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Yang D, Yang C, Huang L, Guan M, Song C. Role of ubiquitination-driven metabolisms in oncogenesis and cancer therapy. Semin Cancer Biol 2025; 110:17-35. [PMID: 39929409 DOI: 10.1016/j.semcancer.2025.02.004] [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: 08/26/2024] [Revised: 01/17/2025] [Accepted: 02/04/2025] [Indexed: 02/16/2025]
Abstract
Ubiquitination represents one of the most critical post-translational modifications, comprising a multi-stage enzyme process that plays a pivotal role in a myriad of cellular biological activities. The deregulation of the processes of ubiquitination and deubiquitination is associated with the development of cancers and other diseases. This typescript reviews the impact of ubiquitination on metabolic processes, elucidating the regulatory functions of ubiquitination on pivotal enzymes within metabolic pathways in pathological contexts. It underscores the role of ubiquitination-driven metabolism disorders in the etiology of cancers, and oncogenesis, and highlights the potential therapeutic efficacy of targeting ubiquitination-driven enzymes in cancer metabolism, their combination with immune checkpoint inhibitors, and their clinical applications.
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Affiliation(s)
- Dongqin Yang
- Department of Laboratory Medicine of Huashan Hospital, Fudan University, Shanghai 200040, China; Central Laboratory, Huashan Hospital, Fudan University, 12 Middle Urumuqi Road, Shanghai 200040, China
| | - Can Yang
- Department of Laboratory Medicine of Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Linlin Huang
- Central Laboratory, Huashan Hospital, Fudan University, 12 Middle Urumuqi Road, Shanghai 200040, China
| | - Ming Guan
- Department of Laboratory Medicine of Huashan Hospital, Fudan University, Shanghai 200040, China.
| | - Chunhua Song
- Division of Hematology, The Ohio State University Wexner Medical Center, the James Cancer Hospital, Columbus, OH 43210, USA.
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2
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Zhen W, Zhao T, Chen X, Zhang J. Unlocking the Potential of Disulfidptosis: Nanotechnology-Driven Strategies for Advanced Cancer Therapy. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025:e2500880. [PMID: 40269657 DOI: 10.1002/smll.202500880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 04/02/2025] [Indexed: 04/25/2025]
Abstract
Tumor tissues exhibit elevated oxidative stress, with the cystine-glutamate transporter xCT solute carrier family 7 member 11 (xCT/SLC7A11) protecting cancer cells from oxidative damage by facilitating cystine uptake for glutathione synthesis. Disulfidptosis, a newly identified form of programmed cell death (PCD), occurs in cells with high xCT/SLC7A11 expression under glucose-deprived conditions. Distinct from other PCD pathways, disulfidptosis is characterized by aberrant disulfide bond formation and cellular dysfunction, ultimately resulting in cancer cell death. This novel mechanism offers remarkable therapeutic potential by targeting the inherent oxidative stress vulnerabilities of rapidly growing cancer cells. Advances in nanotechnology enable the development of nanomaterials capable of inducing reactive oxygen species (ROS) generation, disrupting disulfide bonds. In addition, they are capable to deliver therapeutic agents directly to tumors, thereby improving therapeutic precision and minimizing off-target effects. Moreover, combining disulfidptosis with ROS-induced immunogenic cell death can remodel the tumor microenvironment and enhance anti-tumor immunity. This review explores the mechanisms underlying disulfidptosis, its therapeutic potential in cancer treatment, and the synergistic role of nanotechnology in amplifying its effects. Selective induction of disulfidptosis using nanomaterials represents a promising strategy for achieving more effective, selective, and less toxic cancer therapies.
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Affiliation(s)
- Wenyao Zhen
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore
- Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
- Theranostics Centre of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 138667, Singapore
| | - Tianzhi Zhao
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore
- Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
- Theranostics Centre of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 138667, Singapore
| | - Xiaoyuan Chen
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074, Singapore
- Department of Chemical and Biomolecular Engineering, College of Design and Engineering, National University of Singapore, Singapore, 117575, Singapore
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore, 117575, Singapore
- Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore, 117544, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore
- Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
- Theranostics Centre of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 138667, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore, 138673, Singapore
| | - Jingjing Zhang
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore
- Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
- Theranostics Centre of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 138667, Singapore
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Mo X, Shen A, Han Y, Xu L, Miao J, Xu D, Ji Q, Cao Y, Ge G, Zhu X, Deng H. Polysaccharide Nanoadjuvants Engineered via Phenotype-Specific Nanoprobe-Assisted Phenotypic Screen Reprogram Macrophage Cell Functions for Cancer and Rheumatoid Arthritis Therapy. ACS NANO 2025; 19:12920-12936. [PMID: 40152971 PMCID: PMC11984301 DOI: 10.1021/acsnano.4c16671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 03/13/2025] [Accepted: 03/25/2025] [Indexed: 03/30/2025]
Abstract
Macrophage plays critical roles in immune-related diseases, acting as a crucial therapeutic target for immunotherapy. Rational design and development of effective therapeutics for macrophage reprogramming are still challenging. Here, we rationally engineered polysaccharide nanoadjuvants to reprogram macrophage functions for enhanced immunotherapy in multiple diseases through a macrophage phenotype-specific nanoprobe (MPSNPr)-assisted high-throughput phenotypic screen. This MPSNPr exhibited high macrophage M1 phenotype specificity because of the formation of H-aggregates on the outer surface and the binding to glucose transporter 1 receptors by the polysaccharide nanocarrier. Based on this MPSNPr, a high-throughput platform was constructed and employed to screen a variety of pharmaceuticals for macrophage reprogramming, being able to identify both pro-inflammatory and anti-inflammatory drug candidates. Polysaccharide nanoadjuvants, Dex-BA and Dex-SAL, were rationally engineered with two potent candidates to amplify macrophage reprogramming efficacy both in vitro and in vivo. Dex-BA significantly inhibited tumor growth by inducing macrophage M1 polarization, dendritic cell maturation, and cytotoxic T cell activation in a mice melanoma model. Dex-SAL alleviated rheumatoid arthritis symptoms with reduced inflammation by reprogramming activated macrophages toward anti-inflammatory phenotype. Our work provides a robust strategy for the rational design and development of effective therapeutics for enhanced macrophage-mediated immunotherapy in diverse diseases.
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Affiliation(s)
- Xuan Mo
- Shanghai
Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary
Integrative Medicine Research, Shanghai
University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Anping Shen
- Shi’s
Center of Orthopedics and Traumatology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yicun Han
- Department
of Medical Oncology & Cancer Institute of Integrative Medicine,
Shuguang Hospital, Shanghai University of
Traditional Chinese Medicine, Shanghai 201203, China
| | - Li Xu
- Shanghai
Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary
Integrative Medicine Research, Shanghai
University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jiaqian Miao
- Shanghai
Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary
Integrative Medicine Research, Shanghai
University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Danni Xu
- Shanghai
Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary
Integrative Medicine Research, Shanghai
University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qing Ji
- Department
of Medical Oncology & Cancer Institute of Integrative Medicine,
Shuguang Hospital, Shanghai University of
Traditional Chinese Medicine, Shanghai 201203, China
| | - Yuelong Cao
- Shi’s
Center of Orthopedics and Traumatology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Guangbo Ge
- Shanghai
Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary
Integrative Medicine Research, Shanghai
University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xinyuan Zhu
- School
of Chemistry and Chemical Engineering, Frontiers Science Center for
Transformative Molecules, Shanghai Jiao
Tong University, Shanghai 200240, China
| | - Hongping Deng
- Shanghai
Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary
Integrative Medicine Research, Shanghai
University of Traditional Chinese Medicine, Shanghai 201203, China
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Liu S, Zhou M, Huang X, Chen P, Li Q, Wang Y, Ge X, Wang F, Xu J, Gu J, Miao L, Deng X. A Mechanistic Study of the Feasibility of Ursodeoxycholic Acid in the Treatment of Colon Adenocarcinoma. Drug Des Devel Ther 2025; 19:1839-1852. [PMID: 40093647 PMCID: PMC11910939 DOI: 10.2147/dddt.s500721] [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: 10/13/2024] [Accepted: 03/01/2025] [Indexed: 03/19/2025] Open
Abstract
Purpose Bile acids promote the progression of colon adenocarcinoma (COAD), and ursodeoxycholic acid (UDCA) is a key drug in promoting bile acid excretion, but its role in COAD unclear. Our study aims to investigate the relationship between COAD and bile acid metabolism and to assess the feasibility of UDCA for the treatment of COAD. Methods Firstly, biological targets closely related to COAD were identified: Based on the cancer genome atlas (TCGA) database, the core genes of COAD were obtained by differential expression analysis and weighted gene-coexpression network analysis (WGCNA), and subjected to gene ontology (GO) function annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Secondly, finding a drug by target, after identifying UDCA as a candidate drug, the feasibility of UDCA in treating COAD was verified in reverse: Using databases to collect potential targets for COAD and UDCA, and the intersecting genes were the potential targets for UDCA to exert anti-tumor effects. Then Autodock was used for molecular docking to analyze the interaction between UDCA and core target proteins. Finally, experimental validation was performed: MTT assay, wound healing, transwell migration, and angiogenesis assays were used to detect the effects of UDCA on cell proliferation, migration, invasion, and neovascularization. Results 2064 differential genes were screened from TCGA. WGCNA obtained the module most relevant to CRC, containing 493 genes. KEGG analysis found that overlapping genes were mainly concentrated in bile acid metabolic pathways. A total of 26 UDCA anti-tumor targets were obtained in database, and 5 core targets were selected by STRING database and Cytoscape software: TNF, CYP27B1, MDM2, MMP2, CASP3. Molecular docking results showed that UDCA had good binding activity with the core targets. In vitro experiment showed UDCA effectively inhibited the proliferation, migration, invasion and neovascularization in colon cancer cells. Conclusion The antitumor activity of ursodeoxycholic acid may be related to cell apoptosis, proliferation, migration and vascular neogenesis.
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Affiliation(s)
- Shuyu Liu
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
- Department of Gastroenterology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Mengyue Zhou
- Department of Gastroenterology, Nanjing Pukou Hospital of Traditional Chinese Medicine, Nanjing, People’s Republic of China
| | - Xiaoli Huang
- Department of Gastroenterology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Peng Chen
- Department of Gastroenterology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Quanpeng Li
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Yuting Wang
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Xianxiu Ge
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Fei Wang
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Jianing Xu
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Jiayi Gu
- Department of Neurology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Lin Miao
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Xueting Deng
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
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Li J, Pan J, Wang L, Ji G, Dang Y. Colorectal Cancer: Pathogenesis and Targeted Therapy. MedComm (Beijing) 2025; 6:e70127. [PMID: 40060193 PMCID: PMC11885891 DOI: 10.1002/mco2.70127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 04/29/2025] Open
Abstract
Colorectal cancer (CRC) ranks among the most prevalent malignant neoplasms globally. A growing body of evidence underscores the pivotal roles of genetic alterations and dysregulated epigenetic modifications in the pathogenesis of CRC. In recent years, the reprogramming of tumor cell metabolism has been increasingly acknowledged as a hallmark of cancer. Substantial evidence suggests a crosstalk between tumor cell metabolic reprogramming and epigenetic modifications, highlighting a complex interplay between metabolism and the epigenetic genome that warrants further investigation. Biomarkers associated with the pathogenesis and metabolic characteristics of CRC hold significant clinical implications. Nevertheless, elucidating the genetic, epigenetic, and metabolic landscapes of CRC continues to pose considerable challenges. Here, we attempt to summarize the key genes driving the onset and progression of CRC and the related epigenetic regulators, clarify the roles of gene expression and signaling pathways in tumor metabolism regulation, and explore the potential crosstalk between epigenetic events and tumor metabolic reprogramming, providing a comprehensive mechanistic explanation for the malignant progression of CRC. Finally, by integrating reliable targets from genetics, epigenetics, and metabolic processes that hold promise for translation into clinical practice, we aim to offer more strategies to overcome the bottlenecks in CRC treatment.
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Affiliation(s)
- Jingyuan Li
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Jiashu Pan
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Lisheng Wang
- Department of BiochemistryMicrobiology and ImmunologyFaculty of MedicineUniversity of OttawaOttawaOntarioCanada
- China‐Canada Centre of Research for Digestive DiseasesUniversity of OttawaOttawaOntarioCanada
| | - Guang Ji
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Yanqi Dang
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
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Liu H, Wang S, Wang J, Guo X, Song Y, Fu K, Gao Z, Liu D, He W, Yang LL. Energy metabolism in health and diseases. Signal Transduct Target Ther 2025; 10:69. [PMID: 39966374 PMCID: PMC11836267 DOI: 10.1038/s41392-025-02141-x] [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: 08/12/2024] [Revised: 11/08/2024] [Accepted: 12/25/2024] [Indexed: 02/20/2025] Open
Abstract
Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.
