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Samoudi A, Abolhasani-Zadeh F, Afgar A, Jalilian E, Zeinalynezhad H, Langroudi L. Treatment of cancer-associated fibroblast-like cells with celecoxib enhances the anti-cancer T helper 1/Treg responses in breast cancer. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:6099-6112. [PMID: 39652176 DOI: 10.1007/s00210-024-03641-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 11/15/2024] [Indexed: 04/11/2025]
Abstract
Tumor inflammation, as one of the hallmarks of cancer, has been the target for anti-cancer treatments. Celecoxib is a selective inhibitor of the enzyme cycloxygenase-2 (COX-2) and inhibits the production of PGE2, which is an important mediator of tumor inflammation produced by cancer cells and cells of the tumor microenvironment. In this study, we aimed at inhibiting COX-2 using celecoxib, expressed in cancer-associated fibroblast (CAF)-like cells isolated from breast cancer and evaluated the alterations in their cytokine profile and gene expression. CAF-like cells were isolated by explant culture from 13 breast cancer tissues. Simultaneously, peripheral blood mononuclear cells (PBMCs) were isolated from patients' blood. CAF-like cells were treated with 10 µM of celecoxib and expression of genes COX-2, smooth muscle actin-alpha (α-SMA), and production of prostaglandin E2 (PGE2), Interleukin 10 (IL10), and transforming growth factor beta1 (TGF-β1) was evaluated. Next, PBMCs were co-cultured with celecoxib-treated CAF-like cells and the expression of genes T-bet, Foxp3, GATA-3; production of cytokines IFN-ɣ, IL-10, IL-4, TGF-β1, and the mediator PGE2 were assessed by real-time-PCR and ELISA, respectively. Isolated CAF-like cells showed expression of fibroblast activation protein (FAP). Treatment with celecoxib was able to efficiently reduce the production of PGE2 and the expression of α-SMA in isolated CAF-like cells. Furthermore, PBMCs in co-culture with these cells showed enhanced Th1 phenotype including T-bet and IFNγ expression and decreased the phenotypical markers of regulatory T cells such as FoxP3 and IL-10 and TGF-β1 production. Our study shows the important role of COX-2 in CAFs by promoting immune suppression. Our results suggested that high expression of COX-2 in CAFs may serve as a new therapeutic, targeting CAFs in enhancing immune responses in breast cancer treatment.
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Affiliation(s)
- Arash Samoudi
- Department of Medical Immunology, School of Medicine, Kerman University of Medical Sciences, Pajoohesh Sq, Kerman, 7616914111, Iran
| | | | - Ali Afgar
- Research center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran
| | - Elnaz Jalilian
- Department of Medical Immunology, School of Medicine, Kerman University of Medical Sciences, Pajoohesh Sq, Kerman, 7616914111, Iran
| | - Hamid Zeinalynezhad
- Department of Surgery, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Ladan Langroudi
- Department of Medical Immunology, School of Medicine, Kerman University of Medical Sciences, Pajoohesh Sq, Kerman, 7616914111, Iran.
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Li J, Wang X, Zhang H, Hu X, Peng X, Jiang W, Zhuo L, Peng Y, Zeng G, Wang Z. Fenamates: Forgotten treasure for cancer treatment and prevention: Mechanisms of action, structural modification, and bright future. Med Res Rev 2025; 45:164-213. [PMID: 39171404 DOI: 10.1002/med.22079] [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: 12/13/2022] [Revised: 08/03/2024] [Accepted: 08/08/2024] [Indexed: 08/23/2024]
Abstract
Fenamates as classical nonsteroidal anti-inflammatory agents are widely used for relieving pain. Preclinical studies and epidemiological data highlight their chemo-preventive and chemotherapeutic potential for cancer. However, comprehensive reviews of fenamates in cancer are limited. To accelerate the repurposing of fenamates, this review summarizes the results of fenamates alone or in combination with existing chemotherapeutic agents. This paper also explores targets of fenamates in cancer therapy, including COX, AKR family, AR, gap junction, FTO, TEAD, DHODH, TAS2R14, ion channels, and DNA. Besides, this paper discusses other mechanisms, such as regulating Wnt/β-catenin, TGF-β, p38 MAPK, and NF-κB pathway, and the regulation of the expressions of Sp, EGR-1, NAG-1, ATF-3, ErbB2, AR, as well as the modulation of the tumor immune microenvironment. Furthermore, this paper outlined the structural modifications of fenamates, highlighting their potential as promising leads for anticancer drugs.
