2 inhibitors in combination with platinum-based chemotherapy failed to demonstrate a survival benefit. Thus, validation and discussion regarding the usefulness of COX-2 inhibitors for patients with NSCLC are required. We conducted a prospective trial using COX-2 inhibitors for the treatment of 50 NSCLC patients accrued between April, 2005 and July, 2006. Patients with untreated advanced NSCLC received oral meloxicam (150 mg daily), carboplatin (area under the curve = 5 mg/ml × min on day 1) and docetaxel (60 mg/m2 on day 1) every 3 weeks. The primary endpoint was response rate. The response and disease control rates were 36.0 and 76.0%, respectively. The time-to-progression (TTP) and overall survival (OS) were 5.7 months [95% confidence interval (CI): 4.6-6.7] and 13.7 months (95% CI: 11.4-15.9), respectively. The 1-year survival ratio was 56.0%. Grade 3 neuropathy was observed in only 1 patient. We performed tumor immunohistochemistry for COX-2 and p27 and investigated the correlation between their expression and clinical outcome. COX-2 expression in the tumor tended to correlate with a higher response rate (50.0% in the high- and 18.2% in the low-COX-2 group; P=0.092). Based on our results and previous reports, various trial designs, such as the prospective use of COX-2 inhibitors only for patients with COX-2-positive NSCLC, including the exploratory analysis of biomarkers associated with the COX-2 pathway, may be worth further consideration.
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Affiliation(s)
- Hiroshi Yokouchi
- Department of Pulmonary Medicine, Fukushima Medical University, Fukushima 960-1295, Japan ; First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Hokkaido 060-8648, Japan
| | - Kenya Kanazawa
- Department of Pulmonary Medicine, Fukushima Medical University, Fukushima 960-1295, Japan
| | - Takashi Ishida
- Department of Pulmonary Medicine, Fukushima Medical University, Fukushima 960-1295, Japan
| | - Satoshi Oizumi
- First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Hokkaido 060-8648, Japan
| | - Naofumi Shinagawa
- First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Hokkaido 060-8648, Japan
| | - Noriaki Sukoh
- Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Hokkaido 003-0804, Japan
| | - Masao Harada
- Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Hokkaido 003-0804, Japan
| | - Shigeaki Ogura
- Department of Respiratory Disease, Sapporo City General Hospital, Sapporo, Hokkaido 060-8604, Japan
| | - Mitsuru Munakata
- Department of Pulmonary Medicine, Fukushima Medical University, Fukushima 960-1295, Japan
| | - Hirotoshi Dosaka-Akita
- Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8648, Japan
| | - Hiroshi Isobe
- Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo, Hokkaido 062-0931, Japan
| | - Masaharu Nishimura
- First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Hokkaido 060-8648, Japan
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A role for cAMP-driven transactivation of EGFR in cancer aggressiveness - therapeutic implications. Med Hypotheses 2014; 83:142-7. [PMID: 24932579 DOI: 10.1016/j.mehy.2014.05.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 04/18/2014] [Accepted: 05/01/2014] [Indexed: 12/29/2022]
Abstract
In many common cancers, production of cAMP boosts cancer proliferation, survival, and aggressiveness, reflecting the fact that, through mechanisms that require further clarification, cAMP can promote tyrosine phosphorylation, notably transactivation of the epidermal growth factor receptor (EGFR). Hormones which activate adenylate cyclase in many cancers include PGE2 - often produced by cox-2 activity within tumors - and adrenergic hormones, acting on beta2 receptors. NSAID cyclooxygenase inhibitors, including low-dose aspirin, clearly reduce risk for many adenocarcinomas, but the impact of cox-2 inhibitors in clinical cancer therapy remains somewhat equivocal. There is increasing evidence that increased sympathetic drive, often reflecting psychic stress or tobacco usage, increases risk for, and promotes the aggressiveness of, many cancers. The non-specific beta antagonist propranolol shows cancer-retardant activity in pre-clinical rodent studies, especially in stressed animals, and a limited amount of epidemiology concludes that concurrent propranolol usage is associated with superior prognosis in breast cancer, ovarian cancer, and melanoma. Epidemiology correlating increased resting heart rate with increased total cancer mortality can be interpreted as compelling evidence that increased sympathetic drive encourages the onset and progression of common cancers. Conversely, hormones which inhibit adenylate cyclase activity in cancers may have potential for cancer control; GABA, which can be administered as a well-tolerated nutraceutical, has potential in this regard. Combination regimens intended to down-regulate cancer cAMP levels, perhaps used in conjunction with EGFR inhibitors, may have considerable potential for suppressing the contribution of cAMP/EGFR to cancer aggressiveness. This model also predicts that certain other hormones which activate adenylate cylase in various tissue may play a yet-unsuspected role in cancer induction and spread.