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Affiliation(s)
- Hui Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuo Wang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianhua Wang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xin Guo
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yujing Song
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kun Fu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenjie Gao
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Danfeng Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Wei He
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Lei-Lei Yang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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Du J, Shen M, Chen J, Yan H, Xu Z, Yang X, Yang B, Luo P, Ding K, Hu Y, He Q. The impact of solute carrier proteins on disrupting substance regulation in metabolic disorders: insights and clinical applications. Front Pharmacol 2025; 15:1510080. [PMID: 39850557 PMCID: PMC11754210 DOI: 10.3389/fphar.2024.1510080] [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: 10/12/2024] [Accepted: 12/20/2024] [Indexed: 01/25/2025] Open
Abstract
Carbohydrates, lipids, bile acids, various inorganic salt ions and organic acids are the main nutrients or indispensable components of the human body. Dysregulation in the processes of absorption, transport, metabolism, and excretion of these metabolites can lead to the onset of severe metabolic disorders, such as type 2 diabetes, non-alcoholic fatty liver disease, gout and hyperbilirubinemia. As the second largest membrane receptor supergroup, several major families in the solute carrier (SLC) supergroup have been found to play key roles in the transport of substances such as carbohydrates, lipids, urate, bile acids, monocarboxylates and zinc ions. Based on common metabolic dysregulation and related metabolic substances, we explored the relationship between several major families of SLC supergroup and metabolic diseases, providing examples of drugs targeting SLC proteins that have been approved or are currently in clinical/preclinical research as well as SLC-related diagnostic techniques that are in clinical use or under investigation. By highlighting these connections, we aim to provide insights that may contribute to the development of improved treatment strategies and targeted therapies for metabolic disorders.
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Affiliation(s)
- Jiangxia Du
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Minhui Shen
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jiajia Chen
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hao Yan
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zhifei Xu
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiaochun Yang
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Bo Yang
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
| | - Peihua Luo
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- Department of Pharmaceutical and Translational Toxicology, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, Zhejiang, China
| | - Kefeng Ding
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yuhuai Hu
- Yuhong Pharmaceutical Technology Co., Ltd., Hangzhou, Zhejiang, China
| | - Qiaojun He
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
- Department of Pharmaceutical and Translational Toxicology, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, Zhejiang, China
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8
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Capelletti MM, Montini O, Ruini E, Tettamanti S, Savino AM, Sarno J. Unlocking the Heterogeneity in Acute Leukaemia: Dissection of Clonal Architecture and Metabolic Properties for Clinical Interventions. Int J Mol Sci 2024; 26:45. [PMID: 39795903 PMCID: PMC11719665 DOI: 10.3390/ijms26010045] [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: 11/21/2024] [Revised: 12/17/2024] [Accepted: 12/19/2024] [Indexed: 01/13/2025] Open
Abstract
Genetic studies of haematological cancers have pointed out the heterogeneity of leukaemia in its different subpopulations, with distinct mutations and characteristics, impacting the treatment response. Next-generation sequencing (NGS) and genome-wide analyses, as well as single-cell technologies, have offered unprecedented insights into the clonal heterogeneity within the same tumour. A key component of this heterogeneity that remains unexplored is the intracellular metabolome, a dynamic network that determines cell functions, signalling, epigenome regulation, immunity and inflammation. Understanding the metabolic diversities among cancer cells and their surrounding environments is therefore essential in unravelling the complexities of leukaemia and improving therapeutic strategies. Here, we describe the currently available methodologies and approaches to addressing the dynamic heterogeneity of leukaemia progression. In the second section, we focus on metabolic leukaemic vulnerabilities in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). Lastly, we provide a comprehensive overview of the most interesting clinical trials designed to target these metabolic dependencies, highlighting their potential to advance therapeutic strategies in leukaemia treatment. The integration of multi-omics data for cancer identification with the metabolic states of tumour cells will enable a comprehensive "micro-to-macro" approach for the refinement of clinical practices and delivery of personalised therapies.
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Affiliation(s)
- Martina Maria Capelletti
- School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy; (M.M.C.); (O.M.); (E.R.); (A.M.S.)
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Orsola Montini
- School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy; (M.M.C.); (O.M.); (E.R.); (A.M.S.)
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Emilio Ruini
- School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy; (M.M.C.); (O.M.); (E.R.); (A.M.S.)
| | - Sarah Tettamanti
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Angela Maria Savino
- School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy; (M.M.C.); (O.M.); (E.R.); (A.M.S.)
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Jolanda Sarno
- School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy; (M.M.C.); (O.M.); (E.R.); (A.M.S.)
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
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Hao ZN, Tan XP, Zhang Q, Li J, Xia R, Ma Z. Lactate and Lactylation: Dual Regulators of T-Cell-Mediated Tumor Immunity and Immunotherapy. Biomolecules 2024; 14:1646. [PMID: 39766353 PMCID: PMC11674224 DOI: 10.3390/biom14121646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 12/14/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
Lactate and its derivative, lactylation, play pivotal roles in modulating immune responses within the tumor microenvironment (TME), particularly in T-cell-mediated cancer immunotherapy. Elevated lactate levels, a hallmark of the Warburg effect, contribute to immune suppression through CD8+ T cell functionality and by promoting regulatory T cell (Treg) activity. Lactylation, a post-translational modification (PTM), alters histone and non-histone proteins, influencing gene expression and further reinforcing immune suppression. In the complex TME, lactate and its derivative, lactylation, are not only associated with immune suppression but can also, under certain conditions, exert immunostimulatory effects that enhance cytotoxic responses. This review describes the dual roles of lactate and lactylation in T-cell-mediated tumor immunity, analyzing how these factors contribute to immune evasion, therapeutic resistance, and immune activation. Furthermore, the article highlights emerging therapeutic strategies aimed at inhibiting lactate production or disrupting lactylation pathways to achieve a balanced regulation of these dual effects. These strategies offer new insights into overcoming tumor-induced immune suppression and hold the potential to improve the efficacy of cancer immunotherapies.
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Affiliation(s)
- Zhi-Nan Hao
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Xiao-Ping Tan
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
- The Third Clinical Medical College of Yangtze University, Jingzhou Hospital of Traditional Chinese Medicine, Jingzhou 434023, China
| | - Qing Zhang
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Jie Li
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Ruohan Xia
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China
| | - Zhaowu Ma
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China
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10
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Hulugalla K, Shofolawe-Bakare OT, Toragall V, Mohammad SA, Mayatt R, Hand K, Anderson J, Chism CM, Misra SK, Shaikh T, Tanner EEL, Smith AE, Sharp J, Fitzkee N, Werfel T. Glycopolymeric Nanoparticles Enrich Less Immunogenic Protein Coronas, Reduce Mononuclear Phagocyte Clearance, and Improve Tumor Delivery Compared to PEGylated Nanoparticles. ACS NANO 2024; 18:30540-30560. [PMID: 39436672 PMCID: PMC12045476 DOI: 10.1021/acsnano.4c08922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/23/2024]
Abstract
Nanoparticles (NPs) offer significant promise as drug delivery vehicles; however, their in vivo efficacy is often hindered by the formation of a protein corona (PC), which influences key physiological responses such as blood circulation time, biodistribution, cellular uptake, and intracellular localization. Understanding NP-PC interactions is crucial for optimizing NP design for biomedical applications. Traditional approaches have utilized hydrophilic polymer coatings like polyethylene glycol (PEG) to resist protein adsorption, but glycopolymer-coated nanoparticles have emerged as potential alternatives due to their biocompatibility and ability to reduce the adsorption of highly immunogenic proteins. In this study, we synthesized and characterized glycopolymer-based poly[2-(diisopropylamino)ethyl methacrylate-b-poly(methacrylamidoglucopyranose) (PDPA-b-PMAG) NPs as an alternative to PEGylated NPs. We characterized the polymers using a range of techniques to establish their molecular weight and chemical composition. PMAG and PEG-based NPs showed equivalent physicochemical properties with sizes of ∼100 nm, spherical morphology, and neutral surface charges. We next assessed the magnitude of protein adsorption on both NPs and catalogued the identity of the adsorbed proteins using mass spectrometry-based techniques. The PMAG NPs were found to adsorb fewer proteins in vitro as well as fewer immunogenic proteins such as Immunoglobulins and Complement proteins. Flow cytometry and confocal microscopy were employed to examine cellular uptake in RAW 264.7 macrophages and MDA-MB-231 tumor cells, where PMAG NPs showed higher uptake into tumor cells over macrophages. In vivo studies in BALB/c mice with orthotopic 4T1 breast cancer xenografts showed that PMAG NPs exhibited prolonged circulation times and enhanced tumor accumulation compared to PEGylated NPs. The biodistribution analysis also revealed greater selectivity for tumor tissue over the liver for PMAG NPs. These findings highlight the potential of glycopolymeric NPs to improve tumor targeting and reduce macrophage uptake compared to PEGylated NPs, offering significant advancements in cancer nanomedicine and immunotherapy.
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Affiliation(s)
- Kenneth Hulugalla
- Department of BioMolecular Sciences, University of Mississippi, University, MS, 38677, USA
| | | | - Veeresh Toragall
- Department of Biomedical Engineering, University of Mississippi, University, MS, 38677, USA
| | - Sk Arif Mohammad
- Department of Biomedical Engineering, University of Mississippi, University, MS, 38677, USA
| | - Railey Mayatt
- Department of Chemistry, Mississippi State University, Starkville, MS, USA
| | - Kelsie Hand
- Department of Biomedical Engineering, University of Mississippi, University, MS, 38677, USA
| | - Joshua Anderson
- Department of Biomedical Engineering, University of Mississippi, University, MS, 38677, USA
| | - Claylee M. Chism
- Department of Chemistry and Biochemistry, University of Mississippi, University, MS, USA
| | - Sandeep K. Misra
- Department of BioMolecular Sciences, University of Mississippi, University, MS, 38677, USA
| | - Tanveer Shaikh
- Department of Chemistry, Mississippi State University, Starkville, MS, USA
| | - Eden E. L. Tanner
- Department of Chemistry and Biochemistry, University of Mississippi, University, MS, USA
| | - Adam E. Smith
- Department of Biomedical Engineering, University of Mississippi, University, MS, 38677, USA
- Department of Chemical Engineering, University of Mississippi, University, MS, 38677, USA
| | - Joshua Sharp
- Department of BioMolecular Sciences, University of Mississippi, University, MS, 38677, USA
| | - Nicholas Fitzkee
- Department of Chemistry, Mississippi State University, Starkville, MS, USA
| | - Thomas Werfel
- Department of BioMolecular Sciences, University of Mississippi, University, MS, 38677, USA
- Department of Biomedical Engineering, University of Mississippi, University, MS, 38677, USA
- Department of Chemical Engineering, University of Mississippi, University, MS, 38677, USA
- Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, MS, 39216, USA
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11
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Peng A, Li J, Xing J, Yao Y, Niu X, Zhang K. The function of nicotinamide phosphoribosyl transferase (NAMPT) and its role in diseases. Front Mol Biosci 2024; 11:1480617. [PMID: 39513038 PMCID: PMC11540786 DOI: 10.3389/fmolb.2024.1480617] [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: 08/14/2024] [Accepted: 10/11/2024] [Indexed: 11/15/2024] Open
Abstract
Nicotinamide phosphoribosyl transferase (NAMPT) is a rate-limiting enzyme in the mammalian nicotinamide adenine dinucleotide (NAD) salvage pathway, and plays a vital role in the regulation of cell metabolic activity, reprogramming, aging and apoptosis. NAMPT synthesizes nicotinamide mononucleotide (NMN) through enzymatic action, which is a key protein involved in host defense mechanism and plays an important role in metabolic homeostasis and cell survival. NAMPT is involved in NAD metabolism and maintains intracellular NAD levels. Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases (HDACs), the members are capable of sensing cellular NAD+ levels. NAMPT-NAD and SIRT constitute a powerful anti-stress defense system. In this paper, the structure, biological function and correlation with diseases of NAMPT are introduced, aiming to provide new ideas for the targeted therapy of related diseases.
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Affiliation(s)
| | | | | | | | | | - Kaiming Zhang
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, State Key Breeding Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Center Hospital, Taiyuan, China
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12
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Kooshan Z, Cárdenas-Piedra L, Clements J, Batra J. Glycolysis, the sweet appetite of the tumor microenvironment. Cancer Lett 2024; 600:217156. [PMID: 39127341 DOI: 10.1016/j.canlet.2024.217156] [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: 02/14/2024] [Revised: 07/17/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024]
Abstract
Cancer cells display an altered metabolic phenotype, characterised by increased glycolysis and lactate production, even in the presence of sufficient oxygen - a phenomenon known as the Warburg effect. This metabolic reprogramming is a crucial adaptation that enables cancer cells to meet their elevated energy and biosynthetic demands. Importantly, the tumor microenvironment plays a pivotal role in shaping and sustaining this metabolic shift in cancer cells. This review explores the intricate relationship between the tumor microenvironment and the Warburg effect, highlighting how communication within this niche regulates cancer cell metabolism and impacts tumor progression and therapeutic resistance. We discuss the potential of targeting the Warburg effect as a promising therapeutic strategy, with the aim of disrupting the metabolic advantage of cancer cells and enhancing our understanding of this complex interplay within the tumor microenvironment.