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Affiliation(s)
- Junfang Li
- School of Pharmacy, Lanzhou University, Lanzhou, Gansu, China
| | - Xiaodong Wang
- School of Pharmacy, Lanzhou University, Lanzhou, Gansu, China
| | - Honghua Zhang
- School of Pharmacy, Lanzhou University, Lanzhou, Gansu, China
| | - Xiaoling Hu
- School of Pharmacy, Lanzhou University, Lanzhou, Gansu, China
| | - Xue Peng
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Weifan Jiang
- Postdoctoral Station for Basic Medicine, School of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Linsheng Zhuo
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Postdoctoral Station for Basic Medicine, School of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yan Peng
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Guo Zeng
- Postdoctoral Station for Basic Medicine, School of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Zhen Wang
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Postdoctoral Station for Basic Medicine, School of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China
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Gu M, Liu Y, Zheng W, Jing Z, Li X, Guo W, Zhao Z, Yang X, Liu Z, Zhu X, Gao W. Combined targeting of senescent cells and senescent macrophages: A new idea for integrated treatment of lung cancer. Semin Cancer Biol 2024; 106-107:43-57. [PMID: 39214157 DOI: 10.1016/j.semcancer.2024.08.006] [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: 07/17/2024] [Revised: 08/18/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
Lung cancer is one of the most common cancers worldwide and a leading cause of cancer-related deaths. Macrophages play a key role in the immune response and the tumour microenvironment. As an important member of the immune system, macrophages have multiple functions, including phagocytosis and clearance of pathogens, modulation of inflammatory responses, and participation in tissue repair and regeneration. In lung cancer, macrophages are considered to be the major cellular component of the tumor-associated inflammatory response and are closely associated with tumorigenesis, progression and metastasis. However, macrophages gradually undergo a senescence process with age and changes in pathological states. Macrophage senescence is an important change in the functional and metabolic state of macrophages and may have a significant impact on lung cancer development. In lung cancer, senescent macrophages interact with other cells in the tumor microenvironment (TME) by secreting senescence-associated secretory phenotype (SASP) factors, which can either promote the proliferation, invasion and metastasis of tumor cells or exert anti-tumor effects through reprogramming or clearance under specific conditions. Therefore, senescent macrophages are considered important potential targets for lung cancer therapy. In this paper, a systematic review of macrophages and their senescence process, and their role in tumors is presented. A variety of inhibitory strategies against senescent macrophages, including enhancing autophagy, inhibiting SASP, reducing DNA damage, and modulating metabolic pathways, were also explored. These strategies are expected to improve lung cancer treatment outcomes by restoring the anti-tumor function of macrophages.
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Affiliation(s)
- Ming Gu
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Yang Liu
- Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Wenhui Zheng
- Department of Anesthesiology, The Shengjing Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Zuoqian Jing
- Department of Ophthalmology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Xiang Li
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Wei Guo
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Zimo Zhao
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Xu Yang
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Zhe Liu
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Xinwang Zhu
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Wei Gao
- Department of Gastrointestinal Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
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Mahboubi-Rabbani M, Abdolghaffari AH, Ghesmati M, Amini A, Zarghi A. Selective COX-2 inhibitors as anticancer agents: a patent review (2018-2023). Expert Opin Ther Pat 2024; 34:733-757. [PMID: 38958471 DOI: 10.1080/13543776.2024.2373771] [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: 12/11/2023] [Accepted: 06/25/2024] [Indexed: 07/04/2024]
Abstract
INTRODUCTION COX-2 is a crucial enzyme in the manufacture of prostaglandins. The enzyme's metabolites might have an important function as regulators of the inflammatory response and other medical conditions such as cancer. Selective COX-2 inhibitors are believed to enhance or reverse the response of cancer chemotherapeutics. AREAS COVERED This study addresses the chemical structures as well as the antitumor activity of new COX-2 inhibitors produced in the recent five years, aiming to provide an insight into the mechanism of COX-2 induced PGE2 powerful signal in cancer development. EXPERT OPINION The significance of selective COX-2 inhibitors as an efficient superfamily of compounds with anti-inflammatory, anti-Alzheimer's, anti-Parkinson's disease, and anticancer properties has piqued the passion of academics in the field of drug development. Long-term usage of selective COX-2 inhibitors, such as celecoxib has been proven in clinical trials to lower the incidence of several human malignancies. Furthermore, celecoxib has the potential to greatly increase the effectiveness of chemotherapy. Our extensive understanding of selective COX-2 inhibitor SAR may aid in the development of safer and more effective selective COX-2 inhibitors as cancer chemopreventive agents. This review focuses on the different structural classes of selective COX-2 inhibitors, with a particular emphasis on their SAR.
