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Yang G, Qian B, He L, Zhang C, Wang J, Qian X, Wang Y. Application prospects of ferroptosis in colorectal cancer. Cancer Cell Int 2025; 25:59. [PMID: 39984914 PMCID: PMC11846473 DOI: 10.1186/s12935-025-03641-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 01/07/2025] [Indexed: 02/23/2025] Open
Abstract
Colorectal cancer (CRC) is a serious threat to human health with the third morbidity and the second cancer-related mortality worldwide. It is urgent to explore more effective strategy for CRC because of the acquired treatment resistance from the non-surgical conventional therapies, including radiation, chemotherapy, targeted therapy and immunotherapy. Ferroptosis is a novel form of programmed cell death characterized by iron-dependent lipid peroxidation species (ROS) accumulation and has been identified as a promising target for cancer treatment, especially for those with treatment resistance. In this review, we mainly summarize the recent studies on the influence and regulation of ferroptosis by which (including gut microbiota) modulating the metabolism of iron, amino acid and lipid. Thus this analysis may provide potential targets for inducing CRC ferroptosis and shed lights on the future application of ferroptosis in CRC.
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Affiliation(s)
- Gen Yang
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Boning Qian
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Liya He
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Chi Zhang
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Jianqiang Wang
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Xinlai Qian
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, Henan, China.
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
- Henan Provincial Key Laboratory of Molecular Oncologic Pathology, Xinxiang, Henan, China.
| | - Yongxia Wang
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, Henan, China.
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
- Henan Provincial Key Laboratory of Molecular Oncologic Pathology, Xinxiang, Henan, China.
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Yu H, Huang Z, Wu J, Zhao Z, Hua Y, Yang Y. Chlorin e6: a promising photosensitizer of anti-tumor and anti-inflammatory effects in PDT. Nanomedicine (Lond) 2025; 20:389-400. [PMID: 39877963 PMCID: PMC11812356 DOI: 10.1080/17435889.2025.2456450] [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: 11/01/2024] [Accepted: 01/17/2025] [Indexed: 01/31/2025] Open
Abstract
Photodynamic therapy (PDT) involves the activation of photosensitizers (PSs) by visible laser light at the target site to catalyze the production of reactive oxygen species, resulting in tumor cell death and blood vessel closure. The efficacy of PDT depends on the PSs, the amount of oxygen, and the intensity of the excitation laser. PSs have been extensively researched, and great efforts have been made to develop an ideal photosensitizer. Chlorin-e6 is an FDA-approved second-generation PSs that has attracted widespread research interest in the medical field, especially with respect to antitumor and anti-inflammatory activity. Chlorin-e6 possesses the advantages of a large absorption coefficient, high strength, low residue in the body, and relatively high safety and thus has promising application prospects. Here we review the use of chlorin-e6 in PDT and discuss the prospects of further development of this technology.
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Affiliation(s)
- Hairong Yu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
- Department of Pharmaceutics, School of Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Ziling Huang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
- Department of Pharmaceutics, School of Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Jiale Wu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
- Department of Pharmaceutics, School of Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Ziming Zhao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
- Department of Pharmaceutics, School of Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Yabing Hua
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
- Department of Pharmaceutics, School of Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Yihua Yang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
- Department of Pharmaceutics, School of Pharmacy, Xuzhou Medical University, Xuzhou, China
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Wang Y, Xu Y, Qu Y, Jin Y, Cao J, Zhan J, Li Z, Chai C, Huang C, Li M. Ferroptosis: A novel cell death modality as a synergistic therapeutic strategy with photodynamic therapy. Photodiagnosis Photodyn Ther 2025; 51:104463. [PMID: 39736368 DOI: 10.1016/j.pdpdt.2024.104463] [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: 09/03/2024] [Revised: 12/24/2024] [Accepted: 12/27/2024] [Indexed: 01/01/2025]
Abstract
Although there has been significant progress in current comprehensive anticancer treatments centered on surgery, postoperative recurrence and tumor metastasis still significantly affect both prognosis and quality of life of the patient. Hence, the development of precisely targeted tumor therapies and exploration of immunotherapy represent additional strategies for tumor treatment. Photodynamic therapy (PDT) is a relatively safe treatment modality that not only induces multiple modes of tumor cell death but also mediates the secondary immunological responses against tumor resistance and metastasis. Ferroptosis, an iron-dependent type of programmed cell death characterized by accumulation of reactive oxygen species and lipid peroxidation products to lethal levels, has emerged as an attractive target trigger for tumor therapies. Recent research has revealed a close association between PDT and ferroptosis, suggesting that combining ferroptosis inducers with PDT could strengthen their synergistic anti-tumor efficiency. Here in this review, we discuss the rationale for combining PDT with ferroptosis inducers and highlight the progress of single-molecule photosensitizers to induce ferroptosis, as well as the applications of photosensitizers combined with other therapeutic drugs for collaborative therapy. Furthermore, given the current research dilemma, we propose potential therapeutic strategies to advance the combined usage of PDT and ferroptosis inducers, providing the basis and guidelines for prospective clinical translation and research directionality with regard to PDT.
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Affiliation(s)
- Yuqing Wang
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yiting Xu
- Central Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, Wuhan 430022, China
| | - Yong Qu
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yifang Jin
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Juanmei Cao
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Department of Dermatology, First Affiliated Hospital, Shihezi University, Shihezi 832008, China
| | - Jinshan Zhan
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhuoxia Li
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chuxing Chai
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Changzheng Huang
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Min Li
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Su C, Xue Y, Fan S, Sun X, Si Q, Gu Z, Wang J, Deng R. Ferroptosis and its relationship with cancer. Front Cell Dev Biol 2025; 12:1423869. [PMID: 39877159 PMCID: PMC11772186 DOI: 10.3389/fcell.2024.1423869] [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: 04/26/2024] [Accepted: 12/23/2024] [Indexed: 01/31/2025] Open
Abstract
Marked by iron buildup and lipid peroxidation, ferroptosis is a relatively new regulatory cell death (RCD) pathway. Many diseases like cancer, myocardial ischemia-reperfusion injury (MIRI), neurological disorders and acute renal failure (AKI) are corelated with ferroptosis. The main molecular processes of ferroptosis discovered yet will be presented here, along with the approaches in which it interacts with tumour-associated signaling pathways and its uses in systemic therapy, radiation therapy, and immunotherapy managing tumors.
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Affiliation(s)
| | | | | | | | | | | | | | - Runzhi Deng
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
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Yang L, Yue Y, Wang Z, Jiang Y, Xue Z, Zhang Y. Elucidating the Mechanisms of Acquired Palbociclib Resistance via Comprehensive Metabolomics Profiling. Curr Issues Mol Biol 2025; 47:24. [PMID: 39852139 PMCID: PMC11763656 DOI: 10.3390/cimb47010024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/12/2024] [Accepted: 12/31/2024] [Indexed: 01/26/2025] Open
Abstract
Palbociclib is a cyclin-dependent kinase 4/6 inhibitor and a commonly used antitumor drug. Many cancers are susceptible to palbociclib resistance, however, the underlying metabolism mechanism and extent of resistance to palbociclib are unknown. In this study, LC-MS metabolomics was used to investigate the metabolite changes of colorectal cancer SW620 cells that were resistant to palbociclib. The study indicated that there were 76 metabolite expression differences between SW620 cells with palbociclib resistance and the parental SW620 cells involving amino acids, glutathione, ABC transporters, and so on. MetaboAnalyst 6.0 metabolic pathway analysis showed that arginine synthesis, β-alanine metabolism, and purine metabolism were disrupted. These results may provide potential clues to the metabolism mechanism of drug resistance in cancer cells that are resistant to palbociclib. Our study has the potential to contribute to the study of anti-palbociclib resistance.
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Affiliation(s)
- Lulu Yang
- Technology Innovation Center of Mass Spectrometry for State Market Regulation, Center for Advanced Measurement Science, National Institute of Metrology, Beijing 100029, China; (L.Y.); (Y.J.)
| | - Yajun Yue
- General Management Department of Laboratory Base, National Institute of Metrology, Beijing 100029, China;
| | - Zhendong Wang
- Center for Advanced Measurement Science, National Institute of Metrology, Beijing 100029, China; (Z.W.); (Y.Z.)
| | - You Jiang
- Technology Innovation Center of Mass Spectrometry for State Market Regulation, Center for Advanced Measurement Science, National Institute of Metrology, Beijing 100029, China; (L.Y.); (Y.J.)
| | - Zhichao Xue
- Technology Innovation Center of Mass Spectrometry for State Market Regulation, Center for Advanced Measurement Science, National Institute of Metrology, Beijing 100029, China; (L.Y.); (Y.J.)
| | - Yongzhuo Zhang
- Center for Advanced Measurement Science, National Institute of Metrology, Beijing 100029, China; (Z.W.); (Y.Z.)
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Wang H, Wang H, Yu G, Xie L, Zhang C, Xu C, Ma X, Miao Z, Yu Y. Naked mesoporous rhodium nanospheres with glutathione depletion and photothermal capabilities for tumor therapy. J Colloid Interface Sci 2025; 677:1075-1083. [PMID: 39180842 DOI: 10.1016/j.jcis.2024.08.079] [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: 04/09/2024] [Revised: 08/03/2024] [Accepted: 08/12/2024] [Indexed: 08/27/2024]
Abstract
Pancreatic and colon cancer are malignant tumors of the digestive system that currently lack effective treatments. In cancer cells, a high level of glutathione (GSH) is indispensable to scavenge excessive reactive oxygen species (ROS) and detoxify xenobiotics, which make it a potential target for cancer therapy. GSH depletion has been proved to improve the therapeutic efficacy of photodynamic therapy. Here, we reported that naked mesoporous rhodium nanospheres (Rh MNs), prepared by soft template redox method, can act as GSH depletion agent and photothermal conversion agent to achieve synergistic therapy respectively. Different from conventional nanoagents, Rh MNs with the characteristics of easy synthesis, simple structure and multiple functions can decrease the GSH level in tumor and depict excellent photothermal ability with a high photothermal conversion efficiency (PTCE) up to 39%. Notably, multiple anti-tumor mechanisms in CT26 and BxPC-3 tumor models, include inhibited anti-apoptosis, DNA replication repair, and GSH synthesis are revealed, and the pancreatic tumor cure rate of the cooperative treatment group is 80%. Collectively, we developed Rh MNs to combine GSH depletion with photothermal therapy for cancer treatment.
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Affiliation(s)
- Haixiang Wang
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, PR China
| | - Hongwei Wang
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China
| | - Gaoyuan Yu
- Department of Thyroid and Breast Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui 230001, PR China
| | - Lijuan Xie
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China
| | - Cong Zhang
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, PR China
| | - Chao Xu
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, PR China
| | - Xiaopeng Ma
- Department of Thyroid and Breast Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui 230001, PR China
| | - Zhaohua Miao
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China.
| | - Yue Yu
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, PR China.
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Poimenova IA, Sozarukova MM, Ratova DMV, Nikitina VN, Khabibullin VR, Mikheev IV, Proskurnina EV, Proskurnin MA. Analytical Methods for Assessing Thiol Antioxidants in Biological Fluids: A Review. Molecules 2024; 29:4433. [PMID: 39339429 PMCID: PMC11433793 DOI: 10.3390/molecules29184433] [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: 08/27/2024] [Revised: 09/13/2024] [Accepted: 09/15/2024] [Indexed: 09/30/2024] Open
Abstract
Redox metabolism is an integral part of the glutathione system, encompassing reduced and oxidized glutathione, hydrogen peroxide, and associated enzymes. This core process orchestrates a network of thiol antioxidants like thioredoxins and peroxiredoxins, alongside critical thiol-containing proteins such as mercaptoalbumin. Modifications to thiol-containing proteins, including oxidation and glutathionylation, regulate cellular signaling influencing gene activities in inflammation and carcinogenesis. Analyzing thiol antioxidants, especially glutathione, in biological fluids offers insights into pathological conditions. This review discusses the analytical methods for biothiol determination, mainly in blood plasma. The study includes all key methodological aspects of spectroscopy, chromatography, electrochemistry, and mass spectrometry, highlighting their principles, benefits, limitations, and recent advancements that were not included in previously published reviews. Sample preparation and factors affecting thiol antioxidant measurements are discussed. The review reveals that the choice of analytical procedures should be based on the specific requirements of the research. Spectrophotometric methods are simple and cost-effective but may need more specificity. Chromatographic techniques have excellent separation capabilities but require longer analysis times. Electrochemical methods enable real-time monitoring but have disadvantages such as interference. Mass spectrometry-based approaches have high sensitivity and selectivity but require sophisticated instrumentation. Combining multiple techniques can provide comprehensive information on thiol antioxidant levels in biological fluids, enabling clearer insights into their roles in health and disease. This review covers the time span from 2010 to mid-2024, and the data were obtained from the SciFinder® (ACS), Google Scholar (Google), PubMed®, and ScienceDirect (Scopus) databases through a combination search approach using keywords.
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Affiliation(s)
- Iuliia A. Poimenova
- Analytical Chemistry Division, Department of Chemistry, Lomonosov Moscow State University, 1-3 Leninskie Gory, 119234 Moscow, Russia; (I.A.P.); (M.M.S.); (D.-M.V.R.); (V.N.N.); (V.R.K.)
| | - Madina M. Sozarukova
- Analytical Chemistry Division, Department of Chemistry, Lomonosov Moscow State University, 1-3 Leninskie Gory, 119234 Moscow, Russia; (I.A.P.); (M.M.S.); (D.-M.V.R.); (V.N.N.); (V.R.K.)
- Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, 117901 Moscow, Russia;
| | - Daria-Maria V. Ratova
- Analytical Chemistry Division, Department of Chemistry, Lomonosov Moscow State University, 1-3 Leninskie Gory, 119234 Moscow, Russia; (I.A.P.); (M.M.S.); (D.-M.V.R.); (V.N.N.); (V.R.K.)
| | - Vita N. Nikitina
- Analytical Chemistry Division, Department of Chemistry, Lomonosov Moscow State University, 1-3 Leninskie Gory, 119234 Moscow, Russia; (I.A.P.); (M.M.S.); (D.-M.V.R.); (V.N.N.); (V.R.K.)
| | - Vladislav R. Khabibullin
- Analytical Chemistry Division, Department of Chemistry, Lomonosov Moscow State University, 1-3 Leninskie Gory, 119234 Moscow, Russia; (I.A.P.); (M.M.S.); (D.-M.V.R.); (V.N.N.); (V.R.K.)