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Affiliation(s)
- Zeinab Kooshan
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Center for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology, Brisbane, Australia
| | - Lilibeth Cárdenas-Piedra
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Center for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology, Brisbane, Australia; ARC Training Centre for Cell & Tissue Engineering Technologies, Brisbane, Australia
| | - Judith Clements
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Center for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology, Brisbane, Australia
| | - Jyotsna Batra
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Center for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology, Brisbane, Australia; ARC Training Centre for Cell & Tissue Engineering Technologies, Brisbane, Australia.
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13
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Tang Q, Wu S, Zhao B, Li Z, Zhou Q, Yu Y, Yang X, Wang R, Wang X, Wu W, Wang S. Reprogramming of glucose metabolism: The hallmark of malignant transformation and target for advanced diagnostics and treatments. Biomed Pharmacother 2024; 178:117257. [PMID: 39137648 DOI: 10.1016/j.biopha.2024.117257] [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: 06/11/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/15/2024] Open
Abstract
Reprogramming of cancer metabolism has become increasingly concerned over the last decade, particularly the reprogramming of glucose metabolism, also known as the "Warburg effect". The reprogramming of glucose metabolism is considered a novel hallmark of human cancers. A growing number of studies have shown that reprogramming of glucose metabolism can regulate many biological processes of cancers, including carcinogenesis, progression, metastasis, and drug resistance. In this review, we summarize the major biological functions, clinical significance, potential targets and signaling pathways of glucose metabolic reprogramming in human cancers. Moreover, the applications of natural products and small molecule inhibitors targeting glucose metabolic reprogramming are analyzed, some clinical agents targeting glucose metabolic reprogramming and trial statuses are summarized, as well as the pros and cons of targeting glucose metabolic reprogramming for cancer therapy are analyzed. Overall, the reprogramming of glucose metabolism plays an important role in the prediction, prevention, diagnosis and treatment of human cancers. Glucose metabolic reprogramming-related targets have great potential to serve as biomarkers for improving individual outcomes and prognosis in cancer patients. The clinical innovations related to targeting the reprogramming of glucose metabolism will be a hotspot for cancer therapy research in the future. We suggest that more high-quality clinical trials with more abundant drug formulations and toxicology experiments would be beneficial for the development and clinical application of drugs targeting reprogramming of glucose metabolism.This review will provide the researchers with the broader perspective and comprehensive understanding about the important significance of glucose metabolic reprogramming in human cancers.
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Affiliation(s)
- Qing Tang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China.
| | - Siqi Wu
- The First Clinical School of Guangzhou University of Chinese Medicine；Department of Oncology, the First Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510000, China; Zhongshan Institute for Drug Discovery, SIMM, CAS, Zhongshan 528400, China
| | - Baiming Zhao
- The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Department of Traditional Chinese Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Zhanyang Li
- School of Biosciences and Biopharmaceutics, Guangdong Province Key Laboratory for Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Qichun Zhou
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China
| | - Yaya Yu
- The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China
| | - Xiaobing Yang
- The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China
| | - Rui Wang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China
| | - Xi Wang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China
| | - Wanyin Wu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China.
| | - Sumei Wang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Guangdong Provincial Hospital of Chinese Medicine; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; The Second Clinical Medical College, The Second Affiliated Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, 510120, P. R. China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China.
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14
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Ozgencil F, Gunindi HB, Eren G. Dual-targeted NAMPT inhibitors as a progressive strategy for cancer therapy. Bioorg Chem 2024; 149:107509. [PMID: 38824699 DOI: 10.1016/j.bioorg.2024.107509] [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: 03/09/2024] [Revised: 04/29/2024] [Accepted: 05/28/2024] [Indexed: 06/04/2024]
Abstract
In mammals, nicotinamide phosphoribosyltransferase (NAMPT) is a crucial enzyme in the nicotinamide adenine dinucleotide (NAD+) synthesis pathway catalyzing the condensation of nicotinamide (NAM) with 5-phosphoribosyl-1-pyrophosphate (PRPP) to produce nicotinamide mononucleotide (NMN). Given the pivotal role of NAD+ in a range of cellular functions, including DNA synthesis, redox reactions, cytokine generation, metabolism, and aging, NAMPT has become a promising target for many diseases, notably cancer. Therefore, various NAMPT inhibitors have been reported and classified as first and second-generation based on their chemical structures and design strategies, dual-targeted being one. However, most NAMPT inhibitors suffer from several limitations, such as dose-dependent toxicity and poor pharmacokinetic properties. Consequently, there is no clinically approved NAMPT inhibitor. Hence, research on discovering more effective and less toxic dual-targeted NAMPT inhibitors with desirable pharmacokinetic properties has drawn attention recently. This review summarizes the previously reported dual-targeted NAMPT inhibitors, focusing on their design strategies and advantages over the single-targeted therapies.
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Affiliation(s)
- Fikriye Ozgencil
- SIRTeam Group, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Türkiye
| | - Habibe Beyza Gunindi
- SIRTeam Group, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Türkiye
| | - Gokcen Eren
- SIRTeam Group, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Türkiye.
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15
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Miller ZA, Muthuswami S, Mueller A, Ma RZ, Sywanycz SM, Naik A, Huang L, Brody RM, Diab A, Carey RM, Lee RJ. GLUT1 inhibitor BAY-876 induces apoptosis and enhances anti-cancer effects of bitter receptor agonists in head and neck squamous carcinoma cells. Cell Death Discov 2024; 10:339. [PMID: 39060287 PMCID: PMC11282258 DOI: 10.1038/s41420-024-02106-z] [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: 03/27/2024] [Revised: 07/12/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are cancers that arise in the mucosa of the upper aerodigestive tract. The five-year patient survival rate is ~50%. Treatment includes surgery, radiation, and/or chemotherapy and is associated with lasting effects even when successful in irradicating the disease. New molecular targets and therapies must be identified to improve outcomes for HNSCC patients. We recently identified bitter taste receptors (taste family 2 receptors, or T2Rs) as a novel candidate family of receptors that activate apoptosis in HNSCC cells through mitochondrial Ca2+ overload and depolarization. We hypothesized that targeting another component of tumor cell metabolism, namely glycolysis, may increase the efficacy of T2R-directed therapies. GLUT1 (SLC2A1) is a facilitated-diffusion glucose transporter expressed by many cancer cells to fuel their increased rates of glycolysis. GLUT1 is already being investigated as a possible cancer target, but studies in HNSCCs are limited. Examination of immortalized HNSCC cells, patient samples, and The Cancer Genome Atlas revealed high expression of GLUT1 and upregulation in some patient tumor samples. HNSCC cells and tumor tissue express GLUT1 on the plasma membrane and within the cytoplasm (perinuclear, likely co-localized with the Golgi apparatus). We investigated the effects of a recently developed small molecule inhibitor of GLUT1, BAY-876. This compound decreased HNSCC glucose uptake, viability, and metabolism and induced apoptosis. Moreover, BAY-876 had enhanced effects on apoptosis when combined at low concentrations with T2R bitter taste receptor agonists. Notably, BAY-876 also decreased TNFα-induced IL-8 production, indicating an additional mechanism of possible tumor-suppressive effects. Our study demonstrates that targeting GLUT1 via BAY-876 to kill HNSCC cells, particularly in combination with T2R agonists, is a potential novel treatment strategy worth exploring further in future translational studies.
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Affiliation(s)
- Zoey A Miller
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
- Pharmacology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Sahil Muthuswami
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Arielle Mueller
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Ray Z Ma
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Sarah M Sywanycz
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Anusha Naik
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Lily Huang
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Robert M Brody
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Ahmed Diab
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Ryan M Carey
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
| | - Robert J Lee
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
- Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
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16
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Gu Q, An Y, Xu M, Huang X, Chen X, Li X, Shan H, Zhang M. Disulfidptosis, A Novel Cell Death Pathway: Molecular Landscape and Therapeutic Implications. Aging Dis 2024; 16:917-945. [PMID: 38739940 PMCID: PMC11964418 DOI: 10.14336/ad.2024.0083] [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: 01/23/2024] [Accepted: 05/02/2024] [Indexed: 05/16/2024] Open
Abstract
Programmed cell death is pivotal for several physiological processes, including immune defense. Further, it has been implicated in the pathogenesis of developmental disorders and the onset of numerous diseases. Multiple modes of programmed cell death, including apoptosis, pyroptosis, necroptosis, and ferroptosis, have been identified, each with their own unique characteristics and biological implications. In February 2023, Liu Xiaoguang and his team discovered "disulfidptosis," a novel pathway of programmed cell death. Their findings demonstrated that disulfidptosis is triggered in glucose-starved cells exhibiting high expression of a protein called SLC7A11. Furthermore, disulfidptosis is marked by a drastic imbalance in the NADPH/NADP+ ratio and the abnormal accumulation of disulfides like cystine. These changes ultimately lead to the destabilization of the F-actin network, causing cell death. Given that high SLC7A11 expression is a key feature of certain cancers, these findings indicate that disulfidptosis could serve as the basis of innovative anti-cancer therapies. Hence, this review delves into the discovery of disulfidptosis, its underlying molecular mechanisms and metabolic regulation, and its prospective applications in disease treatment.
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Affiliation(s)
- Qiuyang Gu
- Institute of Forensic Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Yumei An
- Institute of Forensic Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Mingyuan Xu
- Institute of Forensic Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Xinqi Huang
- Institute of Forensic Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Xueshi Chen
- Institute of Forensic Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Xianzhe Li
- Institute of Forensic Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Haiyan Shan
- Department of Obstetrics and Gynecology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Mingyang Zhang
- Institute of Forensic Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
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17
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Khochare SD, Li X, Yang X, Shi Y, Feng G, Ruchhoeft P, Shih WC, Shan X. Functional Plasmonic Microscope: Characterizing the Metabolic Activity of Single Cells via Sub-nm Membrane Fluctuations. Anal Chem 2024; 96:5771-5780. [PMID: 38563229 DOI: 10.1021/acs.analchem.3c04301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Metabolic abnormalities are at the center of many diseases, and the capability to film and quantify the metabolic activities of a single cell is important for understanding the heterogeneities in these abnormalities. In this paper, a functional plasmonic microscope (FPM) is used to image and measure metabolic activities without fluorescent labels at a single-cell level. The FPM can accurately image and quantify the subnanometer membrane fluctuations with a spatial resolution of 0.5 μm in real time. These active cell membrane fluctuations are caused by metabolic activities across the cell membrane. A three-dimensional (3D) morphology of the bottom cell membrane was imaged and reconstructed with FPM to illustrate the capability of the microscope for cell membrane characterization. Then, the subnanometer cell membrane fluctuations of single cells were imaged and quantified with the FPM using HeLa cells. Cell metabolic heterogeneity is analyzed based on membrane fluctuations of each individual cell that is exposed to similar environmental conditions. In addition, we demonstrated that the FPM could be used to evaluate the therapeutic responses of metabolic inhibitors (glycolysis pathway inhibitor STF 31) on a single-cell level. The result showed that the metabolic activities significantly decrease over time, but the nature of this response varies, depicting cell heterogeneity. A low-concentration dose showed a reduced fluctuation frequency with consistent fluctuation amplitudes, while the high-concentration dose showcased a decreasing trend in both cases. These results have demonstrated the capabilities of the functional plasmonic microscope to measure and quantify metabolic activities for drug discovery.
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Affiliation(s)
- Suraj D Khochare
- Advanced Imaging and Sensing Lab, Department of Electrical and Computer Engineering, University of Houston, Houston, Texas 77204, United States
| | - Xiaoliang Li
- Advanced Imaging and Sensing Lab, Department of Electrical and Computer Engineering, University of Houston, Houston, Texas 77204, United States
| | - Xu Yang
- Advanced Imaging and Sensing Lab, Department of Electrical and Computer Engineering, University of Houston, Houston, Texas 77204, United States
| | - Yaping Shi
- Advanced Imaging and Sensing Lab, Department of Electrical and Computer Engineering, University of Houston, Houston, Texas 77204, United States
| | - Guangxia Feng
- Advanced Imaging and Sensing Lab, Department of Electrical and Computer Engineering, University of Houston, Houston, Texas 77204, United States
| | - Paul Ruchhoeft
- Advanced Imaging and Sensing Lab, Department of Electrical and Computer Engineering, University of Houston, Houston, Texas 77204, United States
| | - Wei-Chuan Shih
- Advanced Imaging and Sensing Lab, Department of Electrical and Computer Engineering, University of Houston, Houston, Texas 77204, United States
| | - Xiaonan Shan
- Advanced Imaging and Sensing Lab, Department of Electrical and Computer Engineering, University of Houston, Houston, Texas 77204, United States
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18
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Zhang Y, Song H, Li M, Lu P. Histone lactylation bridges metabolic reprogramming and epigenetic rewiring in driving carcinogenesis: Oncometabolite fuels oncogenic transcription. Clin Transl Med 2024; 14:e1614. [PMID: 38456209 PMCID: PMC10921234 DOI: 10.1002/ctm2.1614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/13/2024] [Accepted: 02/18/2024] [Indexed: 03/09/2024] Open
Abstract
Heightened lactate production in cancer cells has been linked to various cellular mechanisms such as angiogenesis, hypoxia, macrophage polarisation and T-cell dysfunction. The lactate-induced lactylation of histone lysine residues is noteworthy, as it functions as an epigenetic modification that directly augments gene transcription from chromatin. This epigenetic modification originating from lactate effectively fosters a reliance on transcription, thereby expediting tumour progression and development. Herein, this review explores the correlation between histone lactylation and cancer characteristics, revealing histone lactylation as an innovative epigenetic process that enhances the vulnerability of cells to malignancy. Moreover, it is imperative to acknowledge the paramount importance of acknowledging innovative therapeutic methodologies for proficiently managing cancer by precisely targeting lactate signalling. This comprehensive review illuminates a crucial yet inadequately investigated aspect of histone lactylation, providing valuable insights into its clinical ramifications and prospective therapeutic interventions centred on lactylation.