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Affiliation(s)
- Mohammad Mahboubi-Rabbani
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amir Hossein Abdolghaffari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mahsa Ghesmati
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ali Amini
- Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afshin Zarghi
- Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Xu Y, Wang J, He Z, Rao Z, Zhang Z, Zhou J, Zhou T, Wang H. A review on the effect of COX-2-mediated mechanisms on development and progression of gastric cancer induced by nicotine. Biochem Pharmacol 2024; 220:115980. [PMID: 38081368 DOI: 10.1016/j.bcp.2023.115980] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/07/2023] [Accepted: 12/08/2023] [Indexed: 12/24/2023]
Abstract
Smoking is a documented risk factor for cancer, e.g., gastric cancer. Nicotine, the principal tobacco alkaloid, would exert its role of contribution to gastric cancer development and progression through nicotinic acetylcholine receptors (nAChRs) and β-adrenergic receptors (β-ARs), which then promote cancer cell proliferation, migration and invasion. As a key isoenzyme in conversion of arachidonic acid to prostaglandins, cyclooxygenase-2 (COX-2) has been demonstrated to have a wide range of effects in carcinogenesis and tumor development. At present, many studies have reported the effect of nicotine on gastric cancer by binding to nAChR, as well as indirectly stimulating β-AR to mediate COX-2-related pathways. This review summarizes these studies, and also proposes more potential COX-2-mediated mechanisms. These events might contribute to the growth and progression of gastric cancer exposed to nicotine through tobacco smoke or cigarette substitutes. Also, this review article has therefore the potential not only to make a significant contribution to the treatment and prognosis of gastric cancer for smokers but also to the clinical application of COX-2 antagonists. In addition, this work also discusses the considerable challenges of this field with special reference to the future perspective of COX-2-mediated mechanisms in development and progression of gastric cancer induced by nicotine.
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Affiliation(s)
- Yuqin Xu
- School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
| | - Juan Wang
- School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China
| | - Zihan He
- School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
| | - Zihan Rao
- School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
| | - Zhongwei Zhang
- School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
| | - Jianming Zhou
- School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
| | - Tong Zhou
- School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
| | - Huai Wang
- School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China.
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Aliabadi A, Khanniri E, Mahboubi-Rabbani M, Bayanati M. Dual COX-2/15-LOX inhibitors: A new avenue in the prevention of cancer. Eur J Med Chem 2023; 261:115866. [PMID: 37862815 DOI: 10.1016/j.ejmech.2023.115866] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 10/07/2023] [Accepted: 10/09/2023] [Indexed: 10/22/2023]
Abstract
Dual cyclooxygenase 2/15-lipoxygenase inhibitors constitute a valuable alternative to classical non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 (cyclooxygenase-2) inhibitors for the treatment of inflammatory diseases, as well as preventing the cancer. Indeed, these latter present diverse side effects, which are reduced or absent in dual-acting agents. In this review, COX-2 and 15-LOX (15-lipoxygenase) pathways are first described in order to highlight the therapeutic interest of designing such compounds. Various structural families of dual inhibitors are illustrated. This study discloses various structural families of dual 15-LOX/COX-2 inhibitors, thus pave the way to design potentially-active anticancer agents with balanced dual inhibition of these enzymes.
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Affiliation(s)
- Ali Aliabadi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elham Khanniri
- Department of Food Science and Technology, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Mahboubi-Rabbani
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Maryam Bayanati
- Department of Food Science and Technology, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Zhang Y, Liu Y, Sun J, Zhang W, Guo Z, Ma Q. Arachidonic acid metabolism in health and disease. MedComm (Beijing) 2023; 4:e363. [PMID: 37746665 PMCID: PMC10511835 DOI: 10.1002/mco2.363] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 08/13/2023] [Accepted: 08/17/2023] [Indexed: 09/26/2023] Open
Abstract
Arachidonic acid (AA), an n-6 essential fatty acid, is a major component of mammalian cells and can be released by phospholipase A2. Accumulating evidence indicates that AA plays essential biochemical roles, as it is the direct precursor of bioactive lipid metabolites of eicosanoids such as prostaglandins, leukotrienes, and epoxyeicosatrienoic acid obtained from three distinct enzymatic metabolic pathways: the cyclooxygenase pathway, lipoxygenase pathway, and cytochrome P450 pathway. AA metabolism is involved not only in cell differentiation, tissue development, and organ function but also in the progression of diseases, such as hepatic fibrosis, neurodegeneration, obesity, diabetes, and cancers. These eicosanoids are generally considered proinflammatory molecules, as they can trigger oxidative stress and stimulate the immune response. Therefore, interventions in AA metabolic pathways are effective ways to manage inflammatory-related diseases in the clinic. Currently, inhibitors targeting enzymes related to AA metabolic pathways are an important area of drug discovery. Moreover, many advances have also been made in clinical studies of AA metabolic inhibitors in combination with chemotherapy and immunotherapy. Herein, we review the discovery of AA and focus on AA metabolism in relation to health and diseases. Furthermore, inhibitors targeting AA metabolism are summarized, and potential clinical applications are discussed.