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Azzoli CG, Pisters KM. Neoadjuvant Chemotherapy for Resectable Non-Small Cell Lung Cancer. Lung Cancer 2014. [DOI: 10.1002/9781118468791.ch19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Pan Y, Cheng T, Wang Y, Bryant SH. Pathway analysis for drug repositioning based on public database mining. J Chem Inf Model 2014; 54:407-18. [PMID: 24460210 PMCID: PMC3956470 DOI: 10.1021/ci4005354] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
![]()
Sixteen FDA-approved
drugs were investigated to elucidate their
mechanisms of action (MOAs) and clinical functions by pathway analysis
based on retrieved drug targets interacting with or affected by the
investigated drugs. Protein and gene targets and associated pathways
were obtained by data-mining of public databases including the MMDB,
PubChem BioAssay, GEO DataSets, and the BioSystems databases. Entrez
E-Utilities were applied, and in-house Ruby scripts were developed
for data retrieval and pathway analysis to identify and evaluate relevant
pathways common to the retrieved drug targets. Pathways pertinent
to clinical uses or MOAs were obtained for most drugs. Interestingly,
some drugs identified pathways responsible for other diseases than
their current therapeutic uses, and these pathways were verified retrospectively
by in vitro tests, in vivo tests, or clinical trials. The pathway
enrichment analysis based on drug target information from public databases
could provide a novel approach for elucidating drug MOAs and repositioning,
therefore benefiting the discovery of new therapeutic treatments for
diseases.
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Affiliation(s)
- Yongmei Pan
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health , 8600 Rockville Pike, Bethesda, Maryland 20894, United States
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Abstract
Approximately one third of patients with non-small cell lung cancer have unresectable stage IIIA or stage IIIB disease; combined cytotoxic chemotherapy and radiation therapy delivered concurrently has been established as the standard treatment for such patients. Despite many clinical trials that tested several different radiochemotherapy combinations, it seems that a plateau of efficiencies at the acceptable risk of complications has been reached. Clinical studies indicate that the improved efficacy of radiochemotherapy is associated with the radiosensitizing effects of chemotherapy. Improvement of outcomes of this combined modality by developing novel radiosensitizers is a viable therapeutic strategy. In addition to causing cell death, ionizing radiation also induces a many-faceted signaling response, which activates numerous prosurvival pathways that lead to enhanced proliferation in the endothelial cells and increased vascularization in tumors. Radiation at doses used in the clinic activates cytoplasmic phospholipase A2, leading to increased production of arachidonic acid and lysophosphatidylcholine. The former is the initial step in the generation of eicosanoids, while the later is the initial step in the formation of lysophosphatidic acid, leading to the activation of inflammatory pathways. The echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) is member of the insulin superfamily of receptor tyrosine kinases. The EML4-ALK fusion gene appears unique to lung cancer and signals through extracellular signal regulated kinase and phosphoinositide 3-kinase. Heat shock protein 90 (Hsp90) is often overexpressed and present in an activated multichaperone complex in cancer cells, and it is now regarded as essential for malignant transformation and progression. In this review we focus on radiosensitizing strategies involving the targeting of membrane phospholipids, EML4-ALK, and Hsp90 with specific inhibitors and briefly discuss the combination of radiation with antivascular agents.