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Affiliation(s)
- Yu Zhang
- Department of Clinical MedicineXuzhou Medical UniversityXuzhouJiangsuChina
| | - Hang Song
- Department of OphthalmologyPeking Union Medical College HospitalBeijingChina
| | - Meili Li
- Department of OphthalmologyEye Disease Prevention and Treatment Institute of Xuzhou, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical UniversityXuzhou First People's HospitalXuzhouJiangsuChina
| | - Peirong Lu
- Department of OphthalmologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
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19
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Wen F, Gui G, Wang X, Ye L, Qin A, Zhou C, Zha X. Drug discovery targeting nicotinamide phosphoribosyltransferase (NAMPT): Updated progress and perspectives. Bioorg Med Chem 2024; 99:117595. [PMID: 38244254 DOI: 10.1016/j.bmc.2024.117595] [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: 11/08/2023] [Revised: 12/21/2023] [Accepted: 01/10/2024] [Indexed: 01/22/2024]
Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway, primarily catalyzing the synthesis of nicotinamide mononucleotide (NMN) from nicotinamide (NAM), phosphoribosyl pyrophosphate (PRPP), and adenosine triphosphate (ATP). Metabolic diseases, aging-related diseases, inflammation, and cancers can lead to abnormal expression levels of NAMPT due to the pivotal role of NAD+ in redox metabolism, aging, the immune system, and DNA repair. In addition, NAMPT can be secreted by cells as a cytokine that binds to cell membrane receptors to regulate intracellular signaling pathways. Furthermore, NAMPT is able to reduce therapeutic efficacy by enhancing acquired resistance to chemotherapeutic agents. Recently, a few novel activators and inhibitors of NAMPT for neuroprotection and anti-tumor have been reported, respectively. However, NAMPT activators are still in preclinical studies, and only five NAMPT inhibitors have entered the clinical stage, unfortunately, three of which were terminated or withdrawn due to safety concerns. Novel drug design strategies such as proteolytic targeting chimera (PROTAC), antibody-drug conjugate (ADC), and dual-targeted inhibitors also provide new directions for the development of NAMPT inhibitors. In this perspective, we mainly discuss the structure, biological function, and role of NAMPT in diseases and the currently discovered activators and inhibitors. It is our hope that this work will provide some guidance for the future design and optimization of NAMPT activators and inhibitors.
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Affiliation(s)
- Fei Wen
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Gang Gui
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Xiaoyu Wang
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Li Ye
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Anqi Qin
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Chen Zhou
- Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, USA
| | - Xiaoming Zha
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
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20
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Cheng Q, Shi X, Li Q, Wang L, Wang Z. Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2305662. [PMID: 37941489 PMCID: PMC10797484 DOI: 10.1002/advs.202305662] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 09/15/2023] [Indexed: 11/10/2023]
Abstract
Increasing numbers of studies have shown that tumor cells prefer fermentative glycolysis over oxidative phosphorylation to provide a vast amount of energy for fast proliferation even under oxygen-sufficient conditions. This metabolic alteration not only favors tumor cell progression and metastasis but also increases lactate accumulation in solid tumors. In addition to serving as a byproduct of glycolytic tumor cells, lactate also plays a central role in the construction of acidic and immunosuppressive tumor microenvironment, resulting in therapeutic tolerance. Recently, targeted drug delivery and inherent therapeutic properties of nanomaterials have attracted great attention, and research on modulating lactate metabolism based on nanomaterials to enhance antitumor therapy has exploded. In this review, the advanced tumor therapy strategies based on nanomaterials that interfere with lactate metabolism are discussed, including inhibiting lactate anabolism, promoting lactate catabolism, and disrupting the "lactate shuttle". Furthermore, recent advances in combining lactate metabolism modulation with other therapies, including chemotherapy, immunotherapy, photothermal therapy, and reactive oxygen species-related therapies, etc., which have achieved cooperatively enhanced therapeutic outcomes, are summarized. Finally, foreseeable challenges and prospective developments are also reviewed for the future development of this field.
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Affiliation(s)
- Qian Cheng
- Department of Clinical LaboratoryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China
- Research Center for Tissue Engineering and Regenerative MedicineUnion HospitalHuazhong University of Science and TechnologyWuhan430022China
- Department of Gastrointestinal SurgeryUnion HospitalTongji Medical CollegeHuazhongUniversity of Science and TechnologyWuhan430022China
| | - Xiao‐Lei Shi
- Department of Clinical LaboratoryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China
- Research Center for Tissue Engineering and Regenerative MedicineUnion HospitalHuazhong University of Science and TechnologyWuhan430022China
- Department of Gastrointestinal SurgeryUnion HospitalTongji Medical CollegeHuazhongUniversity of Science and TechnologyWuhan430022China
| | - Qi‐Lin Li
- Department of Clinical LaboratoryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China
- Research Center for Tissue Engineering and Regenerative MedicineUnion HospitalHuazhong University of Science and TechnologyWuhan430022China
- Department of Gastrointestinal SurgeryUnion HospitalTongji Medical CollegeHuazhongUniversity of Science and TechnologyWuhan430022China
| | - Lin Wang
- Department of Clinical LaboratoryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China
- Research Center for Tissue Engineering and Regenerative MedicineUnion HospitalHuazhong University of Science and TechnologyWuhan430022China
- Department of Gastrointestinal SurgeryUnion HospitalTongji Medical CollegeHuazhongUniversity of Science and TechnologyWuhan430022China
| | - Zheng Wang
- Department of Clinical LaboratoryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China
- Hubei Key Laboratory of Regenerative Medicine and Multi‐disciplinary Translational ResearchWuhan430022China
- Department of Gastrointestinal SurgeryUnion HospitalTongji Medical CollegeHuazhongUniversity of Science and TechnologyWuhan430022China
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21
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Rodríguez-Camejo C, Puyol A, Arbildi P, Sóñora C, Fazio L, Siré G, Hernández A. Effects of human donor milk on gut barrier function and inflammation: in vitro study of the beneficial properties to the newborn. Front Immunol 2023; 14:1282144. [PMID: 38022652 PMCID: PMC10663376 DOI: 10.3389/fimmu.2023.1282144] [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: 08/23/2023] [Accepted: 10/19/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction The gastrointestinal and immune systems of premature infants are not fully developed, rendering them more vulnerable to severe complications like necrotizing enterocolitis. Human milk offers a rich array of bioactive factors that collectively contribute to reducing the incidence of gut infections and inflammatory conditions. When a mother's milk is unavailable, preterm infants are often provided with donor human milk processed in Human Milk Banks. However, it remains uncertain whether pasteurized milk confers the same level of risk reduction as unprocessed milk. This uncertainty may stem from the well-documented adverse effects of heat treatment on milk composition. Yet, our understanding of the comprehensive impact on protective mechanisms is limited. Methods In this study, we conducted a comparative analysis of the effects of raw versus pasteurized milk and colostrum versus mature milk on cellular functions associated with the gut epithelial barrier and responses to inflammatory stimuli. We utilized THP-1 and HT-29 cell lines, representing monocyte/macrophages and gut epithelial cells, respectively. Results Our observations revealed that all milk types stimulated epithelial cell proliferation. However, only raw colostrum increased cell migration and interfered with the interaction between E. coli and epithelial cells. Furthermore, the response of epithelial and macrophage cells to lipopolysaccharide (LPS) was enhanced solely by raw colostrum, with a milder effect observed with mature milk. In contrast, both raw and pasteurized milk diminished the LPS induced response in monocytes. Lastly, we examined how milk affected the differentiation of monocytes into macrophages, finding that milk reduced the subsequent inflammatory response of macrophages to LPS. Discussion Our study sheds light on the impact of human milk on certain mechanisms that potentially account for its protective effects against necrotizing enterocolitis, highlighting the detrimental influence of pasteurization on some of these mechanisms. Our findings emphasize the urgency of developing alternative pasteurization methods to better preserve milk properties. Moreover, identifying the key components critically affected by these protective mechanisms could enable their inclusion in donor milk or formula, thereby enhancing immunological benefits for vulnerable newborns.
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Affiliation(s)
- Claudio Rodríguez-Camejo
- Área Inmunología, Departamento de Biociencias (DEPBIO), Facultad de Química, Universidad de la República, Montevideo, Uruguay
- Unidad Asociada de Inmunología, Instituto de Química Biológica (IQB), Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
- Laboratorio de Inmunología, Instituto de Higiene “Prof. Arnoldo Berta”, Universidad de la República, Montevideo, Uruguay
| | - Arturo Puyol
- Banco de Leche “Ruben Panizza”, Centro Hospitalario Pereira Rossell, Administración de los Servicios de Salud del Estado, Montevideo, Uruguay
| | - Paula Arbildi
- Área Inmunología, Departamento de Biociencias (DEPBIO), Facultad de Química, Universidad de la República, Montevideo, Uruguay
- Unidad Asociada de Inmunología, Instituto de Química Biológica (IQB), Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
- Laboratorio de Inmunología, Instituto de Higiene “Prof. Arnoldo Berta”, Universidad de la República, Montevideo, Uruguay
| | - Cecilia Sóñora
- Área Inmunología, Departamento de Biociencias (DEPBIO), Facultad de Química, Universidad de la República, Montevideo, Uruguay
- Unidad Asociada de Inmunología, Instituto de Química Biológica (IQB), Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
- Laboratorio de Inmunología, Instituto de Higiene “Prof. Arnoldo Berta”, Universidad de la República, Montevideo, Uruguay
- Escuela Universitaria de Tecnología Médica (EUTM), Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Laura Fazio
- Banco de Leche “Ruben Panizza”, Centro Hospitalario Pereira Rossell, Administración de los Servicios de Salud del Estado, Montevideo, Uruguay
| | - Gabriela Siré
- Banco de Leche “Ruben Panizza”, Centro Hospitalario Pereira Rossell, Administración de los Servicios de Salud del Estado, Montevideo, Uruguay
| | - Ana Hernández
- Área Inmunología, Departamento de Biociencias (DEPBIO), Facultad de Química, Universidad de la República, Montevideo, Uruguay
- Unidad Asociada de Inmunología, Instituto de Química Biológica (IQB), Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
- Laboratorio de Inmunología, Instituto de Higiene “Prof. Arnoldo Berta”, Universidad de la República, Montevideo, Uruguay
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22
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Wang X, Lin J, Li Z, Wang M. In what area of biology has a "new" type of cell death been discovered? Biochim Biophys Acta Rev Cancer 2023; 1878:188955. [PMID: 37451411 DOI: 10.1016/j.bbcan.2023.188955] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 07/11/2023] [Accepted: 07/11/2023] [Indexed: 07/18/2023]
Abstract
Cell death is a fundamental physiological process that occurs in all organisms and is crucial to each organism's evolution, ability to maintain a stable internal environment, and the development of multiple organ systems. Disulfidptosis is a new mode of cell death that is triggered when cells with high expression of solute carrier family 7 member 11 (SLC7A11) are exposed to glucose starvation to initiate the process of cell death. The disulfidptosis mechanism is a programmed cell death mode that triggers cell death through reduction-oxidation (REDOX) reactions and disulfur bond formation. In disulfidptosis, disulfur bonds play a crucial role and cause the protein in the cell to undergo conformational changes, eventually leading to cell death. This mode of cell death has unique characteristics and regulatory mechanisms in comparison with other modes of cell death. In recent years, an increasing number of studies have shown that the disulfidptosis mechanism plays a key role in the occurrence and development of a variety of diseases. For example, cancer, cardiovascular diseases, neurodegenerative diseases, and liver diseases are all closely related to cell disulfidptosis mechanisms. Therefore, it is of paramount clinical significance to conduct in-depth research regarding this mechanism. This review summarizes the research progress on the disulfidptosis mechanism, including its discovery history, regulatory mechanism, related proteins, and signaling pathways. Potential applications of the disulfidptosis mechanism in disease therapy and future research directions are also discussed. This mechanism represents another subversive discovery after ferroptosis, and provides both a fresh perspective and an innovative strategy for the treatment of cancer, as well as inspiration for the treatment of other diseases.
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Affiliation(s)
- Xixi Wang
- Department of General Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Junyi Lin
- Department of Cardiovascular Medicine, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Zhi Li
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
| | - Minghua Wang
- Department of General Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China.