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Affiliation(s)
- Yiran Zhang
- Department of Orthopedic SurgeryOrthopedic Oncology InstituteThe Second Affiliated Hospital of Air Force Medical UniversityXi'anChina
| | - Yingxiang Liu
- Department of Orthopedic SurgeryOrthopedic Oncology InstituteThe Second Affiliated Hospital of Air Force Medical UniversityXi'anChina
| | - Jin Sun
- Department of Orthopedic SurgeryOrthopedic Oncology InstituteThe Second Affiliated Hospital of Air Force Medical UniversityXi'anChina
| | - Wei Zhang
- Department of PathologyThe Second Affiliated Hospital of Air Force Medical UniversityXi'anChina
| | - Zheng Guo
- Department of Orthopedic SurgeryOrthopedic Oncology InstituteThe Second Affiliated Hospital of Air Force Medical UniversityXi'anChina
| | - Qiong Ma
- Department of Orthopedic SurgeryOrthopedic Oncology InstituteThe Second Affiliated Hospital of Air Force Medical UniversityXi'anChina
- Department of PathologyThe Second Affiliated Hospital of Air Force Medical UniversityXi'anChina
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Li K, Zeng X, Liu P, Zeng X, Lv J, Qiu S, Zhang P. The Role of Inflammation-Associated Factors in Head and Neck Squamous Cell Carcinoma. J Inflamm Res 2023; 16:4301-4315. [PMID: 37791117 PMCID: PMC10544098 DOI: 10.2147/jir.s428358] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/16/2023] [Indexed: 10/05/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC), which originates in the head or neck tissues, is characterized by high rates of recurrence and metastasis. Inflammation is important in HNSCC prognosis. Inflammatory cells and their secreted factors contribute to the various stages of HNSCC development through multiple mechanisms. In this review, the mechanisms through which inflammatory factors, signaling pathways, and cells contribute to the initiation and progression of HNSCC have been discussed in detail. Furthermore, the diagnostic and therapeutic potential of targeting inflammation in HNSCC has been discussed to gain new insights into improving patient prognosis.
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Affiliation(s)
- Kang Li
- Department of Graduate and Scientific Research, Zunyi Medical University Zhuhai Campus, Zhuhai, Guangdong, People’s Republic of China
- Department of Otorhinolaryngology, Longgang Otorhinolaryngology Hospital & Shenzhen Key Laboratory of Otorhinolaryngology, Shenzhen Institute of Otorhinolaryngology, Shenzhen, Guangdong, People’s Republic of China
| | - Xianhai Zeng
- Department of Graduate and Scientific Research, Zunyi Medical University Zhuhai Campus, Zhuhai, Guangdong, People’s Republic of China
- Department of Otorhinolaryngology, Longgang Otorhinolaryngology Hospital & Shenzhen Key Laboratory of Otorhinolaryngology, Shenzhen Institute of Otorhinolaryngology, Shenzhen, Guangdong, People’s Republic of China
| | - Peng Liu
- Department of Graduate and Scientific Research, Zunyi Medical University Zhuhai Campus, Zhuhai, Guangdong, People’s Republic of China
- Department of Otorhinolaryngology, Longgang Otorhinolaryngology Hospital & Shenzhen Key Laboratory of Otorhinolaryngology, Shenzhen Institute of Otorhinolaryngology, Shenzhen, Guangdong, People’s Republic of China
| | - Xiaoxia Zeng
- Department of Otorhinolaryngology, Longgang Otorhinolaryngology Hospital & Shenzhen Key Laboratory of Otorhinolaryngology, Shenzhen Institute of Otorhinolaryngology, Shenzhen, Guangdong, People’s Republic of China
| | - Jie Lv
- School of Computer Science and Engineering, Yulin Normal University, Yulin, Guangxi, People’s Republic of China
| | - Shuqi Qiu
- Department of Graduate and Scientific Research, Zunyi Medical University Zhuhai Campus, Zhuhai, Guangdong, People’s Republic of China
- Department of Otorhinolaryngology, Longgang Otorhinolaryngology Hospital & Shenzhen Key Laboratory of Otorhinolaryngology, Shenzhen Institute of Otorhinolaryngology, Shenzhen, Guangdong, People’s Republic of China
| | - Peng Zhang
- Department of Graduate and Scientific Research, Zunyi Medical University Zhuhai Campus, Zhuhai, Guangdong, People’s Republic of China
- Department of Otorhinolaryngology, Longgang Otorhinolaryngology Hospital & Shenzhen Key Laboratory of Otorhinolaryngology, Shenzhen Institute of Otorhinolaryngology, Shenzhen, Guangdong, People’s Republic of China
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Liu X, Wenisch D, Dahlke P, Jordan PM, Jakupec MA, Kowol CR, Liebing P, Werz O, Keppler BK, Weigand W. Multi-action platinum(IV) prodrugs conjugated with COX-inhibiting NSAIDs. Eur J Med Chem 2023; 257:115515. [PMID: 37295160 DOI: 10.1016/j.ejmech.2023.115515] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/21/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023]
Abstract
In the last decades, inflammation has been recognized as being closely connected to cancer, and joint strategies encompassing chemotherapeutic and anti-inflammatory agents have been extensively studied. In this work, a series of novel cisplatin and oxaliplatin-based Pt(IV) complexes comprising non-steroidal anti-inflammatory drugs (NSAIDs) and their carboxyl ester analogues as axial moieties were synthesized. Several of the cisplatin-based Pt(IV) complexes 22-30 showed increased cytotoxicity in the human cancer cell lines CH1/PA-1, SW480 and A549 compared to the Pt(II) drug. For the most potent complex 26, comprising two aceclofenac (AFC) moieties, the formation of Pt(II)-9-methylguanine (9-MeG) adducts after activation with ascorbic acid (AsA) was proven. Additionally, a significant inhibition of cyclooxygenase (COX) activity and prostaglandin E2 (PGE2) production was observed, as well as increased cellular accumulation, depolarization of mitochondrial membranes, and strong proapoptotic potencies in SW480 cells. Overall, these systematic effects shown in vitro confer 26 as a potential anticancer agent combined with anti-inflammatory properties.