- Federal State Budgetary Institution of Science Institute of African Studies, Russian Academy of Sciences, Spiridonovka St., 30/1, 123001 Moscow, Russia
| | - Ivan V. Mikheev
- Analytical Chemistry Division, Department of Chemistry, Lomonosov Moscow State University, 1-3 Leninskie Gory, 119234 Moscow, Russia; (I.A.P.); (M.M.S.); (D.-M.V.R.); (V.N.N.); (V.R.K.)
| | - Elena V. Proskurnina
- Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, 117901 Moscow, Russia;
- Laboratory of Molecular Biology, Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia
| | - Mikhail A. Proskurnin
- Analytical Chemistry Division, Department of Chemistry, Lomonosov Moscow State University, 1-3 Leninskie Gory, 119234 Moscow, Russia; (I.A.P.); (M.M.S.); (D.-M.V.R.); (V.N.N.); (V.R.K.)
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Zheng Y, Xiong Q, Yang Y, Ma Y, Zhu Q. Identified γ-glutamyl cyclotransferase (GGCT) as a novel regulator in the progression and immunotherapy of pancreatic ductal adenocarcinoma through multi-omics analysis and experiments. J Cancer Res Clin Oncol 2024; 150:318. [PMID: 38914714 PMCID: PMC11196309 DOI: 10.1007/s00432-024-05789-0] [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: 03/20/2024] [Accepted: 05/07/2024] [Indexed: 06/26/2024]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is renowned for its formidable and lethal nature, earning it a notorious reputation among malignant tumors. Due to its challenging early diagnosis, high malignancy, and resistance to chemotherapy drugs, the treatment of pancreatic cancer has long been exceedingly difficult in the realm of oncology. γ-Glutamyl cyclotransferase (GGCT), a vital enzyme in glutathione metabolism, has been implicated in the proliferation and progression of several tumor types, while the biological function of GGCT in pancreatic ductal adenocarcinoma remains unknown. METHODS The expression profile of GGCT was validated through western blotting, immunohistochemistry, and RT-qPCR in both pancreatic cancer tissue samples and cell lines. Functional enrichment analyses including GSVA, ssGSEA, GO, and KEGG were conducted to explore the biological role of GGCT. Additionally, CCK8, Edu, colony formation, migration, and invasion assays were employed to evaluate the impact of GGCT on the proliferation and migration abilities of pancreatic cancer cells. Furthermore, the LASSO machine learning algorithm was utilized to develop a prognostic model associated with GGCT. RESULTS Our study revealed heightened expression of GGCT in pancreatic cancer tissues and cells, suggesting an association with poorer patient prognosis. Additionally, we explored the immunomodulatory effects of GGCT in both pan-cancer and pancreatic cancer contexts, found that GGCT may be associated with immunosuppressive regulation in various types of tumors. Specifically, in patients with high expression of GGCT in pancreatic cancer, there is a reduction in the infiltration of various immune cells, leading to poorer responsiveness to immunotherapy and worse survival rates. In vivo and in vitro assays indicate that downregulation of GGCT markedly suppresses the proliferation and metastasis of pancreatic cancer cells. Moreover, this inhibitory effect appears to be linked to the regulation of GGCT on c-Myc. A prognostic model was constructed based on genes derived from GGCT, demonstrating robust predictive ability for favorable survival prognosis and response to immunotherapy.
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Affiliation(s)
- Ying Zheng
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Qunli Xiong
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Yang Yang
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Yifei Ma
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Qing Zhu
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China.
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Yao L, Zhu X, Shan Y, Zhang L, Yao J, Xiong H. Recent Progress in Anti-Tumor Nanodrugs Based on Tumor Microenvironment Redox Regulation. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2310018. [PMID: 38269480 DOI: 10.1002/smll.202310018] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/30/2023] [Indexed: 01/26/2024]
Abstract
The growth state of tumor cells is strictly affected by the specific abnormal redox status of the tumor microenvironment (TME). Moreover, redox reactions at the biological level are also central and fundamental to essential energy metabolism reactions in tumors. Accordingly, anti-tumor nanodrugs targeting the disruption of this abnormal redox homeostasis have become one of the hot spots in the field of nanodrugs research due to the effectiveness of TME modulation and anti-tumor efficiency mediated by redox interference. This review discusses the latest research results of nanodrugs in anti-tumor therapy, which regulate the levels of oxidants or reductants in TME through a variety of therapeutic strategies, ultimately breaking the original "stable" redox state of the TME and promoting tumor cell death. With the gradual deepening of study on the redox state of TME and the vigorous development of nanomaterials, it is expected that more anti-tumor nano drugs based on tumor redox microenvironment regulation will be designed and even applied clinically.
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Affiliation(s)
- Lan Yao
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, P. R. China
| | - Xiang Zhu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, P. R. China
| | - Yunyi Shan
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, P. R. China
| | - Liang Zhang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, P. R. China
| | - Jing Yao
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, P. R. China
| | - Hui Xiong
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, P. R. China
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10
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Qiao Y, Jia X, Wang Y, Liu L, Zhang M, Jiang X. Polydopamine-encapsulated zinc peroxide nanoparticles to target the metabolism-redox circuit against tumor adaptability for mild photothermal therapy. NANOSCALE HORIZONS 2024; 9:1002-1012. [PMID: 38586973 DOI: 10.1039/d4nh00070f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Regulating the metabolism-redox circuit of cancer cells has emerged as an attractive strategy to improve the therapeutic outcome, while often confronting the glaring issue of resistance due to the multiple adaptive responses of tumor cells. This study presents a simple yet efficient approach to regulate this circuit simultaneously against tumor adaptability by utilizing polydopamine-encapsulated zinc peroxide nanoparticles (ZnO2@PDA NPs). The nanoparticles could deliver large amounts of Zn2+ and H2O2 into tumor cells to unfold an intracellular self-amplifying loop for breaking the balance in zinc and redox homeostasis by H2O2-mediated endogenous Zn2+ release from metallothioneins due to its oxidation by H2O2 and Zn2+-induced in situ H2O2 production by disturbing mitochondrial respiration, ultimately disrupting tumor adaptability to exogenous stimuli. The elevated levels of Zn2+ and H2O2 also inhibited adenosine triphosphate (ATP) generation from glycolysis and mitochondrial respiration to disrupt energy adaptability. Furthermore, insufficient ATP supply could reduce glutathione and heat shock protein expression, thereby sensitizing oxidative stress and enabling PDA-mediated mild photothermal therapy (PTT). Consequently, this trinity nanoplatform, which integrated dual-starvation therapy, amplified oxidative stress, and mild PTT, demonstrated outstanding therapeutic effects and a facile strategy.
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Affiliation(s)
- Yue Qiao
- Department of Radiology, China-Japan Union Hospital, Jilin University, Changchun 130033, Jilin, China.
| | - Xiaodan Jia
- Research Center for Analytical Science, College of Chemistry, Nankai University, Tianjin 300071, China.
| | - Yue Wang
- Research Center for Analytical Science, College of Chemistry, Nankai University, Tianjin 300071, China.
| | - Lin Liu
- Department of Radiology, China-Japan Union Hospital, Jilin University, Changchun 130033, Jilin, China.
| | - Mengchao Zhang
- Department of Radiology, China-Japan Union Hospital, Jilin University, Changchun 130033, Jilin, China.
| | - Xiue Jiang
- Research Center for Analytical Science, College of Chemistry, Nankai University, Tianjin 300071, China.
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, Jilin, China
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11
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Zhu G, Luo D, Zhao Y, Xiang Z, Chen C, Li N, Hao X, Ding X, Zhang Y, Zhao Y. Pacidusin B isolated from Phyllanthus acidus triggers ferroptotic cell death in HT1080 cells. NATURAL PRODUCTS AND BIOPROSPECTING 2024; 14:34. [PMID: 38780674 PMCID: PMC11116305 DOI: 10.1007/s13659-024-00454-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 05/10/2024] [Indexed: 05/25/2024]
Abstract
Cancer cells generally exhibit 'iron addiction' phenotypes, which contribute to their vulnerability to ferroptosis inducers. Ferroptosis is a newly discovered form of programmed cell death caused by iron-dependent lipid peroxidation. In the present study, pacidusin B, a dichapetalin-type triterpenoid from Phyllanthus acidus (L.) Skeels (Euphorbiaceae), induces ferroptosis in the HT1080 human fibrosarcoma cell line. Cells treated with pacidusin B exhibited the morphological characteristic 'ballooning' phenotype of ferroptosis. The biochemical hallmarks of ferroptosis were also observed in pacidusin B-treated cells. Both oxidative stress and ER stress play significant roles in pacidusin B-induced ferroptosis. The activation of the PERK-Nrf2-HO-1 signaling pathway led to iron overload, while inhibition of GPX4 further sensitized cancer cells to ferroptosis. Furthermore, the molecular docking study showed that pacidusin B docked in the same pocket in xCT as the ferroptosis inducer erastin. These results revealed that pacidusin B exerts anticancer effects via inducing ER-mediated ferroptotic cell death.
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Affiliation(s)
- Guangyu Zhu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Dian Luo
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yueqin Zhao
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhengrui Xiang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chao Chen
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Na Li
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
| | - Xiaojiang Hao
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
- Research Unit of Chemical Biology of Natural Anti-Virus Products, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Xiao Ding
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
- Research Unit of Chemical Biology of Natural Anti-Virus Products, Chinese Academy of Medical Sciences, Beijing, 100730, China.
| | - Yingjun Zhang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
- Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
| | - Yuhan Zhao
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
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12
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Huang Y, Wang P, Fan T, Zhang N, Zhao L, Zhong R, Sun G. Energy Blocker Lonidamine Reverses Nimustine Resistance in Human Glioblastoma Cells through Energy Blockade, Redox Homeostasis Disruption, and O6-Methylguanine-DNA Methyltransferase Downregulation: In Vitro and In Vivo Validation. ACS Pharmacol Transl Sci 2024; 7:1518-1532. [PMID: 38751635 PMCID: PMC11092191 DOI: 10.1021/acsptsci.4c00085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 04/04/2024] [Accepted: 04/08/2024] [Indexed: 05/18/2024]
Abstract
Tumor resistance seriously hinders the clinical application of chloroethylnitrosoureas (CENUs), such as O6-methylguanine-DNA methylguanine (MGMT), which can repair O6-alkyl lesions, thereby inhibiting the formation of cytotoxic DNA interstrand cross-links (ICLs). Metabolic differences between tumor and normal cells provide a biochemical basis for novel therapeutic strategies aimed at selectively inhibiting tumor energy metabolism. In this study, the energy blocker lonidamine (LND) was selected as a chemo-sensitizer of nimustine (ACNU) to explore its potential effects and underlying mechanisms in human glioblastoma in vitro and in vivo. A series of cell-level studies showed that LND significantly increased the cytotoxic effects of ACNU on glioblastoma cells. Furthermore, LND plus ACNU enhanced the energy deficiency by inhibiting glycolysis and mitochondrial function. Notably, LND almost completely downregulated MGMT expression by inducing intracellular acidification. The number of lethal DNA ICLs produced by ACNU increased after the LND pretreatment. The combination of LND and ACNU aggravated cellular oxidative stress. In resistant SF763 mouse tumor xenografts, LND plus ACNU significantly inhibited tumor growth with fewer side effects than ACNU alone. Finally, we proposed a new "HMAGOMR" chemo-sensitizing mechanism through which LND may act as a potential chemo-sensitizer to reverse ACNU resistance in glioblastoma: moderate inhibition of hexokinase (HK) activity (H); mitochondrial dysfunction (M); suppressing adenosine triphosphate (ATP)-dependent drug efflux (A); changing redox homeostasis to inhibit GSH-mediated drug inactivation (G) and increasing intracellular oxidative stress (O); downregulating MGMT expression through intracellular acidification (M); and partial inhibition of energy-dependent DNA repair (R).
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Affiliation(s)
- Yaxing Huang
- Beijing
Key Laboratory of Environment & Viral Oncology, College of Chemistry
and Life Science, Beijing University of
Technology, Beijing 100124, China
| | - Peng Wang
- Department
of Neurosurgery, The First Medical Center
of Chinese PLA General Hospital, Beijing 100853, China
| | - Tengjiao Fan
- Beijing
Key Laboratory of Environment & Viral Oncology, College of Chemistry
and Life Science, Beijing University of
Technology, Beijing 100124, China
- Department
of Medical Technology, Beijing Pharmaceutical
University of Staff and Workers, Beijing 100079, China
| | - Na Zhang
- Beijing
Key Laboratory of Environment & Viral Oncology, College of Chemistry
and Life Science, Beijing University of
Technology, Beijing 100124, China
| | - Lijiao Zhao
- Beijing
Key Laboratory of Environment & Viral Oncology, College of Chemistry
and Life Science, Beijing University of
Technology, Beijing 100124, China
| | - Rugang Zhong
- Beijing
Key Laboratory of Environment & Viral Oncology, College of Chemistry
and Life Science, Beijing University of
Technology, Beijing 100124, China
| | - Guohui Sun
- Beijing
Key Laboratory of Environment & Viral Oncology, College of Chemistry
and Life Science, Beijing University of
Technology, Beijing 100124, China
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13
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Ji M, Xu Q, Li X. Dietary methionine restriction in cancer development and antitumor immunity. Trends Endocrinol Metab 2024; 35:400-412. [PMID: 38383161 PMCID: PMC11096033 DOI: 10.1016/j.tem.2024.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/18/2024] [Accepted: 01/19/2024] [Indexed: 02/23/2024]
Abstract
Methionine restriction (MR) has been shown to suppress tumor growth and improve the responses to various anticancer therapies. However, methionine itself is required for the proliferation, activation, and differentiation of T cells that are crucial for antitumor immunity. The dual impact of methionine, that influences both tumor and immune cells, has generated concerns regarding the potential consequences of MR on T cell immunity and its possible role in promoting cancer. In this review we systemically examine current literature on the interactions between dietary methionine, cancer cells, and immune cells. Based on recent findings on MR in immunocompetent animals, we further discuss how tumor stage-specific methionine dependence of immune cells and cancer cells in the tumor microenvironment could ultimately dictate the response of tumors to MR.