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23
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Chu YD, Chen CW, Lai MW, Lim SN, Lin WR. Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly. World J Gastroenterol 2023; 29:4499-4527. [PMID: 37621758 PMCID: PMC10445009 DOI: 10.3748/wjg.v29.i29.4499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/23/2023] [Accepted: 07/03/2023] [Indexed: 08/02/2023] Open
Abstract
Cancer cells exhibit metabolic reprogramming and bioenergetic alteration, utilizing glucose fermentation for energy production, known as the Warburg effect. However, there are a lack of comprehensive reviews summarizing the metabolic reprogramming, bioenergetic alteration, and their oncogenetic links in gastrointestinal (GI) cancers. Furthermore, the efficacy and treatment potential of emerging anticancer drugs targeting these alterations in GI cancers require further evaluation. This review highlights the interplay between aerobic glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS) in cancer cells, as well as hypotheses on the molecular mechanisms that trigger this alteration. The role of hypoxia-inducible transcription factors, tumor suppressors, and the oncogenetic link between hypoxia-related enzymes, bioenergetic changes, and GI cancer are also discussed. This review emphasizes the potential of targeting bioenergetic regulators for anti-cancer therapy, particularly for GI cancers. Emphasizing the potential of targeting bioenergetic regulators for GI cancer therapy, the review categorizes these regulators into aerobic glycolysis/ lactate biosynthesis/transportation and TCA cycle/coupled OXPHOS. We also detail various anti-cancer drugs and strategies that have produced pre-clinical and/or clinical evidence in treating GI cancers, as well as the challenges posed by these drugs. Here we highlight that understanding dysregulated cancer cell bioenergetics is critical for effective treatments, although the diverse metabolic patterns present challenges for targeted therapies. Further research is needed to comprehend the specific mechanisms of inhibiting bioenergetic enzymes, address side effects, and leverage high-throughput multi-omics and spatial omics to gain insights into cancer cell heterogeneity for targeted bioenergetic therapies.
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Affiliation(s)
- Yu-De Chu
- Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Chun-Wei Chen
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Wei Lai
- Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Siew-Na Lim
- Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Wey-Ran Lin
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- Department of Medicine, Chang Gung University, Taoyuan 333, Taiwan
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24
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Syamprasad NP, Jain S, Rajdev B, Prasad N, Kallipalli R, Naidu VGM. Aldose reductase and cancer metabolism: The master regulator in the limelight. Biochem Pharmacol 2023; 211:115528. [PMID: 37011733 DOI: 10.1016/j.bcp.2023.115528] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 03/25/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023]
Abstract
It is strongly established that metabolic reprogramming mediates the initiation, progression, and metastasis of a variety of cancers. However, there is no common biomarker identified to link the dysregulated metabolism and cancer progression. Recent studies strongly advise the involvement of aldose reductase (AR) in cancer metabolism. AR-mediated glucose metabolism creates a Warburg-like effect and an acidic tumour microenvironment in cancer cells. Moreover, AR overexpression is associated with the impairment of mitochondria and the accumulation of free fatty acids in cancer cells. Further, AR-mediated reduction of lipid aldehydes and chemotherapeutics are involved in the activation of factors promoting proliferation and chemo-resistance. In this review, we have delineated the possible mechanisms by which AR modulates cellular metabolism for cancer proliferation and survival. An in-depth understanding of cancer metabolism and the role of AR might lead to the use of AR inhibitors as metabolic modulating agents for the therapy of cancer.
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Affiliation(s)
- N P Syamprasad
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila Village, Changsari, Assam 781101, India
| | - Siddhi Jain
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila Village, Changsari, Assam 781101, India
| | - Bishal Rajdev
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila Village, Changsari, Assam 781101, India
| | - Neethu Prasad
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila Village, Changsari, Assam 781101, India
| | - Ravindra Kallipalli
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila Village, Changsari, Assam 781101, India
| | - V G M Naidu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila Village, Changsari, Assam 781101, India.
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25
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Navas LE, Blanco-Alcaina E, Suarez-Martinez E, Verdugo-Sivianes EM, Espinosa-Sanchez A, Sanchez-Diaz L, Dominguez-Medina E, Fernandez-Rozadilla C, Carracedo A, Wu LE, Carnero A. NAD pool as an antitumor target against cancer stem cells in head and neck cancer. J Exp Clin Cancer Res 2023; 42:55. [PMID: 36864434 PMCID: PMC9983242 DOI: 10.1186/s13046-023-02631-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/25/2023] [Indexed: 03/04/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that affect different anatomical locations. Despite this heterogeneity, HNSCC treatment depends on the anatomical location, TNM stage and resectability of the tumor. Classical chemotherapy is based on platinum-derived drugs (cisplatin, carboplatin and oxaliplatin), taxanes (docetaxel, paclitaxel) and 5-fluorouracil1. Despite advances in HNSCC treatment, the rate of tumor recurrence and patient mortality remain high. Therefore, the search for new prognostic identifiers and treatments targeting therapy-resistant tumor cells is vital. Our work demonstrates that there are different subgroups with high phenotypic plasticity within the CSC population in HNSCC. CD10, CD184, and CD166 may identify some of these CSC subpopulations with NAMPT as a common metabolic gene for the resilient cells of these subpopulations. We observed that NAMPT reduction causes a decrease in tumorigenic and stemness properties, migration capacity and CSC phenotype through NAD pool depletion. However, NAMPT-inhibited cells can acquire resistance by activating the NAPRT enzyme of the Preiss-Handler pathway. We observed that coadministration of the NAMPT inhibitor with the NAPRT inhibitor cooperated inhibiting tumor growth. The use of an NAPRT inhibitor as an adjuvant improved NAMPT inhibitor efficacy and reduced the dose and toxicity of these inhibitors. Therefore, it seems that the reduction in the NAD pool could have efficacy in tumor therapy. This was confirmed by in vitro assays supplying the cells with products of inhibited enzymes (NA, NMN or NAD) and restoring their tumorigenic and stemness properties. In conclusion, the coinhibition of NAMPT and NAPRT improved the efficacy of antitumor treatment, indicating that the reduction in the NAD pool is important to prevent tumor growth.
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Affiliation(s)
- Lola E. Navas
- grid.9224.d0000 0001 2168 1229Instituto de Biomedicina de Sevilla (IBIS)/HUVR/CSIC, Hospital Universitario Virgen del Rocío, Ed. IBIS, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avda. Manuel Siurot S/N, 41013 Seville, Spain ,grid.413448.e0000 0000 9314 1427CIBER de Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Elena Blanco-Alcaina
- grid.9224.d0000 0001 2168 1229Instituto de Biomedicina de Sevilla (IBIS)/HUVR/CSIC, Hospital Universitario Virgen del Rocío, Ed. IBIS, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avda. Manuel Siurot S/N, 41013 Seville, Spain ,grid.413448.e0000 0000 9314 1427CIBER de Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Elisa Suarez-Martinez
- grid.9224.d0000 0001 2168 1229Instituto de Biomedicina de Sevilla (IBIS)/HUVR/CSIC, Hospital Universitario Virgen del Rocío, Ed. IBIS, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avda. Manuel Siurot S/N, 41013 Seville, Spain ,grid.413448.e0000 0000 9314 1427CIBER de Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Eva M. Verdugo-Sivianes
- grid.9224.d0000 0001 2168 1229Instituto de Biomedicina de Sevilla (IBIS)/HUVR/CSIC, Hospital Universitario Virgen del Rocío, Ed. IBIS, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avda. Manuel Siurot S/N, 41013 Seville, Spain ,grid.413448.e0000 0000 9314 1427CIBER de Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Asuncion Espinosa-Sanchez
- grid.9224.d0000 0001 2168 1229Instituto de Biomedicina de Sevilla (IBIS)/HUVR/CSIC, Hospital Universitario Virgen del Rocío, Ed. IBIS, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avda. Manuel Siurot S/N, 41013 Seville, Spain ,grid.413448.e0000 0000 9314 1427CIBER de Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Laura Sanchez-Diaz
- grid.9224.d0000 0001 2168 1229Instituto de Biomedicina de Sevilla (IBIS)/HUVR/CSIC, Hospital Universitario Virgen del Rocío, Ed. IBIS, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avda. Manuel Siurot S/N, 41013 Seville, Spain ,grid.413448.e0000 0000 9314 1427CIBER de Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Eduardo Dominguez-Medina
- grid.11794.3a0000000109410645BioFarma-USEF Research Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Ceres Fernandez-Rozadilla
- grid.488911.d0000 0004 0408 4897Grupo de Medicina Xenómica (USC), Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain
| | - Angel Carracedo
- grid.488911.d0000 0004 0408 4897Grupo de Medicina Xenómica (USC), Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain ,grid.413448.e0000 0000 9314 1427CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Lindsay E. Wu
- grid.1005.40000 0004 4902 0432School of Medical Sciences, UNSW Sydney, Sydney, NSW Australia
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla (IBIS)/HUVR/CSIC, Hospital Universitario Virgen del Rocío, Ed. IBIS, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avda. Manuel Siurot S/N, 41013, Seville, Spain. .,CIBER de Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain.
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Targeting of Glucose Transport and the NAD Pathway in Neuroendocrine Tumor (NET) Cells Reveals New Treatment Options. Cancers (Basel) 2023; 15:cancers15051415. [PMID: 36900207 PMCID: PMC10001048 DOI: 10.3390/cancers15051415] [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: 12/28/2022] [Revised: 02/12/2023] [Accepted: 02/18/2023] [Indexed: 02/25/2023] Open
Abstract
(1) Background: the potency of drugs that interfere with glucose metabolism, i.e., glucose transporters (GLUT) and nicotinamide phosphoribosyltransferase (NAMPT) was analyzed in neuroendocrine tumor (NET, BON-1, and QPG-1 cells) and small cell lung cancer (SCLC, GLC-2, and GLC-36 cells) tumor cell lines. (2) Methods: the proliferation and survival rate of tumor cells was significantly affected by the GLUT-inhibitors fasentin and WZB1127, as well as by the NAMPT inhibitors GMX1778 and STF-31. (3) Results: none of the NET cell lines that were treated with NAMPT inhibitors could be rescued with nicotinic acid (usage of the Preiss-Handler salvage pathway), although NAPRT expression could be detected in two NET cell lines. We finally analyzed the specificity of GMX1778 and STF-31 in NET cells in glucose uptake experiments. As previously shown for STF-31 in a panel NET-excluding tumor cell lines, both drugs specifically inhibited glucose uptake at higher (50 μM), but not at lower (5 μM) concentrations. (4) Conclusions: our data suggest that GLUT and especially NAMPT inhibitors are potential candidates for the treatment of NET tumors.
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Zhang J, Zou S, Fang L. Metabolic reprogramming in colorectal cancer: regulatory networks and therapy. Cell Biosci 2023; 13:25. [PMID: 36755301 PMCID: PMC9906896 DOI: 10.1186/s13578-023-00977-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 02/01/2023] [Indexed: 02/10/2023] Open
Abstract
With high prevalence and mortality, together with metabolic reprogramming, colorectal cancer is a leading cause of cancer-related death. Metabolic reprogramming gives tumors the capacity for long-term cell proliferation, making it a distinguishing feature of cancer. Energy and intermediate metabolites produced by metabolic reprogramming fuel the rapid growth of cancer cells. Aberrant metabolic enzyme-mediated tumor metabolism is regulated at multiple levels. Notably, tumor metabolism is affected by nutrient levels, cell interactions, and transcriptional and posttranscriptional regulation. Understanding the crosstalk between metabolic enzymes and colorectal carcinogenesis factors is particularly important to advance research for targeted cancer therapy strategies via the investigation into the aberrant regulation of metabolic pathways. Hence, the abnormal roles and regulation of metabolic enzymes in recent years are reviewed in this paper, which provides an overview of targeted inhibitors for targeting metabolic enzymes in colorectal cancer that have been identified through tumor research or clinical trials.
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Affiliation(s)
- Jieping Zhang
- grid.12981.330000 0001 2360 039XDepartment of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuanchun Er Heng Road, Guangzhou, 510655 Guangdong China ,Guangdong Institute of Gastroenterology, Guangzhou, 510655 China
| | - Shaomin Zou
- grid.12981.330000 0001 2360 039XDepartment of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuanchun Er Heng Road, Guangzhou, 510655 Guangdong China ,Guangdong Institute of Gastroenterology, Guangzhou, 510655 China
| | - Lekun Fang
- Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuanchun Er Heng Road, Guangzhou, 510655, Guangdong, China. .,Guangdong Institute of Gastroenterology, Guangzhou, 510655, China.