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Affiliation(s)
- Xiao Liu
- Institute for Inorganic and Analytical Chemistry, Friedrich Schiller Universität Jena, Humboldt Str. 8, 07743, Jena, Germany
| | - Dominik Wenisch
- Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Strasse 42, 1090, Vienna, Austria
| | - Philipp Dahlke
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743, Jena, Germany
| | - Paul M Jordan
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743, Jena, Germany
| | - Michael A Jakupec
- Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Strasse 42, 1090, Vienna, Austria; Research Cluster 'Translational Cancer Therapy Research', University of Vienna, Währinger Strasse 42, 1090, Vienna, Austria
| | - Christian R Kowol
- Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Strasse 42, 1090, Vienna, Austria; Research Cluster 'Translational Cancer Therapy Research', University of Vienna, Währinger Strasse 42, 1090, Vienna, Austria
| | - Phil Liebing
- Institute for Inorganic and Analytical Chemistry, Friedrich Schiller Universität Jena, Humboldt Str. 8, 07743, Jena, Germany
| | - Oliver Werz
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743, Jena, Germany.
| | - Bernhard K Keppler
- Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Strasse 42, 1090, Vienna, Austria; Research Cluster 'Translational Cancer Therapy Research', University of Vienna, Währinger Strasse 42, 1090, Vienna, Austria.
| | - Wolfgang Weigand
- Institute for Inorganic and Analytical Chemistry, Friedrich Schiller Universität Jena, Humboldt Str. 8, 07743, Jena, Germany.
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Na H, Song Y, Lee HW. Emphasis on Adipocyte Transformation: Anti-Inflammatory Agents to Prevent the Development of Cancer-Associated Adipocytes. Cancers (Basel) 2023; 15:cancers15020502. [PMID: 36672449 PMCID: PMC9856688 DOI: 10.3390/cancers15020502] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/05/2023] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Of the various cell types in the tumor microenvironment (TME), adipocytes undergo a dynamic transformation when activated by neighboring cancer cells. Although these adipocytes, known as cancer-associated adipocytes (CAAs), have been reported to play a crucial role in tumor progression, the factors that mediate their transformation remain elusive. In this review, we discuss the hypothesis that inflammatory signals involving NF-ĸB activation can induce lipolysis and adipocyte dedifferentiation. This provides a mechanistic understanding of CAA formation and introduces the concept of preventing adipocyte transformation via anti-inflammatory agents. Indeed, epidemiological studies indicate a higher efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in obese patients with cancer, suggesting that NSAIDs can modulate the TME. Inhibition of cyclooxygenase-2 (COX-2) and prostaglandin production leads to the suppression of inflammatory signals such as NF-ĸB. Thus, we suggest the use of NSAIDs in cancer patients with metabolic disorders to prevent the transformation of TME components. Moreover, throughout this review, we attempt to expand our knowledge of CAA transformation to improve the clinical feasibility of targeting CAAs.
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Affiliation(s)
- Heeju Na
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
| | - Yaechan Song
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
| | - Han-Woong Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
- Gemcro Corporation, Seoul 03722, Republic of Korea
- Correspondence: ; Tel.: +82-2-2123-7642
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11
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Firnau MB, Brieger A. CK2 and the Hallmarks of Cancer. Biomedicines 2022; 10:1987. [PMID: 36009534 PMCID: PMC9405757 DOI: 10.3390/biomedicines10081987] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 08/08/2022] [Accepted: 08/10/2022] [Indexed: 11/29/2022] Open
Abstract
Cancer is a leading cause of death worldwide. Casein kinase 2 (CK2) is commonly dysregulated in cancer, impacting diverse molecular pathways. CK2 is a highly conserved serine/threonine kinase, constitutively active and ubiquitously expressed in eukaryotes. With over 500 known substrates and being estimated to be responsible for up to 10% of the human phosphoproteome, it is of significant importance. A broad spectrum of diverse types of cancer cells has been already shown to rely on disturbed CK2 levels for their survival. The hallmarks of cancer provide a rationale for understanding cancer's common traits. They constitute the maintenance of proliferative signaling, evasion of growth suppressors, resisting cell death, enabling of replicative immortality, induction of angiogenesis, the activation of invasion and metastasis, as well as avoidance of immune destruction and dysregulation of cellular energetics. In this work, we have compiled evidence from the literature suggesting that CK2 modulates all hallmarks of cancer, thereby promoting oncogenesis and operating as a cancer driver by creating a cellular environment favorable to neoplasia.