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Understanding clinical strategies that may impact tumour growth and metastatic spread at the time of cancer surgery. Best Pract Res Clin Anaesthesiol 2013; 27:427-39. [DOI: 10.1016/j.bpa.2013.10.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Accepted: 10/07/2013] [Indexed: 12/19/2022]
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Abstract
The development of targeted therapies in lung cancer (mainly non-small cell lung cancer) has led to improvement in clinical outcomes and a more personalized approach to the management of these patients. This article discusses the main categories of novel targeted agents and the evidence behind their use.
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Affiliation(s)
- Shobha Silva
- Department of Oncology, Weston Park Hospital, Whitham Road, Sheffield S10 2SJ, UK
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Liu CH, Bao HG, Ge YL, Wang SK, Shen Y, Xu L. Celecoxib inhibits insulin-like growth factor 1 induced growth and invasion in non-small cell lung cancer. Oncol Lett 2013; 5:1943-1947. [PMID: 23833672 PMCID: PMC3701083 DOI: 10.3892/ol.2013.1277] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Accepted: 02/18/2013] [Indexed: 12/20/2022] Open
Abstract
Despite a large number of studies indicating that celecoxib plays an important role in the prevention and treatment of tumors, the detailed molecular mechanisms are not well understood. The aim of the present study was to investigate the effect of celecoxib on insulin-like growth factor 1 (IGF-1)-induced growth and invasion in non-small cell lung cancer (NSCLC). For these experiments, IGF-1-induced cell growth and invasion were analyzed in A549 cells in the presence and absence of celecoxib. The effects of celecoxib on the expression of phosphorylated type-1 IGF receptor (IGF-1R) and phosphorylated AKT (p-AKT) were examined using western blot analysis. The influence of celecoxib on IGF-binding protein-3 (IGFBP-3) expression was analyzed using ELISA. Celecoxib inhibited IGF-1-stimulated growth and invasion in a dose-dependent manner. Celecoxib also reduced the expression of IGF-1R, IGFBP-3 and phosphorylation of AKT. The results suggest that modulating the IGF axis may be a new mechanism for the anticancer effect of celecoxib on NSCLC.
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Affiliation(s)
- Chen-Hui Liu
- Departments of Anesthesiology, Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing 210006, P.R. China
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Prediagnostic nonsteroidal anti-inflammatory drug use and lung cancer survival in the VITAL study. J Thorac Oncol 2013; 7:1503-12. [PMID: 22982651 DOI: 10.1097/jto.0b013e3182641bdc] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Inflammation is important for lung oncogenesis. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to improve colorectal cancer survival. However, few studies have examined the association in lung cancer patients. METHODS The VITamins And Lifestyle (VITAL) cohort includes Washington State residents, aged 50 to 76 years, who completed a baseline questionnaire between 2000 and 2002. Participants responded on the frequency and duration of use of individual NSAIDs in the previous 10 years. Subjects of this study were 785 members of the cohort, who were identified with incident lung cancer from baseline through 2007 through linkage to a population-based cancer registry. Participants were followed for lung cancer death through linkage to state records of death through 2009. Adjusted proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between NSAIDs and lung cancer death. RESULTS Five hundred and twenty-two participants (66%) died from lung cancer. Relative to nonuse, high (≥ 4 days/week and ≥ 4 years) prediagnostic use of regular-strength or low-dose aspirin (HR 0.99, 95% CI: 0.74-1.33 and HR 0.89, 95% CI: 0.67-1.17, respectively) or total nonaspirin NSAIDs (HR 1.20, 95% CI: 0.79-1.83) did not reduce lung cancer death. However, high use of ibuprofen was associated with a 62% increased risk of lung cancer death (HR 1.62, 95% CI: 1.01-2.58). CONCLUSIONS Long-term, prediagnostic NSAID use does not improve lung cancer survival overall. Use of ibuprofen may reduce survival from lung cancer. Our results underscore the need for further study of the mechanisms of action for individual NSAIDs with regard to cancer survival.