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28
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Xu Y, Hao X, Ren Y, Xu Q, Liu X, Song S, Wang Y. Research progress of abnormal lactate metabolism and lactate modification in immunotherapy of hepatocellular carcinoma. Front Oncol 2023; 12:1063423. [PMID: 36686771 PMCID: PMC9853001 DOI: 10.3389/fonc.2022.1063423] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 12/19/2022] [Indexed: 01/09/2023] Open
Abstract
Tumors meet their energy, biosynthesis, and redox demands through metabolic reprogramming. This metabolic abnormality results in elevated levels of metabolites, particularly lactate, in the tumor microenvironment. Immune cell reprogramming and cellular plasticity mediated by lactate and lactylation increase immunosuppression in the tumor microenvironment and are emerging as key factors in regulating tumor development, metastasis, and the effectiveness of immunotherapies such as immune checkpoint inhibitors. Reprogramming of glucose metabolism and the "Warburg effect" in hepatocellular carcinoma (HCC) lead to the massive production and accumulation of lactate, so lactate modification in tumor tissue is likely to be abnormal as well. This article reviews the immune regulation of abnormal lactate metabolism and lactate modification in hepatocellular carcinoma and the therapeutic strategy of targeting lactate-immunotherapy, which will help to better guide the medication and treatment of patients with hepatocellular carcinoma.
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Affiliation(s)
- Yiwei Xu
- Marine College, Shandong University, Weihai, China
| | - Xiaodong Hao
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yidan Ren
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Qinchen Xu
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xiaoyan Liu
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Shuliang Song
- Marine College, Shandong University, Weihai, China,*Correspondence: Shuliang Song, ; Yunshan Wang,
| | - Yunshan Wang
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China,*Correspondence: Shuliang Song, ; Yunshan Wang,
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van Geest EP, Götzfried SK, Klein DM, Salitra N, Popal S, Husiev Y, Van der Griend CJ, Zhou X, Siegler MA, Schneider GF, Bonnet S. A
Lock‐and‐Kill
Anticancer Photoactivated Chemotherapy Agent
†. Photochem Photobiol 2022; 99:777-786. [PMID: 36315051 DOI: 10.1111/php.13738] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 10/20/2022] [Indexed: 12/03/2022]
Abstract
Photosubstitutionally active ruthenium complexes show high potential as prodrugs for the photoactivated chemotherapy (PACT) treatment of tumors. One of the problems in PACT is that the localization of the ruthenium compound is hard to trace. Here, a ruthenium PACT prodrug, [Ru(3)(biq)(STF-31)](PF6 )2 (where 3 = 3-(([2,2':6',2″-ter- pyridin]-4'-yloxy)propyl-4-(pyren-1-yl)butanoate) and biq = 2,2'-biquinoline), has been prepared, in which a pyrene tracker is attached via an ester bond. The proximity between the fluorophore and the ruthenium center leads to fluorescence quenching. Upon intracellular hydrolysis of the ester linkage, however, the fluorescence of the pyrene moiety is recovered, thus demonstrating prodrug cellular uptake. Further light irradiation of this molecule liberates by photosubstitution STF-31, a known cytotoxic nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, as well as singlet oxygen via excitation of the free pyrene chromophore. The dark and light cytotoxicity of the prodrug, embedded in liposomes, as well as the appearance of blue emission upon uptake, were evaluated in A375 human skin melanoma cells. The cytotoxicity of the liposome-embedded prodrug was indeed increased by light irradiation. This work realizes an in vitro proof-of-concept of the lock-and-kill principle, which may ultimately be used to design strategies aimed at knowing where and when light irradiation should be realized in vivo.
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Affiliation(s)
| | | | - David M. Klein
- Leiden Institute of Chemistry Leiden University Leiden The Netherlands
| | - Nadiya Salitra
- Leiden Institute of Chemistry Leiden University Leiden The Netherlands
| | - Sorraya Popal
- Leiden Institute of Chemistry Leiden University Leiden The Netherlands
| | - Yurii Husiev
- Leiden Institute of Chemistry Leiden University Leiden The Netherlands
| | | | - Xuequan Zhou
- Leiden Institute of Chemistry Leiden University Leiden The Netherlands
| | | | | | - Sylvestre Bonnet
- Leiden Institute of Chemistry Leiden University Leiden The Netherlands
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An Update on the Metabolic Landscape of Oncogenic Viruses. Cancers (Basel) 2022; 14:cancers14235742. [PMID: 36497226 PMCID: PMC9738352 DOI: 10.3390/cancers14235742] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/10/2022] [Accepted: 11/17/2022] [Indexed: 11/24/2022] Open
Abstract
Viruses play an important role in cancer development as about 12% of cancer types are linked to viral infections. Viruses that induce cellular transformation are known as oncoviruses. Although the mechanisms of viral oncogenesis differ between viruses, all oncogenic viruses share the ability to establish persistent chronic infections with no obvious symptoms for years. During these prolonged infections, oncogenic viruses manipulate cell signaling pathways that control cell cycle progression, apoptosis, inflammation, and metabolism. Importantly, it seems that most oncoviruses depend on these changes for their persistence and amplification. Metabolic changes induced by oncoviruses share many common features with cancer metabolism. Indeed, viruses, like proliferating cancer cells, require increased biosynthetic precursors for virion production, need to balance cellular redox homeostasis, and need to ensure host cell survival in a given tissue microenvironment. Thus, like for cancer cells, viral replication and persistence of infected cells frequently depend on metabolic changes. Here, we draw parallels between metabolic changes observed in cancers or induced by oncoviruses, with a focus on pathways involved in the regulation of glucose, lipid, and amino acids. We describe whether and how oncoviruses depend on metabolic changes, with the perspective of targeting them for antiviral and onco-therapeutic approaches in the context of viral infections.
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Temre MK, Kumar A, Singh SM. An appraisal of the current status of inhibition of glucose transporters as an emerging antineoplastic approach: Promising potential of new pan-GLUT inhibitors. Front Pharmacol 2022; 13:1035510. [PMID: 36386187 PMCID: PMC9663470 DOI: 10.3389/fphar.2022.1035510] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/18/2022] [Indexed: 07/23/2023] Open
Abstract
Neoplastic cells displayed altered metabolism with accelerated glycolysis. Therefore, these cells need a mammoth supply of glucose for which they display an upregulated expression of various glucose transporters (GLUT). Thus, novel antineoplastic strategies focus on inhibiting GLUT to intersect the glycolytic lifeline of cancer cells. This review focuses on the current status of various GLUT inhibition scenarios. The GLUT inhibitors belong to both natural and synthetic small inhibitory molecules category. As neoplastic cells express multiple GLUT isoforms, it is necessary to use pan-GLUT inhibitors. Nevertheless, it is also necessary that such pan-GLUT inhibitors exert their action at a low concentration so that normal healthy cells are left unharmed and minimal injury is caused to the other vital organs and systems of the body. Moreover, approaches are also emerging from combining GLUT inhibitors with other chemotherapeutic agents to potentiate the antineoplastic action. A new pan-GLUT inhibitor named glutor, a piperazine-one derivative, has shown a potent antineoplastic action owing to its inhibitory action exerted at nanomolar concentrations. The review discusses the merits and limitations of the existing GLUT inhibitory approach with possible future outcomes.
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Affiliation(s)
- Mithlesh Kumar Temre
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Ajay Kumar
- Deparment of Zoology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Sukh Mahendra Singh
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
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Bioelectronic medicines: Therapeutic potential and advancements in next-generation cancer therapy. Biochim Biophys Acta Rev Cancer 2022; 1877:188808. [DOI: 10.1016/j.bbcan.2022.188808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/07/2022] [Accepted: 09/27/2022] [Indexed: 11/22/2022]
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Correlation Study on the Expression of INSR, IRS-1, and PD-L1 in Nonsmall Cell Lung Cancer. JOURNAL OF ONCOLOGY 2022; 2022:5233222. [PMID: 36245982 PMCID: PMC9553505 DOI: 10.1155/2022/5233222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 08/05/2022] [Accepted: 08/11/2022] [Indexed: 11/18/2022]
Abstract
Objective To study the expression and correlation of insulin receptor (INSR), insulin receptor substrate-1 (IRS-1), and programmed cell death ligand-1 (PD-L1) in nonsmall cell lung cancer (NSCLC). Methods 45 lung cancer tissues and 30 adjacent normal tissues of NSCLC patients diagnosed in the Second Affiliated Hospital of Shandong First Medical University from June 2019 to August 2020 were selected. The expressions of INSR, IRS-1, and PD-L1 proteins in tumor tissues and adjacent tissues of NSCLC were detected by immunohistochemical staining. Results The expression of INSR and IRS-1 in NSCLC was significantly higher than that in adjacent normal lung tissue (P < 0.05). INSR expression had statistical significance with the degree of pathological differentiation of nonsmall cell carcinoma (P = 0.031), but had no significant association with age, gender, pathological type, TNM stage, and lymph node metastasis status (P > 0.05). There was no significant correlation between IRS-1 positive expression and NSCLC patients' age, gender, pathological typing, degree of differentiation, TNM stage, and lymph node metastasis (P > 0.05). PD-L1 positive expression was correlated with lymph node metastasis of NSCLC (P = 0.028), while there was no significant correlation with gender, age, pathological type, TNM stage, and pathological differentiation degree of NSCLC patients (P > 0.05). Spearman correlation analysis showed that PD-L1 protein expression had a significant positive correlation with IRS-1 protein expression (r = 0.373), but was not correlated with the expression of INSR protein. Conclusion IRS-1 may be involved in the regulation of PD-L1 expression and mediate the occurrence of tumor immune escape, which is expected to become a new target for NSCLC immunotherapy and provide new clinical evidence for immunosuppressive therapy.
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Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies. Cancers (Basel) 2022; 14:cancers14194568. [PMID: 36230492 PMCID: PMC9559313 DOI: 10.3390/cancers14194568] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/14/2022] [Accepted: 09/16/2022] [Indexed: 11/24/2022] Open
Abstract
Simple Summary Reprogramming of glucose metabolism is a hallmark of cancer and can be targeted by therapeutic agents. Some metabolism regulators, such as ivosidenib and enasidenib, have been approved for cancer treatment. Currently, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Furthermore, some natural products have shown efficacy in killing tumor cells by regulating glucose metabolism, offering novel therapeutic opportunities in cancer. However, most of them have failed to be translated into clinical applications due to low selectivity, high toxicity, and side effects. Recent studies suggest that combining glucose metabolism modulators with chemotherapeutic drugs, immunotherapeutic drugs, and other conventional anticancer drugs may be a future direction for cancer treatment. Abstract Reprogramming of glucose metabolism provides sufficient energy and raw materials for the proliferation, metastasis, and immune escape of cancer cells, which is enabled by glucose metabolism-related enzymes that are abundantly expressed in a broad range of cancers. Therefore, targeting glucose metabolism enzymes has emerged as a promising strategy for anticancer drug development. Although several glucose metabolism modulators have been approved for cancer treatment in recent years, some limitations exist, such as a short half-life, poor solubility, and numerous adverse effects. With the rapid development of medicinal chemicals, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Additionally, several studies have found that some natural products can suppress cancer progression by regulating glucose metabolism enzymes. In this review, we summarize the mechanisms underlying the reprogramming of glucose metabolism and present enzymes that could serve as therapeutic targets. In addition, we systematically review the existing drugs targeting glucose metabolism enzymes, including small-molecule modulators and natural products. Finally, the opportunities and challenges for glucose metabolism enzyme-targeted anticancer drugs are also discussed. In conclusion, combining glucose metabolism modulators with conventional anticancer drugs may be a promising cancer treatment strategy.
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Wei Y, Xiang H, Zhang W. Review of various NAMPT inhibitors for the treatment of cancer. Front Pharmacol 2022; 13:970553. [PMID: 36160449 PMCID: PMC9490061 DOI: 10.3389/fphar.2022.970553] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the NAD salvage pathway of mammalian cells and is overexpressed in numerous types of cancers. These include breast cancer, ovarian cancer, prostate cancer, gastric cancer, colorectal cancer, glioma, and b-cell lymphoma. NAMPT is also known to impact the NAD and NADPH pool. Research has demonstrated that NAMPT can be inhibited. NAMPT inhibitors are diverse anticancer medicines with significant anti-tumor efficacy in ex vivo tumor models. A few notable NAMPT specific inhibitors which have been produced include FK866, CHS828, and OT-82. Despite encouraging preclinical evidence of the potential utility of NAMPT inhibitors in cancer models, early clinical trials have yielded only modest results, necessitating the adaptation of additional tactics to boost efficacy. This paper examines a number of cancer treatment methods which target NAMPT, including the usage of individual inhibitors, pharmacological combinations, dual inhibitors, and ADCs, all of which have demonstrated promising experimental or clinical results. We intend to contribute further ideas regarding the usage and development of NAMPT inhibitors in clinical therapy to advance the field of research on this intriguing target.