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Affiliation(s)
| | - Angela Brieger
- Department of Internal Medicine I, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
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12
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Li J, Hu X, Zhang H, Peng Y, Li S, Xiong Y, Jiang W, Wang Z. N-2-(Phenylamino) Benzamide Derivatives as Dual Inhibitors of COX-2 and Topo I Deter Gastrointestinal Cancers via Targeting Inflammation and Tumor Progression. J Med Chem 2022; 65:10481-10505. [PMID: 35868003 DOI: 10.1021/acs.jmedchem.2c00635] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Given the close association between inflammation and cancer, combining anti-inflammation therapy is prominent to improve the anticancer effect. Based on I-1, a series of agents targeting COX-2 and Topo I were designed by combining fenamates and phenols. The optimal compound 1H-30 displayed an enhanced inhibitory effect on COX-2 compared to tolfenamic acid and I-1 and showed better inhibition of Topo I than I-1. Importantly, 1H-30 showed potential anticancer effects and suppressed the activation of the NF-κB pathway in cancer cells. 1H-30 inhibited the nuclear translocation of NF-κB and suppressed the production of NO, COX-2, and IL-1β in RAW264.7. In vivo, 1H-30 showed acceptable pharmacokinetic parameters, decreased the tumor growth without affecting the body weight, down-regulated COX-2 and MMP-9, and induced apoptosis in the CT26.WT tumor-bearing mice. Accordingly, 1H-30 as a potential Topo I/COX-2 inhibitor which possessed anti-inflammatory and anticancer effects, with inhibition of the NF-κB pathway, is promising for gastrointestinal cancer therapy.
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Affiliation(s)
- Junfang Li
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China.,State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
| | - Xiaoling Hu
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China.,State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
| | - Honghua Zhang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China.,State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
| | - Yan Peng
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Shuang Li
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Yongxia Xiong
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Weifan Jiang
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Zhen Wang
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China.,School of Pharmacy, Lanzhou University, Lanzhou 730000, China.,State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
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13
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Liang X, Wang J, Liu Y, Wei L, Tian F, Sun J, Han G, Wang Y, Ding C, Guo Z. Polymorphisms of COX/PEG2 pathway-related genes are associated with the risk of lung cancer: A case–control study in China. Int Immunopharmacol 2022; 108:108763. [DOI: 10.1016/j.intimp.2022.108763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/30/2022] [Accepted: 04/03/2022] [Indexed: 12/24/2022]
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14
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He Y, Sun Y, Liao C, Lin F, Xia Z, Qi Y, Chen Y. The Protective Role of Hydrogen Sulfide and Its Impact on Gene Expression Profiling in Rat Model of COPD. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9407927. [PMID: 35340205 PMCID: PMC8956388 DOI: 10.1155/2022/9407927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 01/27/2022] [Indexed: 12/04/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, which is usually caused by exposure to noxious particles or gases. Hydrogen sulfide (H2S), as an endogenous gasotransmitter, is involved in the pathogenesis of COPD, but its role in COPD is little known. To investigate the role of H2S in COPD, a rat model of COPD was established by cigarette smoking (CS) and intratracheal instillation of lipopolysaccharide (LPS). Rats were randomly divided into 4 groups: control, CS + LPS, CS + LPS + sodium hydrosulfide (NaHS, H2S donor), and CS + LPS + propargylglycine (PPG, inhibitor of cystathionine-γ-lyase, and CTH). Lung function in vivo, histology analysis of lung sections, malondialdehyde (MDA) concentration, CTH protein, total superoxide dismutase (T-SOD), and catalase (CAT) activity in lung tissues were assessed. Gene expression profiling of lung was assessed by microarray analysis. The results showed that rats in the CS + LPS group had lower body weight and lung function but higher lung pathological scores, MDA concentration, CTH protein, T-SOD, and CAT activity compared with the control. Compared with CS + LPS group, NaHS treatment decreased lung pathological scores and MDA concentration, while PPG treatment decreased body weight of rats and T-SOD activity, and no significant differences were detected in pathological scores by PPG treatment. Microarray analysis identified multiple differentially expressed genes, and some genes regulated by H2S were involved in oxidative stress, apoptosis, and inflammation pathways. It indicates that H2S may play a protective role in COPD via antioxidative stress and antiapoptosis pathway.