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Affiliation(s)
- Ming Ji
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - Qing Xu
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - Xiaoling Li
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
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14
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Riegel G, Orvain C, Recberlik S, Spaety ME, Poschet G, Venkatasamy A, Yamamoto M, Nomura S, Tsukamoto T, Masson M, Gross I, Le Lagadec R, Mellitzer G, Gaiddon C. The unfolded protein response-glutathione metabolism axis: A novel target of a cycloruthenated complexes bypassing tumor resistance mechanisms. Cancer Lett 2024; 585:216671. [PMID: 38290658 DOI: 10.1016/j.canlet.2024.216671] [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: 10/13/2023] [Revised: 12/22/2023] [Accepted: 01/20/2024] [Indexed: 02/01/2024]
Abstract
Platinum-based drugs remain the reference treatment for gastric cancer (GC). However, the frequency of resistance, due to mutations in TP53 or alterations in the energy and redox metabolisms, impairs the efficacy of current treatments, highlighting the need for alternative therapeutic options. Here, we show that a cycloruthenated compound targeting the redox metabolism, RDC11, induces higher cytotoxicity than oxaliplatin in GC cells and is more potent in reducing tumor growth in vivo. Detailed investigations into the mode of action of RDC11 indicated that it targets the glutathione (GSH) metabolism, which is an important drug resistance mechanism. We demonstrate that cycloruthenated complexes regulate the expression of enzymes of the transsulfuration pathway via the Unfolded Protein Response (UPR) and its effector ATF4. Furthermore, RDC11 induces the expression of SLC7A11 encoding for the cystine/glutamate antiporter xCT. These effects lead to a lower cellular GSH content and elevated oxygen reactive species production, causing the activation of a caspase-independent apoptosis. Altogether, this study provides the first evidence that cycloruthenated complexes target the GSH metabolism, neutralizing thereby a major resistance mechanism towards platinum-based chemotherapies and anticancer immune response.
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Affiliation(s)
- Gilles Riegel
- University of Strasbourg, INSERM UMR_S 1113, "Streinth" Laboratory, Strasbourg, France
| | - Christophe Orvain
- University of Strasbourg, INSERM UMR_S 1113, "Streinth" Laboratory, Strasbourg, France; INSERM, UMR 1260, CRBS, Regenerative Nanomedicine, "HERIIT" Laboratory, University of Strasbourg, Strasbourg, France
| | - Sevda Recberlik
- University of Strasbourg, INSERM UMR_S 1113, "Streinth" Laboratory, Strasbourg, France; INSERM, UMR 1260, CRBS, Regenerative Nanomedicine, "HERIIT" Laboratory, University of Strasbourg, Strasbourg, France
| | - Marie-Elodie Spaety
- University of Strasbourg, INSERM UMR_S 1113, "Streinth" Laboratory, Strasbourg, France
| | - Gernot Poschet
- Centre for Organismal Studies (COS), University of Heidelberg, Heidelberg, Germany
| | - Aina Venkatasamy
- University of Strasbourg, INSERM UMR_S 1113, "Streinth" Laboratory, Strasbourg, France; IHU-Strasbourg, Institute of Image-Guided Surgery, Strasbourg, France
| | - Masami Yamamoto
- Department of Laboratory of Physiological Pathology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Sachiyo Nomura
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tetsyua Tsukamoto
- Department of Diagnostic Pathology, Graduate School of Medicine, Fujita Health University, Toyoake, Japan
| | - Murielle Masson
- University of Strasbourg, INSERM UMR_S 1113, "Streinth" Laboratory, Strasbourg, France; University of Strasbourg, CNRS BSC-UMR 7242, Ecole Supérieure de Biotechnologie, Illkirch, France
| | - Isabelle Gross
- University of Strasbourg, INSERM UMR_S 1113, "SMART" Laboratory, Strasbourg, France; INSERM, UMR 1260, CRBS, Regenerative Nanomedicine, "HERIIT" Laboratory, University of Strasbourg, Strasbourg, France
| | - Ronan Le Lagadec
- Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, 04510, Ciudad de México, Mexico
| | - Georg Mellitzer
- University of Strasbourg, INSERM UMR_S 1113, "Streinth" Laboratory, Strasbourg, France; INSERM, UMR 1260, CRBS, Regenerative Nanomedicine, "HERIIT" Laboratory, University of Strasbourg, Strasbourg, France.
| | - Christian Gaiddon
- University of Strasbourg, INSERM UMR_S 1113, "Streinth" Laboratory, Strasbourg, France.
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15
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Liu W, Wang Y, Xia L, Li J. Research Progress of Plant-Derived Natural Products against Drug-Resistant Cancer. Nutrients 2024; 16:797. [PMID: 38542707 PMCID: PMC10975298 DOI: 10.3390/nu16060797] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/04/2024] [Accepted: 03/04/2024] [Indexed: 01/04/2025] Open
Abstract
As one of the malignant diseases globally, cancer seriously endangers human physical and mental health because of its high morbidity and mortality. Conventional cancer treatment strategies, such as surgical resection and chemoradiotherapy, are effective at the early stage of cancer but have limited efficacy for advanced cancer. Along with cancer progress and treatment, resistance develops gradually within the population of tumor cells. As a consequence, drug resistance become the major cause that leads to disease progression and poor clinical prognosis in some patients. The mechanisms of cancer drug resistance are quite complex and involve various molecular and cellular mechanisms. Therefore, exploring the mechanisms and finding specific targets are becoming imperative to overcome drug resistance. In recent years, plant-derived natural products have been evaluated as potential therapeutic candidates against cancer with drug resistance due to low side effects and high anticancer efficacy. A growing number of studies have shown that natural products can achieve superior antitumor effects through multiple signaling pathways. The mechanisms include regulation of multiple drug resistance (MDR)-related genes, inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, induction of autophagy, and blockade of the cell cycle. This paper reviews the molecular and cellular mechanisms of cancer drug resistance, as well as the therapeutic effects and mechanisms of plant-derived natural products against cancer drug resistance. It provides references for developing therapeutic medication for drug-resistant cancer treatment with high efficacy and low side effects.
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Affiliation(s)
| | | | - Lijie Xia
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China; (W.L.); (Y.W.)
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China; (W.L.); (Y.W.)
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16
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Fu Q, Yang X, Wang M, Zhu K, Wang Y, Song J. Activatable Probes for Ratiometric Imaging of Endogenous Biomarkers In Vivo. ACS NANO 2024; 18:3916-3968. [PMID: 38258800 DOI: 10.1021/acsnano.3c10659] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Dynamic variations in the concentration and abnormal distribution of endogenous biomarkers are strongly associated with multiple physiological and pathological states. Therefore, it is crucial to design imaging systems capable of real-time detection of dynamic changes in biomarkers for the accurate diagnosis and effective treatment of diseases. Recently, ratiometric imaging has emerged as a widely used technique for sensing and imaging of biomarkers due to its advantage of circumventing the limitations inherent to conventional intensity-dependent signal readout methods while also providing built-in self-calibration for signal correction. Here, the recent progress of ratiometric probes and their applications in sensing and imaging of biomarkers are outlined. Ratiometric probes are classified according to their imaging mechanisms, and ratiometric photoacoustic imaging, ratiometric optical imaging including photoluminescence imaging and self-luminescence imaging, ratiometric magnetic resonance imaging, and dual-modal ratiometric imaging are discussed. The applications of ratiometric probes in the sensing and imaging of biomarkers such as pH, reactive oxygen species (ROS), reactive nitrogen species (RNS), glutathione (GSH), gas molecules, enzymes, metal ions, and hypoxia are discussed in detail. Additionally, this Review presents an overview of challenges faced in this field along with future research directions.
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Affiliation(s)
- Qinrui Fu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, Shandong 266021, China
| | - Xiao Yang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, Shandong 266021, China
| | - Mengzhen Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, Shandong 266021, China
| | - Kang Zhu
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Yin Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, Shandong 266021, China
| | - Jibin Song
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
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17
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Chen TH, Wang HC, Chang CJ, Lee SY. Mitochondrial Glutathione in Cellular Redox Homeostasis and Disease Manifestation. Int J Mol Sci 2024; 25:1314. [PMID: 38279310 PMCID: PMC10816320 DOI: 10.3390/ijms25021314] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/15/2024] [Accepted: 01/19/2024] [Indexed: 01/28/2024] Open
Abstract
Mitochondria are critical for providing energy to maintain cell viability. Oxidative phosphorylation involves the transfer of electrons from energy substrates to oxygen to produce adenosine triphosphate. Mitochondria also regulate cell proliferation, metastasis, and deterioration. The flow of electrons in the mitochondrial respiratory chain generates reactive oxygen species (ROS), which are harmful to cells at high levels. Oxidative stress caused by ROS accumulation has been associated with an increased risk of cancer, and cardiovascular and liver diseases. Glutathione (GSH) is an abundant cellular antioxidant that is primarily synthesized in the cytoplasm and delivered to the mitochondria. Mitochondrial glutathione (mGSH) metabolizes hydrogen peroxide within the mitochondria. A long-term imbalance in the ratio of mitochondrial ROS to mGSH can cause cell dysfunction, apoptosis, necroptosis, and ferroptosis, which may lead to disease. This study aimed to review the physiological functions, anabolism, variations in organ tissue accumulation, and delivery of GSH to the mitochondria and the relationships between mGSH levels, the GSH/GSH disulfide (GSSG) ratio, programmed cell death, and ferroptosis. We also discuss diseases caused by mGSH deficiency and related therapeutics.
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Affiliation(s)
- Tsung-Hsien Chen
- Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan;
| | - Hsiang-Chen Wang
- Department of Mechanical Engineering, National Chung Cheng University, Chiayi 62102, Taiwan;
| | - Chia-Jung Chang
- Division of Critical Care Medicine, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan
| | - Shih-Yu Lee
- Division of Critical Care Medicine, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan
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18
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Liao W, Xiao S, Yang J, Shi X, Zheng Y. Multifunctional nanogel based on carboxymethyl cellulose interfering with cellular redox homeostasis enhances phycocyanobilin photodynamic therapy. Carbohydr Polym 2024; 323:121416. [PMID: 37940295 DOI: 10.1016/j.carbpol.2023.121416] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 08/28/2023] [Accepted: 09/17/2023] [Indexed: 11/10/2023]
Abstract
The redox homeostasis defense mechanism of tumor cells is one of the prime reasons for the unsatisfactory effect of photodynamic therapy (PDT). So far, little attention has been paid to this obstacle. In this work, we reported a synthesizing simple yet versatile nanogel (BCPS), synthesized by cystamine dihydrochloride functionalized sodium carboxymethylcellulose (CMC-SS), bovine serum albumin, and Phycocyanobilin self-assembly. The BCPS reduced the levels of glutathione molecules by reacting with glutathione, thereby interfering with intracellular redox homeostasis and enhancing the sensitivity of tumor cells to PDT. The BCPS was shown to possess excellent serum stability, high blood compatibility, low toxic side effects, and higher reactive oxygen species (ROS) utilization. After irradiation, the BCPS could significantly increase intracellular ROS level by approximately 1.6-fold and decrease the IC50 to HeLa cells by approximately 1.5-fold, compared to the pre-functional drugs BCP. This proposed strategy, based on increasing the utilization rate of ROS in tumor cells is promising for application potentials in tumor therapy.
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Affiliation(s)
- Wenqiang Liao
- College of Chemistry, Fuzhou University, No. 2 Xueyuan Road, Fuzhou 350108, China; International Joint Laboratory of Intelligent Health Care, Fuzhou University, No. 2 Xueyuan Road, Fuzhou 350108, China
| | - Siqi Xiao
- College of Chemistry, Fuzhou University, No. 2 Xueyuan Road, Fuzhou 350108, China; International Joint Laboratory of Intelligent Health Care, Fuzhou University, No. 2 Xueyuan Road, Fuzhou 350108, China
| | - Jianmin Yang
- College of Biological Science and Engineering, Fuzhou University, No. 2 Xueyuan Road, Fuzhou 350108, China; Fujian Key Laboratory of Medical Instrument and Pharmaceutical Technology, Fuzhou University, No. 2 Xueyuan Road, Fuzhou 350108, China; International Joint Laboratory of Intelligent Health Care, Fuzhou University, No. 2 Xueyuan Road, Fuzhou 350108, China
| | - Xianai Shi
- College of Biological Science and Engineering, Fuzhou University, No. 2 Xueyuan Road, Fuzhou 350108, China; Fujian Key Laboratory of Medical Instrument and Pharmaceutical Technology, Fuzhou University, No. 2 Xueyuan Road, Fuzhou 350108, China; International Joint Laboratory of Intelligent Health Care, Fuzhou University, No. 2 Xueyuan Road, Fuzhou 350108, China
| | - Yunquan Zheng
- College of Chemistry, Fuzhou University, No. 2 Xueyuan Road, Fuzhou 350108, China; Fujian Key Laboratory of Medical Instrument and Pharmaceutical Technology, Fuzhou University, No. 2 Xueyuan Road, Fuzhou 350108, China; International Joint Laboratory of Intelligent Health Care, Fuzhou University, No. 2 Xueyuan Road, Fuzhou 350108, China.
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19
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de Lagarde VM, Chevalier L, Méausoone C, Cazier F, Dewaele D, Cazier-Dennin F, Janona M, Logie C, Achard S, André V, Rogez-Florent T, Monteil C, Corbiere C. Acute and repeated exposures of normal human bronchial epithelial (NHBE) cells culture to particles from a coloured pyrotechnic smoke. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2024; 105:104327. [PMID: 38006978 DOI: 10.1016/j.etap.2023.104327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 11/17/2023] [Accepted: 11/21/2023] [Indexed: 11/27/2023]
Abstract
Coloured pyrotechnic smokes are frequently used in the military field and occasionally by civilians, but their health hazards have been little studied. The main concern could rise from inhalation of smoke particles. Our previous study showed that acute exposure to particles from a red signalling smoke (RSS) induced an antioxidant and inflammatory responses in small airway epithelial cells. The aim of this study was to further explore the toxicity of RSS particles at a more proximal level of the respiratory tract, using normal human bronchial epithelial cells grown at the Air-Liquid Interface. Acute exposure (24 h) induced an oxidative stress that persisted 24 h post-exposure, associated with particle internalization and epithelium morphological changes (cuboidal appearance and loss of cilia). Repeated exposures (4×16h) to RSS particles did not trigger oxidative stress but cell morphological changes occurred. Overall, this study provides a better overview of the toxic effects of coloured smoke particles.