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Affiliation(s)
- Yichen Wei
- West China School of Pharmacy, Sichuan University, Chengdu, China
- State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Haotian Xiang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
| | - Wenqiu Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Wenqiu Zhang,
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The role of metabolic reprogramming in cancer metastasis and potential mechanism of traditional Chinese medicine intervention. Biomed Pharmacother 2022; 153:113376. [DOI: 10.1016/j.biopha.2022.113376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/30/2022] [Accepted: 07/06/2022] [Indexed: 11/22/2022] Open
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Navas LE, Carnero A. Nicotinamide Adenine Dinucleotide (NAD) Metabolism as a Relevant Target in Cancer. Cells 2022; 11:cells11172627. [PMID: 36078035 PMCID: PMC9454445 DOI: 10.3390/cells11172627] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/25/2022] [Accepted: 08/16/2022] [Indexed: 11/22/2022] Open
Abstract
NAD+ is an important metabolite in cell homeostasis that acts as an essential cofactor in oxidation–reduction (redox) reactions in various energy production processes, such as the Krebs cycle, fatty acid oxidation, glycolysis and serine biosynthesis. Furthermore, high NAD+ levels are required since they also participate in many other nonredox molecular processes, such as DNA repair, posttranslational modifications, cell signalling, senescence, inflammatory responses and apoptosis. In these nonredox reactions, NAD+ is an ADP-ribose donor for enzymes such as sirtuins (SIRTs), poly-(ADP-ribose) polymerases (PARPs) and cyclic ADP-ribose (cADPRs). Therefore, to meet both redox and nonredox NAD+ demands, tumour cells must maintain high NAD+ levels, enhancing their synthesis mainly through the salvage pathway. NAMPT, the rate-limiting enzyme of this pathway, has been identified as an oncogene in some cancer types. Thus, NAMPT has been proposed as a suitable target for cancer therapy. NAMPT inhibition causes the depletion of NAD+ content in the cell, leading to the inhibition of ATP synthesis. This effect can cause a decrease in tumour cell proliferation and cell death, mainly by apoptosis. Therefore, in recent years, many specific inhibitors of NAMPT have been developed, and some of them are currently in clinical trials. Here we review the NAD metabolism as a cancer therapy target.
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Affiliation(s)
- Lola E. Navas
- Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, 41013 Sevilla, Spain
- CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, 41013 Sevilla, Spain
- CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence:
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Feng Z, Ou Y, Hao L. The roles of glycolysis in osteosarcoma. Front Pharmacol 2022; 13:950886. [PMID: 36059961 PMCID: PMC9428632 DOI: 10.3389/fphar.2022.950886] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 07/25/2022] [Indexed: 12/02/2022] Open
Abstract
Metabolic reprogramming is of great significance in the progression of various cancers and is critical for cancer progression, diagnosis, and treatment. Cellular metabolic pathways mainly include glycolysis, fat metabolism, glutamine decomposition, and oxidative phosphorylation. In cancer cells, reprogramming metabolic pathways is used to meet the massive energy requirement for tumorigenesis and development. Metabolisms are also altered in malignant osteosarcoma (OS) cells. Among reprogrammed metabolisms, alterations in aerobic glycolysis are key to the massive biosynthesis and energy demands of OS cells to sustain their growth and metastasis. Numerous studies have demonstrated that compared to normal cells, glycolysis in OS cells under aerobic conditions is substantially enhanced to promote malignant behaviors such as proliferation, invasion, metastasis, and drug resistance of OS. Glycolysis in OS is closely related to various oncogenes and tumor suppressor genes, and numerous signaling pathways have been reported to be involved in the regulation of glycolysis. In recent years, a vast number of inhibitors and natural products have been discovered to inhibit OS progression by targeting glycolysis-related proteins. These potential inhibitors and natural products may be ideal candidates for the treatment of osteosarcoma following hundreds of preclinical and clinical trials. In this article, we explore key pathways, glycolysis enzymes, non-coding RNAs, inhibitors, and natural products regulating aerobic glycolysis in OS cells to gain a deeper understanding of the relationship between glycolysis and the progression of OS and discover novel therapeutic approaches targeting glycolytic metabolism in OS.
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Zhu Y, Xu P, Huang X, Shuai W, Liu L, Zhang S, Zhao R, Hu X, Wang G. From Rate-Limiting Enzyme to Therapeutic Target: The Promise of NAMPT in Neurodegenerative Diseases. Front Pharmacol 2022; 13:920113. [PMID: 35903330 PMCID: PMC9322656 DOI: 10.3389/fphar.2022.920113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/08/2022] [Indexed: 11/15/2022] Open
Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD) salvage pathway in mammals. It is of great significance in the metabolic homeostasis and cell survival via synthesizing nicotinamide mononucleotide (NMN) through enzymatic activities, serving as a key protein involved in the host's defense mechanism. The NAMPT metabolic pathway connects NAD-dependent sirtuin (SIRT) signaling, constituting the NAMPT-NAD-SIRT cascade, which is validated as a strong intrinsic defense system. Neurodegenerative diseases belong to the central nervous system (CNS) disease that seriously endangers human health. The World Health Organization (WHO) proposed that neurodegenerative diseases will become the second leading cause of human death in the next two decades. However, effective drugs for neurodegenerative diseases are scant. NAMPT is specifically highly expressed in the hippocampus, which mediates cell self-renewal and proliferation and oligodendrocyte synthesis by inducing the biosynthesis of NAD in neural stem cells/progenitor cells. Owing to the active biological function of NAMPT in neurogenesis, targeting NAMPT may be a powerful therapeutic strategy for neurodegenerative diseases. This study aims to review the structure and biological functions, the correlation with neurodegenerative diseases, and treatment advance of NAMPT, aiming to provide a novel idea for targeted therapy of neurodegenerative diseases.
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Affiliation(s)
- Yumeng Zhu
- Innovation Center of Nursing Research, West China School of Nursing, Department of Gastrointestinal Surgery, National Clinical Research Center for Geriatrics, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Ping Xu
- Emergency Department, Institute of Medical Big Data, Zigong Academy of Big Data for Science and Artificial Intelligence, Zigong Fourth People’s Hospital, Zigong, China
| | - Xuan Huang
- Innovation Center of Nursing Research, West China School of Nursing, Department of Gastrointestinal Surgery, National Clinical Research Center for Geriatrics, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Wen Shuai
- Innovation Center of Nursing Research, West China School of Nursing, Department of Gastrointestinal Surgery, National Clinical Research Center for Geriatrics, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Li Liu
- Innovation Center of Nursing Research, West China School of Nursing, Department of Gastrointestinal Surgery, National Clinical Research Center for Geriatrics, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Shuai Zhang
- Innovation Center of Nursing Research, West China School of Nursing, Department of Gastrointestinal Surgery, National Clinical Research Center for Geriatrics, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Zhao
- Innovation Center of Nursing Research, West China School of Nursing, Department of Gastrointestinal Surgery, National Clinical Research Center for Geriatrics, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Xiuying Hu
- Innovation Center of Nursing Research, West China School of Nursing, Department of Gastrointestinal Surgery, National Clinical Research Center for Geriatrics, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Guan Wang
- Innovation Center of Nursing Research, West China School of Nursing, Department of Gastrointestinal Surgery, National Clinical Research Center for Geriatrics, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
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Vallejo FA, Sanchez A, Cuglievan B, Walters WM, De Angulo G, Vanni S, Graham RM. NAMPT Inhibition Induces Neuroblastoma Cell Death and Blocks Tumor Growth. Front Oncol 2022; 12:883318. [PMID: 35814452 PMCID: PMC9261286 DOI: 10.3389/fonc.2022.883318] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 05/17/2022] [Indexed: 11/24/2022] Open
Abstract
High-risk neuroblastoma (NB) portends very poor prognoses in children. Targeting tumor metabolism has emerged as a novel therapeutic strategy. High levels of nicotinamide-adenine-dinucleotide (NAD+) are required for rapid cell proliferation. Nicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme for NAD+ salvage and is overexpressed in several cancers. Here, we determine the potential of NAMPT as a therapeutic target for NB treatment. NAMPT inhibition cytotoxicity was determined by trypan blue exclusion and LDH assays. Neuroblastoma stem cell self-renewal was evaluated by neurosphere assay. Protein expression was evaluated via Western blot. The effect of targeting NAMPT in vivo was determined using an NB1691-xenografted mouse model. Robust NAMPT expression was demonstrated in multiple N-MYC amplified, high-risk neuroblastoma cell lines. NAMPT inhibition with STF-118804 (STF) decreased ATP, induced apoptosis, and reduced NB stem cell neurosphere formation. STF treatment down-regulated N-MYC levels and abrogated AKT activation. AKT and glycolytic pathway inhibitors in combination with NAMPT inhibition induced robust, greater-than-additive neuroblastoma cell death. Lastly, STF treatment blocked neuroblastoma tumor growth in mouse xenograft models. NAMPT is a valid therapeutic target as inhibition promoted neuroblastoma cell death in vitro and prevented tumor growth in vivo. Further investigation is warranted to establish this therapy’s role as an adjunctive modality.
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Affiliation(s)
- Frederic A. Vallejo
- Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Anthony Sanchez
- Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Radiology and Imaging Sciences, University of Utah Hospital, Salt Lake City, UT, United States
| | - Branko Cuglievan
- Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Pediatrics Patient Care, Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Winston M. Walters
- Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Guillermo De Angulo
- Department of Hematology/Oncology and Immunology, Nicklaus Children’s Hospital, Miami, FL, United States
| | - Steven Vanni
- Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Neurosurgery, HCA Florida University Hospital, Davie, FL, United States
- Dr. Kiran C. Patel College of Allopathic Medicine, Davie, FL, United States
| | - Regina M. Graham
- Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, United States
- Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, United States
- *Correspondence: Regina M. Graham,
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Fujii T, Katoh M, Ootsubo M, Nguyen OTT, Iguchi M, Shimizu T, Tabuchi Y, Shimizu Y, Takeshima H, Sakai H. Cardiac glycosides stimulate endocytosis of GLUT1 via intracellular Na + ,K + -ATPase α3-isoform in human cancer cells. J Cell Physiol 2022; 237:2980-2991. [PMID: 35511727 DOI: 10.1002/jcp.30762] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 03/23/2022] [Accepted: 04/11/2022] [Indexed: 01/20/2023]
Abstract
Glucose transporter GLUT1 plays a primary role in the glucose metabolism of cancer cells. Here, we found that cardiac glycosides (CGs) such as ouabain, oleandrin, and digoxin, which are Na+ ,K+ -ATPase inhibitors, decreased the GLUT1 expression in the plasma membrane of human cancer cells (liver cancer HepG2, colon cancer HT-29, gastric cancer MKN45, and oral cancer KB cells). The effective concentration of ouabain was lower than that for inhibiting the activity of Na+ ,K+ -ATPase α1-isoform (α1NaK) in the plasma membrane. The CGs also inhibited [3 H]2-deoxy- d-glucose uptake, lactate secretion, and proliferation of the cancer cells. In intracellular vesicles of human cancer cells, Na+ ,K+ -ATPase α3-isoform (α3NaK) is abnormally expressed. Here, a low concentration of ouabain inhibited the activity of α3NaK. Knockdown of α3NaK significantly inhibited the ouabain-decreased GLUT1 expression in HepG2 cells, while the α1NaK knockdown did not. Consistent with the results in human cancer cells, CGs had no effect on GLUT1 expression in rat liver cancer dRLh-84 cells where α3NaK was not endogenously expressed. Interestingly, CGs decreased GLUT expression in the dRLh-84 cells exogenously expressing α3NaK. In HepG2 cells, α3NaK was found to be colocalized with TPC1, a Ca2+ -releasing channel activated by nicotinic acid adenine dinucleotide phosphate (NAADP). The CGs-decreased GLUT1 expression was significantly inhibited by a Ca2+ chelator, a Ca2+ -ATPase inhibitor, and a NAADP antagonist. The GLUT1 decrease was also attenuated by inhibitors of dynamin and phosphatidylinositol-3 kinases (PI3Ks). In conclusion, the binding of CGs to intracellular α3NaK elicits the NAADP-mediated Ca2+ mobilization followed by the dynamin-dependent GLUT1 endocytosis in human cancer cells.
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Affiliation(s)
- Takuto Fujii
- Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Mizuki Katoh
- Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Manami Ootsubo
- Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Oanh T T Nguyen
- Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Mayumi Iguchi
- Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Takahiro Shimizu
- Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Yoshiaki Tabuchi
- Division of Molecular Genetics Research, Life Science Research Center, University of Toyama, Toyama, Japan
| | - Yasuharu Shimizu
- Tokyo Research Center, Kyushin Pharmaceutical Co, Ltd., Tokyo, Japan
| | - Hiroshi Takeshima
- Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Hideki Sakai
- Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan
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Chemotherapy Resistance: Role of Mitochondrial and Autophagic Components. Cancers (Basel) 2022; 14:cancers14061462. [PMID: 35326612 PMCID: PMC8945922 DOI: 10.3390/cancers14061462] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/10/2022] [Accepted: 03/10/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Chemotherapy resistance is a common occurrence during cancer treatment that cancer researchers are attempting to understand and overcome. Mitochondria are a crucial intracellular signaling core that are becoming important determinants of numerous aspects of cancer genesis and progression, such as metabolic reprogramming, metastatic capability, and chemotherapeutic resistance. Mitophagy, or selective autophagy of mitochondria, can influence both the efficacy of tumor chemotherapy and the degree of drug resistance. Regardless of the fact that mitochondria are well-known for coordinating ATP synthesis from cellular respiration in cellular bioenergetics, little is known its mitophagy regulation in chemoresistance. Recent advancements in mitochondrial research, mitophagy regulatory mechanisms, and their implications for our understanding of chemotherapy resistance are discussed in this review. Abstract Cancer chemotherapy resistance is one of the most critical obstacles in cancer therapy. One of the well-known mechanisms of chemotherapy resistance is the change in the mitochondrial death pathways which occur when cells are under stressful situations, such as chemotherapy. Mitophagy, or mitochondrial selective autophagy, is critical for cell quality control because it can efficiently break down, remove, and recycle defective or damaged mitochondria. As cancer cells use mitophagy to rapidly sweep away damaged mitochondria in order to mediate their own drug resistance, it influences the efficacy of tumor chemotherapy as well as the degree of drug resistance. Yet despite the importance of mitochondria and mitophagy in chemotherapy resistance, little is known about the precise mechanisms involved. As a consequence, identifying potential therapeutic targets by analyzing the signal pathways that govern mitophagy has become a vital research goal. In this paper, we review recent advances in mitochondrial research, mitophagy control mechanisms, and their implications for our understanding of chemotherapy resistance.