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Allaj V, Guo C, Nie D. Non-steroid anti-inflammatory drugs, prostaglandins, and cancer. Cell Biosci 2013; 3:8. [PMID: 23388178 PMCID: PMC3599181 DOI: 10.1186/2045-3701-3-8] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Accepted: 01/21/2013] [Indexed: 01/10/2023] Open
Abstract
Fatty acids are involved in multiple pathways and play a pivotal role in health. Eicosanoids, derived from arachidonic acid, have received extensive attention in the field of cancer research. Following release from the phospholipid membrane, arachidonic acid can be metabolized into different classes of eicosanoids through cyclooxygenases, lipoxygenases, or p450 epoxygenase pathways. Non-steroid anti-inflammatory drugs (NSAIDs) are widely consumed as analgesics to relieve minor aches and pains, as antipyretics to reduce fever, and as anti-inflammatory medications. Most NSAIDs are nonselective inhibitors of cyclooxygenases, the rate limiting enzymes in the formation of prostaglandins. Long term use of some NSAIDs has been linked with reduced incidence and mortality in many cancers. In this review, we appraise the biological activities of prostanoids and their cognate receptors in the context of cancer biology. The existing literature supports that these lipid mediators are involved to a great extent in the occurrence and progression of cancer.
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Affiliation(s)
- Viola Allaj
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine and Simmons Cancer Institute, Springfield, IL, 62794, USA.
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Wang ZL, Fan ZQ, Jiang HD, Qu JM. Selective Cox-2 inhibitor celecoxib induces epithelial-mesenchymal transition in human lung cancer cells via activating MEK-ERK signaling. Carcinogenesis 2012; 34:638-46. [DOI: 10.1093/carcin/bgs367] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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Sörenson S, Fohlin H, Lindgren A, Lindskog M, Bergman B, Sederholm C, Ek L, Lamberg K, Clinchy B. Predictive role of plasma vascular endothelial growth factor for the effect of celecoxib in advanced non-small cell lung cancer treated with chemotherapy. Eur J Cancer 2012; 49:115-20. [PMID: 22951014 DOI: 10.1016/j.ejca.2012.07.032] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2012] [Revised: 07/04/2012] [Accepted: 07/31/2012] [Indexed: 01/27/2023]
Abstract
AIM OF THE STUDY The primary purpose of this study is to investigate if pretreatment plasma levels of vascular endothelial growth factor (VEGF) are predictive of the effect of celecoxib on survival in advanced non-small cell lung cancer (NSCLC) treated with palliative chemotherapy. A secondary objective is to describe the course of plasma VEGF levels during and after treatment with cytotoxic chemotherapy combined with celecoxib or placebo. METHODS In a previously published double-blind multicenter phase III trial, 316 patients with NSCLC stage IIIB or IV and World Health Organisation (WHO) performance status 0-2 were randomised to receive celecoxib 400mg b.i.d. or placebo in combination with two-drug platinum-based chemotherapy. Chemotherapy cycle length was three weeks and planned duration of chemotherapy was four cycles. Celecoxib was given for a maximum of one year but was stopped earlier in case of disease progression or prohibitive toxicity. In a subset of patients, plasma VEGF levels were examined at onset of treatment and at 6, 12 and 20 weeks. RESULTS VEGF levels at start of treatment were obtained in 107 patients at four study sites. The median value was 70 pg/ml. Mean values declined during the first 12 weeks and then increased at 20 weeks. A subpopulation treatment effect pattern plot (STEPP) analysis showed an inverse relationship between initial plasma VEGF and the impact of celecoxib on survival with zero effect at 200 pg/ml. The effect on survival by celecoxib in the whole subset of patients was positive (hazard ratio (HR)=0.64 [confidence interval (CI) 0.43-0.95], p=0.028). CONCLUSION Low pretreatment plasma levels of VEGF appear to be predictive of a positive effect of celecoxib on survival.