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Affiliation(s)
| | - Laurence Chevalier
- Université de Rouen Normandie, UNIROUEN, INSA Rouen, CNRS, GPM-UMR6634, 76000 Rouen, France
| | - Clémence Méausoone
- Univ Rouen Normandie, Université Caen Normandie, Normandie Univ, ABTEUR 4651, F-76000 Rouen, France
| | - Fabrice Cazier
- Université du Littoral Côte d'Opale, CCM - Centre Commun de Mesures, 59 375 Dunkerque, France
| | - Dorothée Dewaele
- Université du Littoral Côte d'Opale, CCM - Centre Commun de Mesures, 59 375 Dunkerque, France
| | - Francine Cazier-Dennin
- Université du Littoral Côte d'Opale, EA 4492 - UCEIV - Unité de Chimie Environnementale et Interactions sur le Vivant, SFR Condorcet FR CNRS 417, 59 375 Dunkerque, France
| | - Marion Janona
- Univ Rouen Normandie, Université Caen Normandie, Normandie Univ, ABTEUR 4651, F-76000 Rouen, France
| | - Cathy Logie
- Univ Rouen Normandie, Université Caen Normandie, Normandie Univ, ABTEUR 4651, F-76000 Rouen, France
| | - Sophie Achard
- Université de Paris, Faculté de Pharmacie, Inserm UMR1153 - CRESS, HERA " Health Environmental Risk Assessment ", 75005 Paris, France
| | - Véronique André
- Univ Rouen Normandie, Université Caen Normandie, Normandie Univ, ABTEUR 4651, F-76000 Rouen, France
| | - Tiphaine Rogez-Florent
- Univ Rouen Normandie, Université Caen Normandie, Normandie Univ, ABTEUR 4651, F-76000 Rouen, France
| | - Christelle Monteil
- Univ Rouen Normandie, Université Caen Normandie, Normandie Univ, ABTEUR 4651, F-76000 Rouen, France
| | - Cécile Corbiere
- Univ Rouen Normandie, Université Caen Normandie, Normandie Univ, ABTEUR 4651, F-76000 Rouen, France.
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20
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Fu R, Zhao B, Chen M, Fu X, Zhang Q, Cui Y, Hu X, Zhou W. Moving beyond cisplatin resistance: mechanisms, challenges, and prospects for overcoming recurrence in clinical cancer therapy. Med Oncol 2023; 41:9. [PMID: 38063931 DOI: 10.1007/s12032-023-02237-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 11/03/2023] [Indexed: 12/18/2023]
Abstract
Cisplatin, a classical platinum-based chemotherapy agent, has been a frontline treatment for various cancers for decades. However, its effectiveness has been hindered by the development of resistance, leading to cancer relapse. Addressing this challenge is crucial for both clinical practice and research. Hence, the imperative to unravel the intricate mechanisms underpinning cisplatin resistance and to uncover novel strategies to overcome this barrier holds immense significance. Within this review, we summarized the classification of platinum agents, highlighting their roles in therapeutic landscapes. We discussed the diverse mechanisms behind cisplatin resistance, including diminished intracellular cisplatin accumulation, intracellular detoxification, DNA repair, autophagy responses, heat shock proteins, tumor microenvironment, cancer stem cells, epigenetic regulation, ferroptosis resistance, and metabolic reprogramming. Drawing from this comprehensive understanding, we offered a series of prospective solutions to surmount cisplatin resistance and consequently mitigate the specter of disease recurrence within the realm of clinical cancer therapy.
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Affiliation(s)
- Rui Fu
- The School and Hospital of Stomatology, Tianjin Medical University, Tianjin, 300070, China
| | - Borui Zhao
- The School and Hospital of Stomatology, Tianjin Medical University, Tianjin, 300070, China
| | - Min Chen
- The School and Hospital of Stomatology, Tianjin Medical University, Tianjin, 300070, China
| | - Xiaolong Fu
- Department of Stomatology, Tianjin Haihe Hospital, Tianjin, 300222, China
| | - Qian Zhang
- The School and Hospital of Stomatology, Tianjin Medical University, Tianjin, 300070, China
| | - Yange Cui
- Program in Gene Expression and Regulation, The Wistar Institute, Philadelphia, PA, 19104, USA
| | - Xin Hu
- The School and Hospital of Stomatology, Tianjin Medical University, Tianjin, 300070, China.
| | - Wei Zhou
- Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
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21
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Aleksandrova Y, Neganova M. Deciphering the Mysterious Relationship between the Cross-Pathogenetic Mechanisms of Neurodegenerative and Oncological Diseases. Int J Mol Sci 2023; 24:14766. [PMID: 37834214 PMCID: PMC10573395 DOI: 10.3390/ijms241914766] [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: 08/10/2023] [Revised: 09/22/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
The relationship between oncological pathologies and neurodegenerative disorders is extremely complex and is a topic of concern among a growing number of researchers around the world. In recent years, convincing scientific evidence has accumulated that indicates the contribution of a number of etiological factors and pathophysiological processes to the pathogenesis of these two fundamentally different diseases, thus demonstrating an intriguing relationship between oncology and neurodegeneration. In this review, we establish the general links between three intersecting aspects of oncological pathologies and neurodegenerative disorders, i.e., oxidative stress, epigenetic dysregulation, and metabolic dysfunction, examining each process in detail to establish an unusual epidemiological relationship. We also focus on reviewing the current trends in the research and the clinical application of the most promising chemical structures and therapeutic platforms that have a modulating effect on the above processes. Thus, our comprehensive analysis of the set of molecular determinants that have obvious cross-functional pathways in the pathogenesis of oncological and neurodegenerative diseases can help in the creation of advanced diagnostic tools and in the development of innovative pharmacological strategies.
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Affiliation(s)
- Yulia Aleksandrova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 142432 Chernogolovka, Russia;
| | - Margarita Neganova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 142432 Chernogolovka, Russia;
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, 420088 Kazan, Russia
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22
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Křikavová R, Romanovová M, Jendželovská Z, Majerník M, Masaryk L, Zoufalý P, Milde D, Moncol J, Herchel R, Jendželovský R, Nemec I. Impact of the central atom and halido ligand on the structure, antiproliferative activity and selectivity of half-sandwich Ru(II) and Ir(III) complexes with a 1,3,4-thiadiazole-based ligand. Dalton Trans 2023; 52:12717-12732. [PMID: 37610172 DOI: 10.1039/d3dt01696j] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
Half-sandwich complexes [Ru(η6-pcym)(L1)X]PF6 (1, 3) and [Ir(η5-Cp*)(L1)X]PF6 (2, 4) featuring a thiadiazole-based ligand L1 (2-(furan-2-yl)-5-(pyridin-2-yl)-1,3,4-thiadiazole) were synthesized and characterized by varied analytical methods, including single-crystal X-ray diffraction (X = Cl or I, pcym = p-cymene, Cp* = pentamethylcyclopentadienyl). The structures of the molecules were analysed and interpreted using computational methods such as Density Functional Theory (DFT) and Quantum Theory of Atoms in Molecules (QT-AIM). A 1H NMR spectroscopy study showed that complexes 1-3 exhibited hydrolytic stability while 4 underwent partial iodido/chlorido ligand exchange in phosphate-buffered saline. Moreover, 1-4 demonstrated the ability to oxidize NADH (reduced nicotinamide adenine dinucleotide) to NAD+ with Ir(III) complexes 2 and 4 displaying higher catalytic activity compared to their Ru(II) analogues. None of the complexes interacted with reduced glutathione (GSH). Additionally, 1-4 exhibited greater lipophilicity than cisplatin. In vitro biological analyses were performed in healthy cell lines (CCD-18Co colon and CCD-1072Sk foreskin fibroblasts) as well as in cisplatin-sensitive (A2780) and -resistant (A2780cis) ovarian cancer cell lines. The results indicated that Ir(III) complexes 2 and 4 had no effect on human fibroblasts, demonstrating their selectivity. In contrast, complexes 1 and 4 exhibited moderate inhibitory effects on the metabolic and proliferation activities of the cancer cells tested (selectivity index SI > 3.4 for 4 and 2.6 for cisplatin; SI = IC50(A2780)/IC50(CCD-18Co)), including the cisplatin-resistant cancer cell line. Based on these findings, it is possible to emphasize that mainly complex 4 could represent a further step in the development of selective and highly effective anticancer agents, particularly against resistant tumour types.
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Affiliation(s)
- Radka Křikavová
- Department of Inorganic Chemistry, Faculty of Science, Palacký University Olomouc, 17. listopadu 12, CZ-771 46 Olomouc, Czech Republic.
| | - Michaela Romanovová
- Department of Cellular Biology, Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Šrobárova 2, 041 54 Košice, Slovakia
| | - Zuzana Jendželovská
- Department of Cellular Biology, Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Šrobárova 2, 041 54 Košice, Slovakia
| | - Martin Majerník
- Department of Cellular Biology, Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Šrobárova 2, 041 54 Košice, Slovakia
| | - Lukáš Masaryk
- Department of Inorganic Chemistry, Faculty of Science, Palacký University Olomouc, 17. listopadu 12, CZ-771 46 Olomouc, Czech Republic.
| | - Pavel Zoufalý
- Department of Inorganic Chemistry, Faculty of Science, Palacký University Olomouc, 17. listopadu 12, CZ-771 46 Olomouc, Czech Republic.
| | - David Milde
- Department of Analytical Chemistry, Faculty of Science, Palacký University Olomouc, 17. listopadu 12, CZ-771 46 Olomouc, Czech Republic
| | - Jan Moncol
- Department of Inorganic Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Bratislava SK-81237, Slovakia
| | - Radovan Herchel
- Department of Inorganic Chemistry, Faculty of Science, Palacký University Olomouc, 17. listopadu 12, CZ-771 46 Olomouc, Czech Republic.
| | - Rastislav Jendželovský
- Department of Cellular Biology, Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Šrobárova 2, 041 54 Košice, Slovakia
| | - Ivan Nemec
- Department of Inorganic Chemistry, Faculty of Science, Palacký University Olomouc, 17. listopadu 12, CZ-771 46 Olomouc, Czech Republic.
- Central European Institute of Technology, Brno University of Technology, Purkyňova 123, 61200 Brno, Czech Republic
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23
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Rushing BR, Molina S, Sumner S. Metabolomics Analysis Reveals Altered Metabolic Pathways and Response to Doxorubicin in Drug-Resistant Triple-Negative Breast Cancer Cells. Metabolites 2023; 13:865. [PMID: 37512572 PMCID: PMC10383792 DOI: 10.3390/metabo13070865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/07/2023] [Accepted: 07/15/2023] [Indexed: 07/30/2023] Open
Abstract
This study aimed to investigate metabolic changes following the acquisition of resistance to doxorubicin in the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Two drug-resistant cell lines, DOX-RES-50 and DOX-RES-100, were generated by treating MDA-MB-231 cells with doxorubicin for 24 h and allowing them to recover for six weeks. Both drug-resistant cell lines demonstrated an increase in doxorubicin IC50 values, indicating acquired drug resistance. Metabolomics analysis showed clear separation between the parental MDA-MB-231 cell line and the drug-resistant cell lines. Pathway analysis revealed that arginine and proline metabolism, glutathione metabolism, and beta-alanine metabolism were significantly perturbed in the drug-resistant cell lines compared to the parental cell line. After matching signals to an in-house library of reference standards, significant decreases in short- and medium-chain acylcarnitines and significant increases in long-chain acylcarnitines, 5-oxoproline, and 7-ketodeoxycholic acid were observed in the resistant cell lines as compared to the parental MDA-MB-231 cell line. In addition to baseline metabolic differences, we also investigated differences in metabolic responses in resistant cell lines upon a second exposure at multiple concentrations. Results indicate that whereas the parental MDA-MB-231 cell line had many metabolites that responded to doxorubicin in a dose-dependent manner, the two resistant cell lines lost a dose-dependent response for the majority of these metabolites. The study's findings provide insight into how metabolism is altered during the acquisition of resistance in TNBC cells and how the metabolic response to doxorubicin changes upon repeated treatment. This information can potentially identify novel targets to prevent or reverse multi-drug resistance in TNBC, and also demonstrate the usefulness of metabolomics technology in identifying new mechanisms of drug resistance in cancer and potential drug targets.
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Affiliation(s)
- Blake R Rushing
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USA
| | - Sabrina Molina
- Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USA
| | - Susan Sumner
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USA
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24
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Madaci L, Gard C, Nin S, Venton G, Rihet P, Puthier D, Loriod B, Costello R. The Contribution of Multiplexing Single Cell RNA Sequencing in Acute Myeloid Leukemia. Diseases 2023; 11:96. [PMID: 37489448 PMCID: PMC10366847 DOI: 10.3390/diseases11030096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/26/2023] Open
Abstract
Decades ago, the treatment for acute myeloid leukemia relied on cytarabine and anthracycline. However, advancements in medical research have introduced targeted therapies, initially employing monoclonal antibodies such as ant-CD52 and anti-CD123, and subsequently utilizing specific inhibitors that target molecular mutations like anti-IDH1, IDH2, or FLT3. The challenge lies in determining the role of these therapeutic options, considering the inherent tumor heterogeneity associated with leukemia diagnosis and the clonal drift that this type of tumor can undergo. Targeted drugs necessitate an examination of various therapeutic targets at the individual cell level rather than assessing the entire population. It is crucial to differentiate between the prognostic value and therapeutic potential of a specific molecular target, depending on whether it is found in a terminally differentiated cell with limited proliferative potential or a stem cell with robust capabilities for both proliferation and self-renewal. However, this cell-by-cell analysis is accompanied by several challenges. Firstly, the scientific aspect poses difficulties in comparing different single cell analysis experiments despite efforts to standardize the results through various techniques. Secondly, there are practical obstacles as each individual cell experiment incurs significant financial costs and consumes a substantial amount of time. A viable solution lies in the ability to process multiple samples simultaneously, which is a distinctive feature of the cell hashing technique. In this study, we demonstrate the applicability of the cell hashing technique for analyzing acute myeloid leukemia cells. By comparing it to standard single cell analysis, we establish a strong correlation in various parameters such as quality control, gene expression, and the analysis of leukemic blast markers in patients. Consequently, this technique holds the potential to become an integral part of the biological assessment of acute myeloid leukemia, contributing to the personalized and optimized management of the disease, particularly in the context of employing targeted therapies.