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Affiliation(s)
- Yanjing He
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing, China
- Department of Anesthesiology, The University of Hong Kong, Hong Kong, China
| | - Yun Sun
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing, China
| | - Chengcheng Liao
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing, China
| | - Fan Lin
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing, China
| | - Zhengyuan Xia
- Department of Anesthesiology, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, The University of Hong Kong, Hong Kong, China
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yongfen Qi
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Yahong Chen
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing, China
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15
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Gupta YH, Khanom A, Acton SE. Control of Dendritic Cell Function Within the Tumour Microenvironment. Front Immunol 2022; 13:733800. [PMID: 35355992 PMCID: PMC8960065 DOI: 10.3389/fimmu.2022.733800] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 02/09/2022] [Indexed: 12/12/2022] Open
Abstract
The tumour microenvironment (TME) presents a major block to anti-tumour immune responses and to effective cancer immunotherapy. The inflammatory mediators such as cytokines, chemokines, growth factors and prostaglandins generated in the TME alter the phenotype and function of dendritic cells (DCs) that are critical for a successful adaptive immune response against the growing tumour. In this mini review we discuss how tumour cells and the surrounding stroma modulate DC maturation and trafficking to impact T cell function. Fibroblastic stroma and the associated extracellular matrix around tumours can also provide physical restrictions to infiltrating DCs and other leukocytes. We discuss interactions between the inflammatory TME and infiltrating immune cell function, exploring how the inflammatory TME affects generation of T cell-driven anti-tumour immunity. We discuss the open question of the relative importance of antigen-presentation site; locally within the TME versus tumour-draining lymph nodes. Addressing these questions will potentially increase immune surveillance and enhance anti-tumour immunity.
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Affiliation(s)
- Yukti Hari Gupta
- Stromal Immunology Laboratory, MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
| | | | - Sophie E. Acton
- Stromal Immunology Laboratory, MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
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16
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Sun Z, Sun X, Chen Z, Du J, Wu Y. Head and Neck Squamous Cell Carcinoma: Risk Factors, Molecular Alterations, Immunology and Peptide Vaccines. Int J Pept Res Ther 2021; 28:19. [PMID: 34903958 PMCID: PMC8653808 DOI: 10.1007/s10989-021-10334-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2021] [Indexed: 12/29/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) arises from the epithelial lining of the oral cavity, hypopharynx, oropharynx, and larynx. There are several potential risk factors that cause the generation of HNSCC, including cigarette smoking, alcohol consumption, betel quid chewing, inadequate nutrition, poor oral hygiene, HPV and Epstein–Barr virus, and Candida albicans infections. HNSCC has causative links to both environmental factors and genetic mutations, with the latter playing a more critical role in cancer progression. These molecular changes to epithelial cells include the inactivation of cancer suppressor genes and proto-oncogenes overexpression, resulting in tumour cell proliferation and distant metastasis. HNSCC patients have impaired dendritic cell (DC) and natural killer (NK) cell functions, increased production of higher immune-suppressive molecules, loss of regulatory T cells and co-stimulatory molecules and major histocompatibility complex (MHC) class Ι molecules, lower number of lymphocyte subsets, and a poor response to antigen-presenting cells. At present, the standard treatment modalities for HNSCC patients include surgery, chemotherapy and radiotherapy, and combinatorial therapy. Despite advances in the development of novel treatment modalities over the last few decades, survival rates of HNSCC patients have not increased. To establish effective immunotherapies, a greater understanding of interactions between the immune system and HNSCC is required, and there is a particular need to develop novel therapeutic options. A therapeutic cancer vaccine has been proposed as a promising method to improve outcome by inducing a powerful adaptive immune response that leads to cancer cell elimination. Compared with other vaccines, peptide cancer vaccines are more robust and specific. In the past few years, there have been remarkable achievements in peptide-based vaccines for HNSCC patients. Here, we summarize the latest molecular alterations in HNSCC, explore the immune response to HNSCC, and discuss the latest developments in peptide-based cancer vaccine strategies. This review highlights areas for valuable future research focusing on peptide-based cancer vaccines.
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Affiliation(s)
- Zhe Sun
- Department of Stomatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021 China
| | - Xiaodong Sun
- Department of Endodontics, Gaoxin Branch of Jinan Stomatological Hospital, Jinan, Shandong 250000 China
| | - Zhanwei Chen
- Department of Stomatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021 China
| | - Juan Du
- Department of Stomatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021 China
| | - Yihua Wu
- Department of Stomatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021 China
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17
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Neganova M, Liu J, Aleksandrova Y, Klochkov S, Fan R. Therapeutic Influence on Important Targets Associated with Chronic Inflammation and Oxidative Stress in Cancer Treatment. Cancers (Basel) 2021; 13:6062. [PMID: 34885171 PMCID: PMC8657135 DOI: 10.3390/cancers13236062] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 11/28/2021] [Accepted: 11/28/2021] [Indexed: 01/17/2023] Open
Abstract
Chronic inflammation and oxidative stress are the interconnected pathological processes, which lead to cancer initiation and progression. The growing level of oxidative and inflammatory damage was shown to increase cancer severity and contribute to tumor spread. The overproduction of reactive oxygen species (ROS), which is associated with the reduced capacity of the endogenous cell defense mechanisms and/or metabolic imbalance, is the main contributor to oxidative stress. An abnormal level of ROS was defined as a predisposing factor for the cell transformation that could trigger pro-oncogenic signaling pathways, induce changes in gene expression, and facilitate accumulation of mutations, DNA damage, and genomic instability. Additionally, the activation of transcription factors caused by a prolonged oxidative stress, including NF-κB, p53, HIF1α, etc., leads to the expression of several genes responsible for inflammation. The resulting hyperactivation of inflammatory mediators, including TNFα, TGF-β, interleukins, and prostaglandins can contribute to the development of neoplasia. Pro-inflammatory cytokines were shown to trigger adaptive reactions and the acquisition of resistance by tumor cells to apoptosis, while promoting proliferation, invasion, and angiogenesis. Moreover, the chronic inflammatory response leads to the excessive production of free radicals, which further aggravate the initiated reactions. This review summarizes the recent data and progress in the discovery of mechanisms that associate oxidative stress and chronic inflammation with cancer onset and metastasis. In addition, the review provides insights for the development of therapeutic approaches and the discovery of natural substances that will be able to simultaneously inhibit several key oncological and inflammation-related targets.