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Affiliation(s)
- Sverre Sörenson
- Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Sweden.
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Liu DZ, Ander BP. Cell cycle inhibition without disruption of neurogenesis is a strategy for treatment of aberrant cell cycle diseases: an update. ScientificWorldJournal 2012; 2012:491737. [PMID: 22547985 PMCID: PMC3323905 DOI: 10.1100/2012/491737] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2011] [Accepted: 11/17/2011] [Indexed: 12/12/2022] Open
Abstract
Since publishing our earlier report describing a strategy for the treatment of central nervous system (CNS) diseases by inhibiting the cell cycle and without disrupting neurogenesis (Liu et al. 2010), we now update and extend this strategy to applications in the treatment of cancers as well. Here, we put forth the concept of "aberrant cell cycle diseases" to include both cancer and CNS diseases, the two unrelated disease types on the surface, by focusing on a common mechanism in each aberrant cell cycle reentry. In this paper, we also summarize the pharmacological approaches that interfere with classical cell cycle molecules and mitogenic pathways to block the cell cycle of tumor cells (in treatment of cancer) as well as to block the cell cycle of neurons (in treatment of CNS diseases). Since cell cycle inhibition can also block proliferation of neural progenitor cells (NPCs) and thus impair brain neurogenesis leading to cognitive deficits, we propose that future strategies aimed at cell cycle inhibition in treatment of aberrant cell cycle diseases (i.e., cancers or CNS diseases) should be designed with consideration of the important side effects on normal neurogenesis and cognition.
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Affiliation(s)
- Da-Zhi Liu
- Department of Neurology and the MIND Institute, University of California at Davis, Sacramento, CA 95817, USA.
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Autocrine prostaglandin E2 signaling promotes tumor cell survival and proliferation in childhood neuroblastoma. PLoS One 2012; 7:e29331. [PMID: 22276108 PMCID: PMC3261878 DOI: 10.1371/journal.pone.0029331] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2011] [Accepted: 11/25/2011] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Prostaglandin E(2) (PGE(2)) is an important mediator in tumor-promoting inflammation. High expression of cyclooxygenase-2 (COX-2) has been detected in the embryonic childhood tumor neuroblastoma, and treatment with COX inhibitors significantly reduces tumor growth. Here, we have investigated the significance of a high COX-2 expression in neuroblastoma by analysis of PGE(2) production, the expression pattern and localization of PGE(2) receptors and intracellular signal transduction pathways activated by PGE(2). PRINCIPAL FINDINGS A high expression of the PGE(2) receptors, EP1, EP2, EP3 and EP4 in primary neuroblastomas, independent of biological and clinical characteristics, was detected using immunohistochemistry. In addition, mRNA and protein corresponding to each of the receptors were detected in neuroblastoma cell lines. Immunofluorescent staining revealed localization of the receptors to the cellular membrane, in the cytoplasm, and in the nuclear compartment. Neuroblastoma cells produced PGE(2) and stimulation of serum-starved neuroblastoma cells with PGE(2) increased the intracellular concentration of calcium and cyclic AMP with subsequent phosphorylation of Akt. Addition of 16,16-dimethyl PGE(2) (dmPGE(2)) increased cell viability in a time, dose- and cell line-dependent manner. Treatment of neuroblastoma cells with a COX-2 inhibitor resulted in a diminished cell growth and viability that was reversed by the addition of dmPGE(2). Similarly, PGE(2) receptor antagonists caused a decrease in neuroblastoma cell viability in a dose-dependent manner. CONCLUSIONS These findings demonstrate that PGE(2) acts as an autocrine and/or paracrine survival factor for neuroblastoma cells. Hence, specific targeting of PGE(2) signaling provides a novel strategy for the treatment of childhood neuroblastoma through the inhibition of important mediators of tumor-promoting inflammation.
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