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Affiliation(s)
- Lamia Madaci
- TAGC, INSERM, UMR1090, Aix Marseille University, Parc Scientifique de Luminy, 13009 Marseille, France
| | - Charlyne Gard
- TAGC, INSERM, UMR1090, Aix Marseille University, Parc Scientifique de Luminy, 13009 Marseille, France
| | - Sébastien Nin
- TAGC, INSERM, UMR1090, Aix Marseille University, Parc Scientifique de Luminy, 13009 Marseille, France
| | - Geoffroy Venton
- TAGC, INSERM, UMR1090, Aix Marseille University, Parc Scientifique de Luminy, 13009 Marseille, France
- Hematology and Cellular Therapy Department, Conception Hospital, 13005 Marseille, France
| | - Pascal Rihet
- TAGC, INSERM, UMR1090, Aix Marseille University, Parc Scientifique de Luminy, 13009 Marseille, France
| | - Denis Puthier
- TAGC, INSERM, UMR1090, Aix Marseille University, Parc Scientifique de Luminy, 13009 Marseille, France
| | - Béatrice Loriod
- TAGC, INSERM, UMR1090, Aix Marseille University, Parc Scientifique de Luminy, 13009 Marseille, France
| | - Régis Costello
- TAGC, INSERM, UMR1090, Aix Marseille University, Parc Scientifique de Luminy, 13009 Marseille, France
- Hematology and Cellular Therapy Department, Conception Hospital, 13005 Marseille, France
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25
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Yan X, Han R, Fan W, Shan B, Yang J, Zhao X. Mechanism of 5-chloro-2-methyl-4-isothiazolin-3-one (CMIT) in controlling microbial problems in aircraft fuel systems. RSC Adv 2023; 13:19485-19494. [PMID: 37388151 PMCID: PMC10301881 DOI: 10.1039/d3ra02970k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 06/20/2023] [Indexed: 07/01/2023] Open
Abstract
This research investigated the potential use of 5-chloro-2-methyl-4-isothiazolin-3-one (CMIT) as a biocide in aircraft fuel systems, which is rarely studied due to the unique properties of such systems. The study assessed the effectiveness of CMIT against three microbial isolates using minimum inhibitory concentrations and bacteriostatic tests, and showed that CMIT had good activity against them. Electrochemical studies were conducted to determine the impact of CMIT on the 7B04 aluminum alloy, which demonstrated that CMIT acted as a cathodic inhibitor and exhibited certain levels of short-term and long-term corrosion inhibition effects at concentrations of 100 mg L-1 and 60 mg L-1, respectively. Additionally, the research provided insights into the mechanisms governing microbial problems by studying the reaction of CMIT with glutathione and sulfate. Overall, the study suggested that CMIT may be a useful biocide in aircraft fuel systems and provided important information on its efficacy and mechanism of action.
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Affiliation(s)
- Xiaohan Yan
- School of Ocean, Yantai University Yantai 264005 China
| | - Ruifang Han
- School of Ocean, Yantai University Yantai 264005 China
| | - Weijie Fan
- Qingdao Campus of Naval Aeronautical University Qingdao 266041 China
| | - Borong Shan
- Qingdao Campus of Naval Aeronautical University Qingdao 266041 China
| | - Jie Yang
- School of Ocean, Yantai University Yantai 264005 China
| | - Xiaodong Zhao
- School of Ocean, Yantai University Yantai 264005 China
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26
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Michalkova R, Kello M, Cizmarikova M, Bardelcikova A, Mirossay L, Mojzis J. Chalcones and Gastrointestinal Cancers: Experimental Evidence. Int J Mol Sci 2023; 24:ijms24065964. [PMID: 36983038 PMCID: PMC10059739 DOI: 10.3390/ijms24065964] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/10/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Colorectal (CRC) and gastric cancers (GC) are the most common digestive tract cancers with a high incidence rate worldwide. The current treatment including surgery, chemotherapy or radiotherapy has several limitations such as drug toxicity, cancer recurrence or drug resistance and thus it is a great challenge to discover an effective and safe therapy for CRC and GC. In the last decade, numerous phytochemicals and their synthetic analogs have attracted attention due to their anticancer effect and low organ toxicity. Chalcones, plant-derived polyphenols, received marked attention due to their biological activities as well as for relatively easy structural manipulation and synthesis of new chalcone derivatives. In this study, we discuss the mechanisms by which chalcones in both in vitro and in vivo conditions suppress cancer cell proliferation or cancer formation.
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Affiliation(s)
- Radka Michalkova
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia
| | - Martina Cizmarikova
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia
| | - Annamaria Bardelcikova
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia
| | - Ladislav Mirossay
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia
| | - Jan Mojzis
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia
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27
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Chen T, Chen J, Zeng T, Huang Q, Chen D, Chen H, Chen J, Zheng B, Wang M, Chen S, Dai J, Sun H, Chen T, Huang Y, Zhao L, Ma S, Liu X. WZ35 inhibits gastric cancer cell metastasis by depleting glutathione to promote cellular metabolic remodeling. Cancer Lett 2023; 555:216044. [PMID: 36574880 DOI: 10.1016/j.canlet.2022.216044] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 12/18/2022] [Accepted: 12/21/2022] [Indexed: 12/25/2022]
Abstract
This study aimed at elucidating the crosstalk between redox reaction and metabolic remodeling through uncovering the mechanism underlying WZ35-mediated reactive oxygen species (ROS) production and regulation of amino acid metabolism to inhibit gastric cancer (GC) cell metastasis. The activity and biosafety of curcumin analog, WZ35, were verified in vitro and in vivo. The potential molecular mechanism underlying WZ35-mediated enhanced radiotherapeutic sensitivity by reduced Glutathione (GSH) depletion was elucidated by RNA sequencing, single-cell sequencing (scRNA-seq), metabolic mass spectrometry, and other molecular experiments. Compared to curcumin, WZ35 proved more potent anti-proliferative and anti-metastasis properties. Importantly, we demonstrated that WZ35 could consume GSH in multiple ways, including by reduction of raw materials and consumption reserves, inhibition of reformation, and enhanced decomposition. Mechanistically, we identify that WZ35 maintains the GSH depletion phenotype through the ROS-YAP-AXL-ALKBH5-GLS2 loop, further backing the relevance of metabolic remodeling in the tumor microenvironment with tumor metastasis and the role of m6A in tumor metastasis. Collectively, our study identified WZ35 as a novel GSH depletion agent and a previously undiscovered GSH depletion loop mechanism in GC cell metastasis.
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Affiliation(s)
- Tongke Chen
- Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Junbo Chen
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Tianni Zeng
- Department of Oncology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310007, China
| | - Qianying Huang
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Di Chen
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Hong Chen
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Jiayao Chen
- Wenzhou Medical University Renji College, Wenzhou, 325035, Zhejiang Province, China
| | - Bin Zheng
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Mengting Wang
- School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Shinuo Chen
- Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Jichen Dai
- Second Medical College of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Hanxiao Sun
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Tongzuan Chen
- Department of General Surgery, The Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou, 325000, China
| | - Yuwen Huang
- Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Liqian Zhao
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China.
| | - Shumei Ma
- School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325000, China.
| | - Xiaodong Liu
- School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325000, China.
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28
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Xue ZP, Cu X, Xu K, Peng JH, Liu HR, Zhao RT, Wang Z, Wang T, Xu ZS. The effect of glutathione biosynthesis of Streptococcus thermophilus ST-1 on cocultured Lactobacillus delbrueckii ssp. bulgaricus ATCC11842. J Dairy Sci 2023; 106:884-896. [PMID: 36460506 DOI: 10.3168/jds.2022-22123] [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: 03/26/2022] [Accepted: 09/03/2022] [Indexed: 11/30/2022]
Abstract
Streptococcus thermophilus and Lactobacillus delbrueckii ssp. bulgaricus are the main species used for yogurt preparation. Glutathione (GSH) can be synthesized by S. thermophilus and plays a crucial role in combating environmental stress. However, the effect of GSH biosynthesis by S. thermophilus on cocultured L. delbrueckii ssp. bulgaricus is still unknown. In this study, a mutant S. thermophilus ΔgshF was constructed by deleting the GSH synthase. The wild strain S. thermophilus ST-1 and ΔgshF mutants were cocultured with L. delbrueckii ssp. bulgaricus ATCC11842 by using Transwell chambers (Guangzhou Shuopu Biotechnology Co., Ltd.), respectively. It was proven that the GSH synthesized by S. thermophilus ST-1 could be absorbed and used by L. delbrueckii ssp. bulgaricus ATCC11842, and promote growth ability and stress tolerance of L. delbrueckii ssp. bulgaricus ATCC11842. The biomass of L. delbrueckii ssp. bulgaricus ATCC11842 cocultured with S. thermophilus ST-1 or ΔgshF (adding exogenous GSH) increased by 1.8 and 1.4 times compared with the biomass of L. delbrueckii ssp. bulgaricus ATCC11842 cocultured with S. thermophilus ΔgshF. Meanwhile, after H2O2 and low-temperature treatments, the bacterial viability of L. delbrueckii ssp. bulgaricus cocultured with S. thermophilus ΔgshF, with or without GSH, was decreased by 41 and 15% compared with that of L. delbrueckii ssp. bulgaricus cocultured with S. thermophilus ST-1. Furthermore, transcriptome analysis showed that the expression levels of genes involved in purine nucleotide and pyrimidine nucleotide metabolism in L. delbrueckii ssp. bulgaricus ATCC11842 were at least 3 times increased when cocultured with S. thermophilus (fold change > 3.0). Moreover, compared with the mutant strain ΔgshF, the wild-type strain ST-1 could shorten the fermented curd time by 5.3 hours during yogurt preparation. These results indicated that the GSH synthesized by S. thermophilus during cocultivation effectively enhanced the activity of L. delbrueckii ssp. bulgaricus and significantly improved the quality of fermented milk.
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Affiliation(s)
- Z P Xue
- State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China; Shandong Provincial Key Laboratory of Microbial Engineering, Department of Bioengineering, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China
| | - X Cu
- State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China; Shandong Provincial Key Laboratory of Microbial Engineering, Department of Bioengineering, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China
| | - K Xu
- State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China; Shandong Provincial Key Laboratory of Microbial Engineering, Department of Bioengineering, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China
| | - J H Peng
- State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China; Shandong Provincial Key Laboratory of Microbial Engineering, Department of Bioengineering, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China
| | - H R Liu
- State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China; Shandong Provincial Key Laboratory of Microbial Engineering, Department of Bioengineering, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China
| | - R T Zhao
- State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China; Shandong Provincial Key Laboratory of Microbial Engineering, Department of Bioengineering, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China
| | - Z Wang
- State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China; Shandong Provincial Key Laboratory of Microbial Engineering, Department of Bioengineering, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China
| | - T Wang
- State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China; Shandong Provincial Key Laboratory of Microbial Engineering, Department of Bioengineering, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China.
| | - Z S Xu
- State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China; Shandong Provincial Key Laboratory of Microbial Engineering, Department of Bioengineering, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, P. R. China.
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29
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Wang D, Duan J, Liu J, Yi H, Zhang Z, Song H, Li Y, Zhang K. Stimuli-Responsive Self-Degradable DNA Hydrogels: Design, Synthesis, and Applications. Adv Healthc Mater 2023:e2203031. [PMID: 36708144 DOI: 10.1002/adhm.202203031] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/11/2023] [Indexed: 01/29/2023]
Abstract
DNA hydrogels play an increasingly important role in biomedicine and bioanalysis applications. Due to their high programmability, multifunctionality and biocompatibility, they are often used as effective carriers for packing drugs, cells, or other bioactive cargoes in vitro and in vivo. However, the stability of the DNA hydrogels prevents their in-demand rapid release of cargoes to achieve a full therapeutic effect in time. For bioanalysis, the generation of signals sometimes needs the DNA hydrogel to be rapidly degraded when sensing target molecules. To meet these requirements, stimulus-responsive DNA hydrogels are designed. By responding to different stimuli, self-degradable DNA hydrogels can switch from gel to solution for quantitative bioanalysis and precision cargo delivery. This review summarizes the recently developed innovative methods for designing stimuli-responsive self-degradable DNA hydrogels and showed their applications in the bioanalysis and biomedicines fields. Challenges, as well as prospects, are also discussed.
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Affiliation(s)
- Danyu Wang
- School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450001, China
| | - Jie Duan
- School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450001, China
| | - Jingwen Liu
- School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450001, China
| | - Hua Yi
- School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450001, China
| | - Zhenzhong Zhang
- School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450001, China
| | - Haiwei Song
- School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450001, China
| | - Yinchao Li
- School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450001, China
| | - Kaixiang Zhang
- School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450001, China
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Spagnuolo C, Moccia S, Tedesco I, Crescente G, Volpe MG, Russo M, Russo GL. Phenolic Extract from Extra Virgin Olive Oil Induces Different Anti-Proliferative Pathways in Human Bladder Cancer Cell Lines. Nutrients 2022; 15:nu15010182. [PMID: 36615840 PMCID: PMC9823665 DOI: 10.3390/nu15010182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/23/2022] [Accepted: 12/26/2022] [Indexed: 01/03/2023] Open
Abstract
Regular consumption of olive oil is associated with protection against chronic-degenerative diseases, such as cancer. Epidemiological evidence indicates an inverse association between olive oil intake and bladder cancer risk. Bladder cancer is among the most common forms of cancer; in particular, the transitional cell carcinoma histotype shows aggressive behavior. We investigated the anti-proliferative effects of a phenolic extract prepared from an extra virgin olive oil (EVOOE) on two human bladder cancer cell lines, namely RT112 and J82, representing the progression from low-grade to high-grade tumors, respectively. In RT112, the EVOOE reduced cell viability (IC50 = 240 μg/mL at 24 h), triggering a non-protective form of autophagy, evidenced by the autophagosome formation and the increase in LC-3 lipidation. In J82, EVOOE induced a strong decrease in cell viability after 24 h of treatment (IC50 = 65.8 μg/mL) through rapid and massive apoptosis, assessed by Annexin V positivity and caspase-3 and -9 activation. Moreover, in both bladder cancer cell lines, EVOOE reduced intracellular reactive oxygen species, but this antioxidant effect was not correlated with its anti-proliferative outcomes. Data obtained suggest that the mixture of phenolic compounds in extra virgin olive oil activates different anti-proliferative pathways.