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Affiliation(s)
- Margarita Neganova
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Erqi, Zhengzhou 450000, China; (M.N.); (J.L.)
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia;
| | - Junqi Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Erqi, Zhengzhou 450000, China; (M.N.); (J.L.)
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yulia Aleksandrova
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia;
| | - Sergey Klochkov
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia;
| | - Ruitai Fan
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Erqi, Zhengzhou 450000, China; (M.N.); (J.L.)
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
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18
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An Investigation of the Antigastric Cancer Effect in Tumor Microenvironment of Radix Rhei Et Rhizome: A Network Pharmacology Study. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:9913952. [PMID: 34257692 PMCID: PMC8249119 DOI: 10.1155/2021/9913952] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 05/20/2021] [Accepted: 06/11/2021] [Indexed: 12/17/2022]
Abstract
Background Tumor microenvironment (TME) takes a vital effect on the occurrence and development of cancer. Radix Rhei Et Rhizome (RRER, Da-Huang in pinyin), a classical Chinese herb, has been widely used in gastric cancer (GC) for many years in China. However, inadequate systematic studies have focused on the anti-GC effect of RRER in TME. This study intended to uncover the mechanism of it by network pharmacology. Methods We collected compounds and targets of RRER from traditional Chinese medicine system pharmacology database and analysis platform (TCMSP) and SwissTargetPrediction. GC targets were obtained from GeneCards. Protein-protein interaction (PPI) network and RRER-GC-target network were built by STRING and Cytoscape 3.2.1. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed using Database for Annotation, Visualization, and Integrated Discovery (DAVID). Results We obtained 92 compounds of RRER. A total of 10 key compounds and 20 key targets were selected by “RRER-GC-target network” topological analysis. GO analysis showed that the biological process mainly involved in response to the tumor necrosis factor, positive regulation of fibroblast proliferation, and DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest. Molecular functions included cyclin-dependent protein serine/threonine kinase activity, RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding, and transmembrane receptor protein tyrosine kinase activity. Cellular components mainly were centrosome, cell surface, and membrane. KEGG pathway enrichment results mainly involved in the p53 signaling pathway, estrogen signaling pathway, and regulation of lipolysis in adipocytes. Conclusion This study explored the anti-GC mechanism of RRER from the perspective of TME based on network pharmacology, which contributed to the development and application of RRER.
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Jara-Gutiérrez Á, Baladrón V. The Role of Prostaglandins in Different Types of Cancer. Cells 2021; 10:cells10061487. [PMID: 34199169 PMCID: PMC8231512 DOI: 10.3390/cells10061487] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/06/2021] [Accepted: 06/09/2021] [Indexed: 12/12/2022] Open
Abstract
The prostaglandins constitute a family of lipids of 20 carbon atoms that derive from polyunsaturated fatty acids such as arachidonic acid. Traditionally, prostaglandins have been linked to inflammation, female reproductive cycle, vasodilation, or bronchodilator/bronchoconstriction. Recent studies have highlighted the involvement of these lipids in cancer. In this review, existing information on the prostaglandins associated with different types of cancer and the advances related to the potential use of them in neoplasm therapies have been analyzed. We can conclude that the effect of prostaglandins depends on multiple factors, such as the target tissue, their plasma concentration, and the prostaglandin subtype, among others. Prostaglandin D2 (PGD2) seems to hinder tumor progression, while prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2α) seem to provide greater tumor progression and aggressiveness. However, more studies are needed to determine the role of prostaglandin I2 (PGI2) and prostaglandin J2 (PGJ2) in cancer due to the conflicting data obtained. On the other hand, the use of different NSAIDs (non-steroidal anti-inflammatory drugs), especially those selective of COX-2 (cyclooxygenase 2), could have a crucial role in the fight against different neoplasms, either as prophylaxis or as an adjuvant treatment. In addition, multiple targets, related to the action of prostaglandins on the intracellular signaling pathways that are involved in cancer, have been discovered. Thus, in depth research about the prostaglandins involved in different cancer and the different targets modulated by them, as well as their role in the tumor microenvironment and the immune response, is necessary to obtain better therapeutic tools to fight cancer.
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