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Obukhova L, Kopytova T, Murach E, Shchelchkova N, Kontorshchikova C, Medyanik I, Orlinskaya N, Grishin A, Kontorshchikov M, Badanina D. Glutathione and Its Metabolic Enzymes in Gliomal Tumor Tissue and the Peritumoral Zone at Different Degrees of Anaplasia. Curr Issues Mol Biol 2022; 44:6439-6449. [PMID: 36547100 PMCID: PMC9777065 DOI: 10.3390/cimb44120439] [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: 11/07/2022] [Revised: 12/10/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
This research was aimed at investigating the features of free radical activity and the parameters of glutathione metabolism in tumor tissues and the peritumoral zone at different degrees of glial tumor anaplasia. We analyzed postoperative material from 20 patients with gliomas of different degrees of anaplasia. The greatest differences compared to adjacent noncancerous tissues were found in the tumor tissue: an increased amount of glutathione and glutathione-related enzymes at Grades I and II, and a decrease of these parameters at Grades III and IV. For the peritumoral zone of Grades I and II, the indices changed in different directions, while for Grades III and IV, they occurred synchronously with the tumor tissue changes. For Low Grade and High Grade gliomas, opposite trends were revealed regarding changes in the level of glutathione and the enzymes involved in its metabolism and in the free radical activity in the peritumoral zone. The content of glutathione and the enzymes involved in its metabolism decreased with the increasing degree of glioma anaplasia. In contrast, free radical activity increased. The glutathione system is an active participant in the antioxidant defense of the body and can be used to characterize the cell condition of gliomas at different stages of tumor development.
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Ying M, Hu X. Tracing the electron flow in redox metabolism: The appropriate distribution of electrons is essential to maintain redox balance in cancer cells. Semin Cancer Biol 2022; 87:32-47. [PMID: 36374644 DOI: 10.1016/j.semcancer.2022.10.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 10/08/2022] [Accepted: 10/14/2022] [Indexed: 11/09/2022]
Abstract
Cancer cells are characterized by sustained proliferation, which requires a huge demand of fuels to support energy production and biosynthesis. Energy is produced by the oxidation of the fuels during catabolism, and biosynthesis is achieved by the reduction of smaller units or precursors. Therefore, the oxidation-reduction (redox) reactions in cancer cells are more active compared to those in the normal counterparts. The higher activity of redox metabolism also induces a more severe oxidative stress, raising the question of how cancer cells maintain the redox balance. In this review, we overview the redox metabolism of cancer cells in an electron-tracing view. The electrons are derived from the nutrients in the tumor microenvironment and released during catabolism. Most of the electrons are transferred to NAD(P) system and then directed to four destinations: energy production, ROS generation, reductive biosynthesis and antioxidant system. The appropriate distribution of these electrons achieved by the function of redox regulation network is essential to maintain redox homeostasis in cancer cells. Interfering with the electron distribution and disrupting redox balance by targeting the redox regulation network may provide therapeutic implications for cancer treatment.
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Affiliation(s)
- Minfeng Ying
- Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009 Hangzhou, Zhejiang, China.
| | - Xun Hu
- Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009 Hangzhou, Zhejiang, China.
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Obukhova L, Kopytova T, Murach E, Shchelchkova N, Kontorshchikova C, Medyanik I, Orlinskaya N, Grishin A, Kontorshchikov M, Badanina D. Relationship between Glutathione-Dependent Enzymes and the Immunohistochemical Profile of Glial Neoplasms. Biomedicines 2022; 10:biomedicines10102393. [PMID: 36289655 PMCID: PMC9598304 DOI: 10.3390/biomedicines10102393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/15/2022] [Accepted: 09/20/2022] [Indexed: 11/25/2022] Open
Abstract
This research aimed to investigate the relationships between the parameters of glutathione metabolism and the immunohistochemical characteristics of glial tumors. Postoperative material from 20 patients with gliomas of different grades of anaplasia was analyzed. Bioinformatic analysis of the interactions between the gliomas’ immunohistochemical markers and their glutathione-dependent enzymes was carried out using the STRING, BioGrid, while Signor databases revealed interactions between such glioma markers as IDH and p53 and the glutathione exchange enzymes (glutathione peroxidase, glutathione reductase, glutathione S-transferase). The most pronounced relationship with glutathione metabolism was demonstrated by the level of the nuclear protein Ki67 as a marker of proliferative activity, and the presence of the IDH1 mutation as one of the key genetic events of gliomagenesis. The glutathione system is an active participant in the body’s antioxidant defense, involving the p53 markers and MGMT promoter methylation. It allows characterization of the gliomal cells’ status at different stages of tumor development.
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Cheraghi O, Dabirmanesh B, Ghazi F, Amanlou M, Atabakhshi-kashi M, Fathollahi Y, Khajeh K. The effect of Nrf2 deletion on the proteomic signature in a human colorectal cancer cell line. BMC Cancer 2022; 22:979. [PMID: 36100939 PMCID: PMC9472369 DOI: 10.1186/s12885-022-10055-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 09/05/2022] [Indexed: 12/03/2022] Open
Abstract
Background Colorectal cancer is one of the most common cancer and the third leading cause of death worldwide. Increased generation of reactive oxygen species (ROS) is observed in many types of cancer cells. Several studies have reported that an increase in ROS production could affect the expression of proteins involved in ROS-scavenging, detoxification and drug resistance. Nuclear factor erythroid 2 related factor 2 (Nrf2) is a known transcription factor for cellular response to oxidative stress. Several researches exhibited that Nrf2 could exert multiple functions and expected to be a promising therapeutic target in many cancers. Here, Nrf2 was knocked down in colorectal cancer cell line HT29 and changes that occurred in signaling pathways and survival mechanisms were evaluated. Methods The influence of chemotherapy drugs (doxorubicin and cisplatin), metastasis and cell viability were investigated. To explore the association between specific pathways and viability in HT29-Nrf2−, proteomic analysis, realtime PCR and western blotting were performed. Results In the absence of Nrf2 (Nrf2−), ROS scavenging and detoxification potential were dramatically faded and the HT29-Nrf2− cells became more susceptible to drugs. However, a severe decrease in viability was not observed. Bioinformatic analysis of proteomic data revealed that in Nrf2− cells, proteins involved in detoxification processes, respiratory electron transport chain and mitochondrial-related compartment were down regulated. Furthermore, proteins related to MAPKs, JNK and FOXO pathways were up regulated that possibly helped to overcome the detrimental effect of excessive ROS production. Conclusions Our results revealed MAPKs, JNK and FOXO pathways connections in reducing the deleterious effect of Nrf2 deficiency, which can be considered in cancer therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10055-y.
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The Role of SLC7A11 in Cancer: Friend or Foe? Cancers (Basel) 2022; 14:cancers14133059. [PMID: 35804831 PMCID: PMC9264807 DOI: 10.3390/cancers14133059] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/12/2022] [Accepted: 06/15/2022] [Indexed: 11/17/2022] Open
Abstract
SLC7A11 controls the uptake of extracellular cystine in exchange for glutamate at a ratio of 1:1, and it is overexpressed in a variety of tumours. Accumulating evidence has shown that the expression of SLC7A11 is fine-tuned at multiple levels, and plays diverse functional and pharmacological roles in tumours, such as cellular redox homeostasis, cell growth and death, and cell metabolism. Many reports have suggested that the inhibition of SLC7A11 expression and activity is favourable for tumour therapy; thus, SLC7A11 is regarded as a potential therapeutic target. However, emerging evidence also suggests that on some occasions, the inhibition of SLC7A11 is beneficial to the survival of cancer cells, and confers the development of drug resistance. In this review, we first briefly introduce the biological properties of SLC7A11, including its structure and physiological functions, and further summarise its regulatory network and potential regulators. Then, focusing on its role in cancer, we describe the relationships of SLC7A11 with tumourigenesis, survival, proliferation, metastasis, and therapeutic resistance in more detail. Finally, since SLC7A11 has been linked to cancer through multiple approaches, we propose that its contribution and regulatory mechanism require further elucidation. Thus, more personalised therapeutic strategies should be adapted when targeting SLC7A11.
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Guo J, Liu K, Wang J, Jiang H, Zhang M, Liu Y, Shan C, Hu F, Fu W, Zhang C, Li J, Chen Y. A rational foundation for micheliolide-based combination strategy by targeting redox and metabolic circuit in cancer cells. Biochem Pharmacol 2022; 200:115037. [DOI: 10.1016/j.bcp.2022.115037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/24/2022] [Accepted: 04/06/2022] [Indexed: 11/02/2022]
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Enhanced antitumor effect of L-buthionine sulfoximine or ionizing radiation by copper complexes with 2,2´-biquinoline and sulfonamides on A549 2D and 3D lung cancer cell models. J Biol Inorg Chem 2022; 27:329-343. [PMID: 35247094 DOI: 10.1007/s00775-022-01933-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 02/07/2022] [Indexed: 12/28/2022]
Abstract
Two ternary copper(II) complexes with 2,2'-biquinoline (BQ) and with sulfonamides: sulfamethazine (SMT) or sulfaquinoxaline (SDQ) whose formulae are Cu(SMT)(BQ)Cl and Cu(SDQ)(BQ)Cl·CH3OH, in what follows SMTCu and SDQCu, respectively, induced oxidative stress by increasing ROS level from 1.0 μM and the reduction potential of the couple GSSG/GSH2. The co-treatment with L-buthionine sulfoximine (BSO), which inhibits the production of GSH, enhanced the effect of copper complexes on tumor cell viability and on oxidative damage. Both complexes generated DNA strand breaks given by-at least partially-the oxidation of pyrimidine bases, which caused the arrest of the cell cycle in the G2/M phase. These phenomena triggered processes of apoptosis proven by activation of caspase 3 and externalization of phosphatidylserine and loss of cell integrity from 1.0 μM. The combination with BSO induced a marked increase in the apoptotic population. On the other hand, an improved cell proliferation effect was observed when combining SDQCu with a radiation dose of 2 Gy from 1.0 μM or with 6 Gy from 1.5 μM. Finally, studies in multicellular spheroids demonstrated that even though copper(II) complexes did not inhibit cell invasion in collagen gels up to 48 h of treatment at the higher concentrations, multicellular resistance outperformed several drugs currently used in cancer treatment. Overall, our results reveal an antitumor effect of both complexes in monolayer and multicellular spheroids and an improvement with the addition of BSO. However, only SDQCu was the best adjuvant of ionizing radiation treatment.
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Liu Y, Yang H, Liu Q, Pan M, Wang D, Pan S, Zhang W, Wei J, Zhao X, Ji J. Selenocystine-Derived Label-Free Fluorescent Schiff Base Nanocomplex for siRNA Delivery Synergistically Kills Cancer Cells. Molecules 2022; 27:1302. [PMID: 35209090 PMCID: PMC8878402 DOI: 10.3390/molecules27041302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 01/24/2022] [Accepted: 02/08/2022] [Indexed: 11/16/2022] Open
Abstract
Chemo and siRNA synergic treatments for tumors is a promising new therapeutic trend. Selenocystine, a selenium analog of cysteine, has been considered a potential antitumor agent due to its redox perturbing role. In this study, we developed a nanocarrier for siRNA based on a selenocystine analog engineered polyetherimide and achieved traceable siRNA delivery and the synergic killing of tumor cells. Notably, we applied the label-free Schiff base fluorescence mechanism, which enabled us to trace the siRNA delivery and to monitor the selenocystine analogs' local performance. A novel selenocystine-derived fluorescent Schiff base linker was used to crosslink the polyetherimide, thereby generating a traceable siRNA delivery vehicle with green fluorescence. Moreover, we found that this compound induced tumor cells to undergo senescence. Together with the delivery of a siRNA targeting the anti-apoptotic BCL-xl/w genes in senescent cells, it achieved a synergistic inhibition function by inducing both senescence and apoptosis of tumor cells. Therefore, this study provides insights into the development of label-free probes, prodrugs, and materials towards the synergic strategies for cancer therapy.
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Affiliation(s)
- Yang Liu
- Center of Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou 310058, China;
| | - Haoying Yang
- Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences & School of Pharmacy, Henan University, Kaifeng 475004, China; (H.Y.); (Q.L.); (M.P.); (S.P.); (W.Z.)
| | - Qian Liu
- Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences & School of Pharmacy, Henan University, Kaifeng 475004, China; (H.Y.); (Q.L.); (M.P.); (S.P.); (W.Z.)
| | - Mingming Pan
- Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences & School of Pharmacy, Henan University, Kaifeng 475004, China; (H.Y.); (Q.L.); (M.P.); (S.P.); (W.Z.)
| | - Danli Wang
- Zhoushan Hospital of Zhejiang Province, Zhoushan 316004, China;
| | - Shiyuan Pan
- Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences & School of Pharmacy, Henan University, Kaifeng 475004, China; (H.Y.); (Q.L.); (M.P.); (S.P.); (W.Z.)
| | - Weiran Zhang
- Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences & School of Pharmacy, Henan University, Kaifeng 475004, China; (H.Y.); (Q.L.); (M.P.); (S.P.); (W.Z.)
| | - Jinfeng Wei
- Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences & School of Pharmacy, Henan University, Kaifeng 475004, China; (H.Y.); (Q.L.); (M.P.); (S.P.); (W.Z.)
| | - Xiaowei Zhao
- Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences & School of Pharmacy, Henan University, Kaifeng 475004, China; (H.Y.); (Q.L.); (M.P.); (S.P.); (W.Z.)
| | - Junfeng Ji
- Center of Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou 310058, China;
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Zhao L, Zhou X, Xie F, Zhang L, Yan H, Huang J, Zhang C, Zhou F, Chen J, Zhang L. Ferroptosis in cancer and cancer immunotherapy. Cancer Commun (Lond) 2022; 42:88-116. [PMID: 35133083 PMCID: PMC8822596 DOI: 10.1002/cac2.12250] [Citation(s) in RCA: 353] [Impact Index Per Article: 117.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/16/2021] [Accepted: 12/30/2021] [Indexed: 01/17/2023] Open
Abstract
The hallmark of tumorigenesis is the successful circumvention of cell death regulation for achieving unlimited replication and immortality. Ferroptosis is a newly identified type of cell death dependent on lipid peroxidation which differs from classical programmed cell death in terms of morphology, physiology and biochemistry. The broad spectrum of injury and tumor tolerance are the main reasons for radiotherapy and chemotherapy failure. The effective rate of tumor immunotherapy as a new treatment method is less than 30%. Ferroptosis can be seen in radiotherapy, chemotherapy, and tumor immunotherapy; therefore, ferroptosis activation may be a potential strategy to overcome the drug resistance mechanism of traditional cancer treatments. In this review, the characteristics and causes of cell death by lipid peroxidation in ferroptosis are briefly described. In addition, the three metabolic regulations of ferroptosis and its crosstalk with classical signaling pathways are summarized. Collectively, these findings suggest the vital role of ferroptosis in immunotherapy based on the interaction of ferroptosis with tumor immunotherapy, chemotherapy and radiotherapy, thus, indicating the remarkable potential of ferroptosis in cancer treatment.
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Affiliation(s)
- Lei Zhao
- Epartment of urology surgery Zhejiang hospital Zhejiang University School of Medicine Hangzhou China
- School of MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network Life Sciences Institute Zhejiang University Hangzhou Zhejiang 310058 China
| | - Xiaoxue Zhou
- School of MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network Life Sciences Institute Zhejiang University Hangzhou Zhejiang 310058 China
| | - Feng Xie
- Institutes of Biology and Medical Science Soochow University Suzhou 215123 P. R. China
| | - Lei Zhang
- Department of Orthopaedic Surgery the Third Affiliated Hospital of Wenzhou Medical University Rui'an Jiangsu 325000 P. R. China
| | - Haiyan Yan
- School of Medicine Zhejiang University City College Hangzhou Zhejiang 310015 China
| | - Jun Huang
- School of MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network Life Sciences Institute Zhejiang University Hangzhou Zhejiang 310058 China
| | - Chong Zhang
- School of Medicine Zhejiang University City College Hangzhou Zhejiang 310015 China
| | - Fangfang Zhou
- Institutes of Biology and Medical Science Soochow University Suzhou 215123 P. R. China
| | - Jun Chen
- Epartment of urology surgery Zhejiang hospital Zhejiang University School of Medicine Hangzhou China
| | - Long Zhang
- School of MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network Life Sciences Institute Zhejiang University Hangzhou Zhejiang 310058 China
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Hansel C, Hlouschek J, Xiang K, Melnikova M, Thomale J, Helleday T, Jendrossek V, Matschke J. Adaptation to Chronic-Cycling Hypoxia Renders Cancer Cells Resistant to MTH1-Inhibitor Treatment Which Can Be Counteracted by Glutathione Depletion. Cells 2021; 10:3040. [PMID: 34831264 PMCID: PMC8616547 DOI: 10.3390/cells10113040] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/28/2021] [Accepted: 11/03/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor hypoxia and hypoxic adaptation of cancer cells represent major barriers to successful cancer treatment. We revealed that improved antioxidant capacity contributes to increased radioresistance of cancer cells with tolerance to chronic-cycling severe hypoxia/reoxygenation stress. We hypothesized, that the improved tolerance to oxidative stress will increase the ability of cancer cells to cope with ROS-induced damage to free deoxy-nucleotides (dNTPs) required for DNA replication and may thus contribute to acquired resistance of cancer cells in advanced tumors to antineoplastic agents inhibiting the nucleotide-sanitizing enzyme MutT Homologue-1 (MTH1), ionizing radiation (IR) or both. Therefore, we aimed to explore potential differences in the sensitivity of cancer cells exposed to acute and chronic-cycling hypoxia/reoxygenation stress to the clinically relevant MTH1-inhibitor TH1579 (Karonudib) and to test whether a multi-targeting approach combining the glutathione withdrawer piperlongumine (PLN) and TH1579 may be suited to increase cancer cell sensitivity to TH1579 alone and in combination with IR. Combination of TH1579 treatment with radiotherapy (RT) led to radiosensitization but was not able to counteract increased radioresistance induced by adaptation to chronic-cycling hypoxia/reoxygenation stress. Disruption of redox homeostasis using PLN sensitized anoxia-tolerant cancer cells to MTH1 inhibition by TH1579 under both normoxic and acute hypoxic treatment conditions. Thus, we uncover a glutathione-driven compensatory resistance mechanism towards MTH1-inhibition in form of increased antioxidant capacity as a consequence of microenvironmental or therapeutic stress.
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Affiliation(s)
- Christine Hansel
- Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; (C.H.); (J.H.); (K.X.); (M.M.); (J.T.); (V.J.)
| | - Julian Hlouschek
- Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; (C.H.); (J.H.); (K.X.); (M.M.); (J.T.); (V.J.)
| | - Kexu Xiang
- Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; (C.H.); (J.H.); (K.X.); (M.M.); (J.T.); (V.J.)
| | - Margarita Melnikova
- Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; (C.H.); (J.H.); (K.X.); (M.M.); (J.T.); (V.J.)
| | - Juergen Thomale
- Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; (C.H.); (J.H.); (K.X.); (M.M.); (J.T.); (V.J.)
| | - Thomas Helleday
- Science for Life Laboratory, Karolinska Institutet, 17121 Stockholm, Sweden;
| | - Verena Jendrossek
- Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; (C.H.); (J.H.); (K.X.); (M.M.); (J.T.); (V.J.)
| | - Johann Matschke
- Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; (C.H.); (J.H.); (K.X.); (M.M.); (J.T.); (V.J.)
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Fiorillo M, Ózsvári B, Sotgia F, Lisanti MP. High ATP Production Fuels Cancer Drug Resistance and Metastasis: Implications for Mitochondrial ATP Depletion Therapy. Front Oncol 2021; 11:740720. [PMID: 34722292 PMCID: PMC8554334 DOI: 10.3389/fonc.2021.740720] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/07/2021] [Indexed: 12/25/2022] Open
Abstract
Recently, we presented evidence that high mitochondrial ATP production is a new therapeutic target for cancer treatment. Using ATP as a biomarker, we isolated the “metabolically fittest” cancer cells from the total cell population. Importantly, ATP-high cancer cells were phenotypically the most aggressive, with enhanced stem-like properties, showing multi-drug resistance and an increased capacity for cell migration, invasion and spontaneous metastasis. In support of these observations, ATP-high cells demonstrated the up-regulation of both mitochondrial proteins and other protein biomarkers, specifically associated with stemness and metastasis. Therefore, we propose that the “energetically fittest” cancer cells would be better able to resist the selection pressure provided by i) a hostile micro-environment and/or ii) conventional chemotherapy, allowing them to be naturally-selected for survival, based on their high ATP content, ultimately driving tumor recurrence and distant metastasis. In accordance with this energetic hypothesis, ATP-high MDA-MB-231 breast cancer cells showed a dramatic increase in their ability to metastasize in a pre-clinical model in vivo. Conversely, metastasis was largely prevented by treatment with an FDA-approved drug (Bedaquiline), which binds to and inhibits the mitochondrial ATP-synthase, leading to ATP depletion. Clinically, these new therapeutic approaches could have important implications for preventing treatment failure and avoiding cancer cell dormancy, by employing ATP-depletion therapy, to target even the fittest cancer cells.
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Affiliation(s)
- Marco Fiorillo
- Translational Medicine, School of Science, Engineering and Environment (SEE), University of Salford, Greater Manchester, United Kingdom.,The Department of Pharmacy, Health and Nutritional Sciences, The University of Calabria, Cosenza, Italy
| | - Béla Ózsvári
- Translational Medicine, School of Science, Engineering and Environment (SEE), University of Salford, Greater Manchester, United Kingdom
| | - Federica Sotgia
- Translational Medicine, School of Science, Engineering and Environment (SEE), University of Salford, Greater Manchester, United Kingdom
| | - Michael P Lisanti
- Translational Medicine, School of Science, Engineering and Environment (SEE), University of Salford, Greater Manchester, United Kingdom
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Yang C, Xi M, Liu H, Bai H, Jiang C, Liu Q, Fan P. Association of Polymorphisms of Glutamate Cysteine Ligase Genes GCLC C-129 T and GCLM C-588 T with Risk of Polycystic Ovary Syndrome in Chinese Women. Reprod Sci 2021; 29:1790-1800. [PMID: 34642912 DOI: 10.1007/s43032-021-00764-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 10/03/2021] [Indexed: 01/18/2023]
Abstract
Polycystic ovary syndrome (PCOS) is generally considered a multifactorial disease caused by interactions between multiple susceptible genes and environmental factors. Glutamate cysteine ligase (GCL) is the rate-limiting enzyme in glutathione biosynthesis. This study examined the relationship between single nucleotide polymorphisms (SNPs) in the GCL catalytic subunit (GCLC C-129 T) and the modifier subunit (GCLM C-588 T) and PCOS. The two SNPs were genotyped in 1017 PCOS patients and 793 control women. Clinical, metabolic, hormonal, and oxidative stress parameters were also assessed. The frequencies of the CT + TT genotypes (21.6% vs. 27.7%) and T allele (11.5% vs. 14.7%) of SNP GCLC C-129 T were significantly lower in hyperandrogenism (HA)-PCOS patients than in control women. Logistic regression analysis revealed that the relative hazard of HA-PCOS was lower in individuals with the -129 T allele (CT + TT genotypes) than in those with the CC genotype (OR = 0.723, 95% CI: 0.571-0.915, P = 0.007). When using the GCLC-CC/GCLM-CC combined genotype as the reference category, the GCLC-CT + TT/GCLM-CC combined genotype was a protective factor for PCOS with HA (OR = 0.743, 95% CI: 0.566-0.976, P = 0.033). HA-PCOS patients with the -129 T allele had lower waist circumference, waist-to-hip ratio, and body mass index (BMI) and lower fasting insulin concentration and homeostatic model assessment of insulin resistance after correcting for age and BMI (P < 0.05). The T allele of SNP GCLC C-129 T and its combination with the CC genotype of SNP GCLM C-588 T are associated with decreased risk of HA-PCOS in Chinese women.
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Affiliation(s)
- Chunyi Yang
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Mingrong Xi
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hongwei Liu
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Huai Bai
- Laboratory of Genetic Disease and Perinatal Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chenyu Jiang
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qingqing Liu
- Laboratory of Genetic Disease and Perinatal Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ping Fan
- Laboratory of Genetic Disease and Perinatal Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
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Appunni S, Rubens M, Ramamoorthy V, Tonse R, Saxena A, McGranaghan P, Kaiser A, Kotecha R. Emerging Evidence on the Effects of Dietary Factors on the Gut Microbiome in Colorectal Cancer. Front Nutr 2021; 8:718389. [PMID: 34708063 PMCID: PMC8542705 DOI: 10.3389/fnut.2021.718389] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/13/2021] [Indexed: 12/22/2022] Open
Abstract
Dietary factors have important role in modulating the gut microbiome, which in-turn regulates the molecular events in colonic mucosa. The composition and resulting metabolism of the gut microbiome are decisive factors in colorectal cancer (CRC) tumorigenesis. Altered gut microbiome is associated with impaired immune response, and the release of carcinogenic or genotoxic substances which are the major microbiome-induced mechanisms implicated in CRC pathogenesis. Diets low in dietary fibers and phytomolecules as well as high in red meat are important dietary changes which predispose to CRC. Dietary fibers which reach the colon in an undigested form are further metabolized by the gut microbiome into enterocyte friendly metabolites such as short chain fatty acid (SCFA) which provide anti-inflammatory and anti-proliferative effects. Healthy microbiome supported by dietary fibers and phytomolecules could decrease cell proliferation by regulating the epigenetic events which activate proto-oncogenes and oncogenic pathways. Emerging evidence show that predominance of microbes such as Fusobacterium nucleatum can predispose the colonic mucosa to malignant transformation. Dietary and lifestyle modifications have been demonstrated to restrict the growth of potentially harmful opportunistic organisms. Synbiotics can protect the intestinal mucosa by improving immune response and decreasing the production of toxic metabolites, oxidative stress and cell proliferation. In this narrative review, we aim to update the emerging evidence on how diet could modulate the gut microbial composition and revive colonic epithelium. This review highlights the importance of healthy plant-based diet and related supplements in CRC prevention by improving the gut microbiome.
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Affiliation(s)
- Sandeep Appunni
- Government Medical College, Kozhikode, India
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Muni Rubens
- Office of Clinical Research, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, United States
| | | | - Raees Tonse
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, United States
| | - Anshul Saxena
- Baptist Health South Florida, Miami, FL, United States
- Department of Radiation Oncology, Florida International University, Miami, FL, United States
| | - Peter McGranaghan
- Office of Clinical Research, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, United States
| | - Adeel Kaiser
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, United States
- Department of Radiation Oncology, Florida International University, Miami, FL, United States
| | - Rupesh Kotecha
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, United States
- Department of Radiation Oncology, Florida International University, Miami, FL, United States
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Zhang KR, Zhang YF, Lei HM, Tang YB, Ma CS, Lv QM, Wang SY, Lu LM, Shen Y, Chen HZ, Zhu L. Targeting AKR1B1 inhibits glutathione de novo synthesis to overcome acquired resistance to EGFR-targeted therapy in lung cancer. Sci Transl Med 2021; 13:eabg6428. [PMID: 34613810 DOI: 10.1126/scitranslmed.abg6428] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Ke-Ren Zhang
- Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences and Respiratory Department, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yu-Fei Zhang
- Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences and Respiratory Department, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hui-Min Lei
- Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences and Respiratory Department, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Ya-Bin Tang
- Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences and Respiratory Department, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Chun-Shuang Ma
- Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences and Respiratory Department, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Qian-Ming Lv
- Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences and Respiratory Department, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Shi-Yi Wang
- Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences and Respiratory Department, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Li-Ming Lu
- Central Laboratory, Shanghai Chest Hospital and Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Ying Shen
- Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences and Respiratory Department, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hong-Zhuan Chen
- Department of Clinical Pharmacy, Institute of Interdisciplinary Integrative Biomedical Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Liang Zhu
- Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences and Respiratory Department, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Niu B, Liao K, Zhou Y, Wen T, Quan G, Pan X, Wu C. Application of glutathione depletion in cancer therapy: Enhanced ROS-based therapy, ferroptosis, and chemotherapy. Biomaterials 2021; 277:121110. [PMID: 34482088 DOI: 10.1016/j.biomaterials.2021.121110] [Citation(s) in RCA: 558] [Impact Index Per Article: 139.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 08/18/2021] [Accepted: 08/27/2021] [Indexed: 01/17/2023]
Abstract
Glutathione (GSH) is an important member of cellular antioxidative system. In cancer cells, a high level of GSH is indispensable to scavenge excessive reactive oxygen species (ROS) and detoxify xenobiotics, which make it a potential target for cancer therapy. Plenty of studies have shown that loss of intracellular GSH makes cancer cells more susceptible to oxidative stress and chemotherapeutic agents. GSH depletion has been proved to improve the therapeutic efficacy of ROS-based therapy (photodynamic therapy, sonodynamic therapy, and chemodynamic therapy), ferroptosis, and chemotherapy. In this review, various strategies for GSH depletion used in cancer therapy are comprehensively summarized and discussed. First, the functions of GSH in cancer cells are analyzed to elucidate the necessity of GSH depletion in cancer therapy. Then, the synthesis and metabolism of GSH are briefly introduced to bring up some crucial targets for GSH modulation. Finally, different approaches to GSH depletion in the literature are classified and discussed in detail according to their mechanisms. Particularly, functional materials with GSH-consuming ability based on nanotechnology are elaborated due to their unique advantages and potentials. This review presents the ingenious application of GSH-depleting strategy in cancer therapy for improving the outcomes of various therapeutic regimens, which may provide useful guidance for designing intelligent drug delivery system.
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Affiliation(s)
- Boyi Niu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Kaixin Liao
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Yixian Zhou
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Ting Wen
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Guilan Quan
- College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Xin Pan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
| | - Chuanbin Wu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China; College of Pharmacy, Jinan University, Guangzhou, 510632, China.
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Hu YW, Liu Y, Guo EY, Wang YY, Xu WQ, Gao Y, Jiang XY, Feng F, Xu J, Liu WY. Naphtho-γ-pyrone Dimers from an Endozoic Aspergillus niger and the Effects of Coisolated Monomers in Combination with Cisplatin on a Cisplatin-Resistant A549 Cell Line. JOURNAL OF NATURAL PRODUCTS 2021; 84:1889-1897. [PMID: 34156846 DOI: 10.1021/acs.jnatprod.0c01262] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Chemotherapy resistance is one of the main causes of lung cancer treatment failure, and a combination regimen may be an effective way to overcome this. Here we report 5 new (1-3, 7, and 9) and 15 known polyketides, isolated from an endozoic Aspergillus niger. The structures of the new compounds were determined by the interpretation of IR, HRESIMS, NMR, and ECD spectra. The ESI-MS/MS fragmentation of the isolated naphtho-γ-pyrone isomers in positive mode is discussed. The effects of isolated compounds in combination with cisplatin (DDP) on a DDP-resistant A549 cell line (A459/DDP) are investigated. The most active compound, 12, could reduce the ratio of GSH/GSSG, promote the generation of intracellular ROS, and cooperate with DDP to down-regulated levels of Nrf2, Akt, HO-1, and NQO1, suggesting that inhibition of Nrf2 and Akt pathways might be involved in the combined effect of 12 and DDP in A549/DDP cells.
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Affiliation(s)
- Yun-Wei Hu
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Ying Liu
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Er-Yan Guo
- Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Yu-Ying Wang
- Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Wan-Qi Xu
- Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Yan Gao
- Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Xue-Yang Jiang
- Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Feng Feng
- Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
- Jiangsu Food & Pharmaceutical Science College, Huaian 223003, People's Republic of China
| | - Jian Xu
- Department of Traditional Chinese Medicine, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Wen-Yuan Liu
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, People's Republic of China
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Amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy-based "combo" nanoagent together with PD-L1 blockade in reversing multidrug resistance. J Nanobiotechnology 2021; 19:200. [PMID: 34225744 PMCID: PMC8256488 DOI: 10.1186/s12951-021-00947-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 06/28/2021] [Indexed: 12/07/2022] Open
Abstract
BACKGROUND Recent studies have demonstrated that multidrug resistance (MDR) is a critical factor in the low efficacy of cancer chemotherapy. The main mechanism of MDR arises from the overexpression of P-glycoprotein (P-gp), which actively enhances drug efflux and limits the effectiveness of chemotherapeutic agents. RESULTS In this study, we fabricated a "combo" nanoagent equipping with triple synergistic strategies for enhancing antitumor efficacy against MDR cells. Tumor homing-penetrating peptide endows the nanosystem with targeting and penetrating capabilities in the first stage of tumor internalization. The abundant amine groups of polyethylenimine (PEI)-modified nanoparticles then trigger a proton sponge effect to promote endo/lysosomal escape, which enhances the intracellular accumulation and retention of anticancer drugs. Furthermore, copper tetrakis(4-carboxyphenyl)porphyrin (CuTCPP) encapsulated in the nanosystem, effectively scavenges endogenous glutathione (GSH) to reduce the detoxification mediated by GSH and sensitize the cancer cells to drugs, while simultaneously serving as a photoacoustic imaging (PAI) contrast agent for image visualization. Moreover, we also verify that these versatile nanoparticles in combination with PD-1/PD-L1 blockade therapy can not only activate immunological responses but also inhibit P-gp expression to obliterate primary and metastatic tumors. CONCLUSION This work shows a significant enhancement in therapeutic efficacy against MDR cells and syngeneic tumors by using multiple MDR reversing strategies compared to an equivalent dose of free paclitaxel.
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Deng H, Yang Y, Zuo T, Fang T, Xu Y, Yang J, Zhang J, Shen Q. Multifunctional ZnO@CuS nanoparticles cluster synergize chemotherapy and photothermal therapy for tumor metastasis. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2021; 34:102399. [PMID: 33864912 DOI: 10.1016/j.nano.2021.102399] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 03/03/2021] [Accepted: 03/23/2021] [Indexed: 12/13/2022]
Abstract
The poor drug delivery and unsatisfying therapeutic effects remain to be the primary challenges for cancer therapy. Nanosystem that combines multiple functions into a single platform is an ideal strategy. Here, a smart drug delivery nanoplatform (Z@C-D/P) based on ZnO@CuS nanoparticles, loaded with doxorubicin (DOX) and pirfenidone (PFD) was constructed. Importantly, the β-CD-DMA and PEG-DMA could be activated in the mild acidic tumor microenvironment, then the nanosystem underwent charge reversal and PFD release. PFD could inhibit cancer-associated fibroblasts (CAFs) activation and enhance tumor penetration. And the residual nanostructure ZnO@CuS could trigger cascade amplified ROS generation to induce tumor cell death. The photothermal effect further strengthened the anti-tumor efficacy. Finally, the nanosystem showed remarkable inhibition of tumor growth (89.7%) and lung metastasis. The innovatively designed nanosystem integrating chemotherapy and photothermal effect would provide a promising strategy in breast cancer therapy.
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Affiliation(s)
- Huizi Deng
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Yifan Yang
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Tiantian Zuo
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Tianxu Fang
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Yingxin Xu
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Yang
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Zhang
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Qi Shen
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
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Lee N, Park SM, Yee J, Yoon HY, Han JM, Gwak HS. Association Between Glutathione-S-Transferase Gene Polymorphisms and Responses to Tyrosine Kinase Inhibitor Treatment in Patients with Chronic Myeloid Leukemia: A Meta-analysis. Target Oncol 2021; 15:47-54. [PMID: 31974831 DOI: 10.1007/s11523-020-00696-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Although many earlier studies revealed an effect of glutathione-S-transferase (GST) gene polymorphisms on tyrosine kinase inhibitor (TKI) treatment responses in chronic myeloid leukemia (CML) patients, the significance of this relationship remains controversial. OBJECTIVE This study aimed to review and meta-analyze treatment responses to TKIs in patients with CML and GST gene polymorphisms, including GSTT1, GSTM1, and GSTP1. PATIENTS AND METHODS We searched four medical databases, PubMed, Web of Science, the Cochrane Library, and Embase, by using keywords related to GST gene polymorphisms and clinical responses in CML patients receiving TKI treatment. The meta-analysis was performed using RevMan version 5.3 and Comprehensive Meta-Analysis software version 3.0. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to examine the association between GSTT1, GSTM1, and GSTP1 polymorphisms and TKI treatment responses in patients with CML. RESULTS The null polymorphisms of GSTT1 and GSTM1 did not affect TKI treatment responses, while the GSTP1 Ile105Val polymorphism had a significant impact on responses to TKI. Patients who were GSTP1 variant allele carriers (AG + GG) had poor responses to TKI treatment compared to patients who were wild-type homozygote carriers (AA) (OR 1.85, 95% CI 1.31-2.62; p < 0.001). CONCLUSIONS This meta-analysis of patients with CML showed that G allele carriers with GSTP1 Ile105Val polymorphism had significantly worse responses to TKI treatment than wild-type homozygote carriers.
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Affiliation(s)
- Nari Lee
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Su Min Park
- College of Pharmacy, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea
| | - Jeong Yee
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Ha Young Yoon
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Ji Min Han
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea.
| | - Hye Sun Gwak
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea.
- College of Pharmacy, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea.
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50
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Merk R, Heßelbach K, Osipova A, Popadić D, Schmidt-Heck W, Kim GJ, Günther S, Piñeres AG, Merfort I, Humar M. Particulate Matter (PM 2.5) from Biomass Combustion Induces an Anti-Oxidative Response and Cancer Drug Resistance in Human Bronchial Epithelial BEAS-2B Cells. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:E8193. [PMID: 33171923 PMCID: PMC7664250 DOI: 10.3390/ijerph17218193] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/30/2020] [Accepted: 11/03/2020] [Indexed: 02/07/2023]
Abstract
Nearly half of the world's population relies on combustion of solid biofuels to cover fundamental energy demands. Epidemiologic data demonstrate that particularly long-term emissions adversely affect human health. However, pathological molecular mechanisms are insufficiently characterized. Here we demonstrate that long-term exposure to fine particulate matter (PM2.5) from biomass combustion had no impact on cellular viability and proliferation but increased intracellular reactive oxygen species (ROS) levels in bronchial epithelial BEAS-2B cells. Exposure to PM2.5 induced the nuclear factor erythroid 2-related factor 2 (Nrf2) and mediated an anti-oxidative response, including enhanced levels of intracellular glutathione (GSH) and nuclear accumulation of heme oxygenase-1 (HO-1). Activation of Nrf2 was promoted by the c-Jun N-terminal kinase JNK1/2, but not p38 or Akt, which were also induced by PM2.5. Furthermore, cells exposed to PM2.5 acquired chemoresistance to doxorubicin, which was associated with inhibition of apoptosis and elevated levels of GSH in these cells. Our findings propose that exposure to PM2.5 induces molecular defense mechanisms, which prevent cellular damage and may thus explain the initially relative rare complications associated with PM2.5. However, consistent induction of pro-survival pathways may also promote the progression of diseases. Environmental conditions inducing anti-oxidative responses may have the potential to promote a chemoresistant cellular phenotype.
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Affiliation(s)
- Regina Merk
- Department of Pharmaceutical Biology and Biotechnology, Institute of Pharmaceutical Sciences, Albert Ludwigs University Freiburg, 79104 Freiburg, Germany; (R.M.); (K.H.); (A.O.); (D.P.)
| | - Katharina Heßelbach
- Department of Pharmaceutical Biology and Biotechnology, Institute of Pharmaceutical Sciences, Albert Ludwigs University Freiburg, 79104 Freiburg, Germany; (R.M.); (K.H.); (A.O.); (D.P.)
| | - Anastasiya Osipova
- Department of Pharmaceutical Biology and Biotechnology, Institute of Pharmaceutical Sciences, Albert Ludwigs University Freiburg, 79104 Freiburg, Germany; (R.M.); (K.H.); (A.O.); (D.P.)
| | - Désirée Popadić
- Department of Pharmaceutical Biology and Biotechnology, Institute of Pharmaceutical Sciences, Albert Ludwigs University Freiburg, 79104 Freiburg, Germany; (R.M.); (K.H.); (A.O.); (D.P.)
| | - Wolfgang Schmidt-Heck
- Department of Systems Biology and Bioinformatics, Leibniz Institute for Natural Product Research and Infection Biology-Hans-Knöll Institute (HKI), 07745 Jena, Germany;
| | - Gwang-Jin Kim
- Department of Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences, Albert-Ludwigs University Freiburg, 79104 Freiburg, Germany; (G.-J.K.); (S.G.)
| | - Stefan Günther
- Department of Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences, Albert-Ludwigs University Freiburg, 79104 Freiburg, Germany; (G.-J.K.); (S.G.)
| | - Alfonso García Piñeres
- Centro de Investigación en Biología Celular y Molecular (CIBCM), Universidad de Costa Rica, 11501-2060 San José, Costa Rica;
- Escuela de Química, Universidad de Costa Rica, 11501-2060 San José, Costa Rica
| | - Irmgard Merfort
- Department of Pharmaceutical Biology and Biotechnology, Institute of Pharmaceutical Sciences, Albert Ludwigs University Freiburg, 79104 Freiburg, Germany; (R.M.); (K.H.); (A.O.); (D.P.)
- Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs University Freiburg, 79104 Freiburg, Germany
| | - Matjaz Humar
- Department of Pharmaceutical Biology and Biotechnology, Institute of Pharmaceutical Sciences, Albert Ludwigs University Freiburg, 79104 Freiburg, Germany; (R.M.); (K.H.); (A.O.); (D.P.)
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