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Curry A, White D, Cen Y. Small Molecule Regulators Targeting NAD + Biosynthetic Enzymes. Curr Med Chem 2022; 29:1718-1738. [PMID: 34060996 PMCID: PMC8630097 DOI: 10.2174/0929867328666210531144629] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 04/02/2021] [Accepted: 04/07/2021] [Indexed: 01/03/2023]
Abstract
Nicotinamide adenine dinucleotide (NAD+) is a key player in many metabolic pathways as an activated carrier of electrons. In addition to being the cofactor for redox reactions, NAD+ also serves as the substrate for various enzymatic transformations such as adenylation and ADP-ribosylation. Maintaining cellular NAD+ homeostasis has been suggested as an effective anti-aging strategy. Given the importance of NAD+ in regulating a broad spectrum of cellular events, small molecules targeting NAD+ metabolism have been pursued as therapeutic interventions for the treatment of mitochondrial disorders and agerelated diseases. In this article, small molecule regulators of NAD+ biosynthetic enzymes will be reviewed. The focus will be given to the discovery and development of these molecules, the mechanism of action as well as their therapeutic potentials.
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Affiliation(s)
- Alyson Curry
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, USA
| | - Dawanna White
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, USA
| | - Yana Cen
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, USA;,Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, USA,Address correspondence to this author at the Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, USA; Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, USA; Tel: 804-828-7405;
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Kozal K, Jóźwiak P, Krześlak A. Contemporary Perspectives on the Warburg Effect Inhibition in Cancer Therapy. Cancer Control 2021; 28:10732748211041243. [PMID: 34554006 PMCID: PMC8474311 DOI: 10.1177/10732748211041243] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
In the 1920s, Otto Warburg observed the phenomenon of altered glucose metabolism
in cancer cells. Although the initial hypothesis suggested that the alteration
resulted from mitochondrial damage, multiple studies of the subject revealed a
precise, multistage process rather than a random pattern. The phenomenon of
aerobic glycolysis emerges not only from mitochondrial abnormalities common in
cancer cells, but also results from metabolic reprogramming beneficial for their
sustenance. The Warburg effect enables metabolic adaptation of cancer cells to
grow and proliferate, simultaneously enabling their survival in hypoxic
conditions. Altered glucose metabolism of cancer cells includes, inter alia,
qualitative and quantitative changes within glucose transporters, enzymes of the
glycolytic pathway, such as hexokinases and pyruvate kinase, hypoxia-inducible
factor, monocarboxylate transporters, and lactate dehydrogenase. This review
summarizes the current state of knowledge regarding inhibitors of cancer glucose
metabolism with a focus on their clinical potential. The altered metabolic
phenotype of cancer cells allows for targeting of specific mechanisms, which
might improve conventional methods in anti-cancer therapy. However, several
problems such as drug bioavailability, specificity, toxicity, the plasticity of
cancer cells, and heterogeneity of cells in tumors have to be overcome when
designing therapies based on compounds targeted in cancer cell energy
metabolism.
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Affiliation(s)
- Karolina Kozal
- Faculty of Biology and
Environmental Protection, Department of Cytobiochemistry, University of Lodz, Lodz, Poland
| | - Paweł Jóźwiak
- Faculty of Biology and
Environmental Protection, Department of Cytobiochemistry, University of Lodz, Lodz, Poland
| | - Anna Krześlak
- Faculty of Biology and
Environmental Protection, Department of Cytobiochemistry, University of Lodz, Lodz, Poland
- Anna Krzeslak Faculty of Biology and
Environmental Protection, Department of Cytobiochemistry, University of Lodz,
Pomorska 141/143, Lodz 90-131, Poland.
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45
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The Role of Glucose Transporters in Oral Squamous Cell Carcinoma. Biomolecules 2021; 11:biom11081070. [PMID: 34439735 PMCID: PMC8392467 DOI: 10.3390/biom11081070] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/18/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC) is a prevalent malignancy associated with a poor prognosis. The Warburg effect can be observed in OSCCs, with tumours requiring a robust glucose supply. Glucose transporters (GLUTs) and sodium-glucose co-transporters (SGLTs) are overexpressed in multiple malignancies, and are correlated with treatment resistance, clinical factors, and poor overall survival (OS). We conducted a systematic review to evaluate the differences in GLUT/SGLT expression between OSCC and normal oral keratinocytes (NOK), as well as their role in the pathophysiology and prognosis of OSCC. A total of 85 studies were included after screening 781 papers. GLUT-1 is regularly expressed in OSCC and was found to be overexpressed in comparison to NOK, with high expression correlated to tumour stage, treatment resistance, and poor prognosis. No clear association was found between GLUT-1 and tumour grade, metastasis, and fluorodeoxyglucose (FDG) uptake. GLUT-3 was less thoroughly studied but could be detected in most samples and is generally overexpressed compared to NOK. GLUT-3 negatively correlated with overall survival (OS), but there was insufficient data for correlations with other clinical factors. Expression of GLUT-2/GLUT-4/GLUT-8/GLUT-13/SGLT-1/SGLT-2 was only evaluated in a small number of studies with no significant differences detected. GLUTs 7 and 14 have never been evaluated in OSCC. In conclusion, the data demonstrates that GLUT-1 and GLUT-3 have a role in the pathophysiology of OSCC and represent valuable biomarkers to aid OSCC diagnosis and prognostication. Other GLUTs are comparatively understudied and should be further analysed because they may hold promise to improve patient care.
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Abstract
The GLUT is a key regulator of glucose metabolism and is widely expressed on the surface of most cells of the body. GLUT provides a variety of nutrients for the growth, proliferation and differentiation of cells. In recent years, the development of drugs affecting the energy intake of tumor cells has become a research hotspot. GLUT inhibitors are gaining increased attention because they can block the energy supply of malignant tumors. Herein, we elaborate on the structure and function of GLUT1, the structural and functional differences among GLUT1-4 transporters and the relationship between GLUT1 and tumor development, as well as GLUT1 transporter inhibitors, to provide a reference for the development of new GLUT1 inhibitors.
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de Freitas PP, Ribeiro RCB, Dos Santos Guimarães I, Moreira CS, Rocha DR, de Carvalho da Silva F, Ferreira VF, Gimba ERP. (3,3'-Methylene)bis-2-hydroxy-1,4-naphthoquinones induce cytotoxicity against DU145 and PC3 cancer cells by inhibiting cell viability and promoting cell cycle arrest. Mol Biol Rep 2021; 48:3253-3263. [PMID: 34009563 DOI: 10.1007/s11033-021-06406-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 05/08/2021] [Indexed: 10/21/2022]
Abstract
We developed a novel method for the synthesis of bis-naphthoquinones (BNQ), which are hybrids of lawsone (2-hydroxy-1,4-naphthoquinone) and 3-hydroxy-juglone (3,5-dihydroxy-1,4-naphthoquinone). The anticancer activity of three synthesized compounds, named 4 (RC10), 5 (RCDFC), and 6 (RCDOH) was evaluated in vitro against two metastatic prostate cancer (PCa) cell lines, DU145 and PC3, using MTT assays. We found that 4 (RC10) and 5 (RCDFC) induced cytotoxicity against DU145 and PC3 cells. Flow cytometry analysis revealed that these two compounds promoted cell cycle arrest in G1/S and G2/M phases, increased Sub-G1 peak and induced inhibition in cell viability. We also showed that these effects are cell-type context dependent and more selective for these tested PCa cells than for HUVEC non-tumor cells. The two BNQ compounds 4 (RC10) and 5 (RCDFC) displayed promising anticancer activity against the two tested metastatic PCa cell lines, DU145 and PC3. Their effects are mainly associated with inhibition of cell viability, possibly through apoptotic cell death, besides altering the SubG1, G1/S and G2/M phases of cell cycle. 5 (RCDFC) compound was found to be more selective than 4 (RC10), when comparing their cytotoxic effects in relation to HUVEC non-tumoral cells. Future work should also test these compounds in combination with other chemotherapeutic drugs to evaluate their effects on further sensitizing drug-resistant metastatic PCa cells.
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Affiliation(s)
| | - Ruan Carlos Busquet Ribeiro
- Instituto de Química, Universidade Federal Fluminense, Campus do Valonguinho, Niterói, RJ, 24020-150, Brazil
| | - Isabella Dos Santos Guimarães
- Divisão de Pesquisa Clínica e Desenvolvimento Tecnológico, Laboratório de Pesquisa Translacional, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil
| | - Caroline S Moreira
- Instituto de Química, Universidade Federal Fluminense, Campus do Valonguinho, Niterói, RJ, 24020-150, Brazil
| | - David R Rocha
- Instituto de Química, Universidade Federal Fluminense, Campus do Valonguinho, Niterói, RJ, 24020-150, Brazil
| | | | - Vitor Francisco Ferreira
- Departamento de Tecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Fluminense, Santa Rosa, Niterói, RJ, 24241-002, Brazil
| | - Etel Rodrigues Pereira Gimba
- Instituto Nacional de Câncer, Coordenação de Pesquisa, Centro, Rio de Janeiro, RJ, 20231-050, Brazil. .,Departamento de Ciências da Natureza, Instituto de Humanidade E Saúde (IHS), Universidade Federal Fluminense, Campus de Rio das Ostras, Rio das Ostras, RJ, 28880-00, Brazil. .,Programa de Pós Graduação Stricto Sensu em Oncologia, Instituto Nacional de Câncer, Centro, Rio de Janeiro, RJ, 20231-050, Brazil. .,Programa de Pós Graduação em Ciências Biomédicas-Fisiologia E Farmacologia, Instituto Biomédico, Universidade Federal Fluminense, Campus do Valonguinho, Niterói, RJ, 24020-150, Brazil.
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Zhang S, Wang X, Zhang R, Cui Y, Zhang H, Song W, Hou X, Fu S, Gao Q, Liu S. A GLUT1 inhibitor-based fluorogenic probe for Warburg effect-targeted drug screening and diagnostic imaging of hyperglycolytic cancers. Anal Chim Acta 2021; 1167:338593. [PMID: 34049629 DOI: 10.1016/j.aca.2021.338593] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/16/2021] [Accepted: 04/27/2021] [Indexed: 11/28/2022]
Abstract
Increased expression of glucose transporters, especially GLUT1 has been proven to be involved in the Warburg effect. Therefore, GLUT1-targeted oncological approaches are being successfully employed for clinical tumor diagnostic imaging (e.g. the 18F-FDG/PET), drug delivery and novel anticancer drug development. Despite the long history of the Warburg effect-targeted cancer diagnosis, other than antibody labeling, there have been no imaging tools developed for direct detection of the GLUT1 expression. Herein, we report the new strategy of using a non-antibody GLUT1 binding probe for Warburg effect-based tumor detection and diagnostic imaging. By specifically inhibits the transport function of GLUT1, the newly designed fluorescent probe, CUM-5, was found to be a useful tool not only for sensitive GLUT1-mediated cancer cell detection, but also for cell-based high-throughput GLUT inhibitor screening. In in vivo studies, CUM-5 shows clear advantages including desirable tumor-to-normal tissue contrast and excellent tumor selectivity (Tm/Bkg and Tm/Torg), as well as high fluorescence stability (long response time) and ideal physiological biocompatibility. In particular, the GLUT1 inhibitor probe offers the potential use for glycolysis-based diagnostic imaging in triple-negative breast cancer which is claimed to have unsatisfactory results with FDG/PET diagnosis, thus remaining a highly metastatic and lethal disease with a need for sensitive and precise identification.
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Affiliation(s)
- Shunjie Zhang
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China
| | - Xinyu Wang
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China
| | - Ru Zhang
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China
| | - Yujun Cui
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China; Transplantation Center, Tianjin First Central Hospital, 24 Fukang Road, Nankai District, Tianjin, 300192, PR China
| | - Heming Zhang
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China; Central Institute of Pharmaceutical Research, CSPC Pharmaceutical Group, 226 Huanhe Road, Shijiazhuang, Hebei, 050035, PR China
| | - Weijie Song
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, West Huanhu Road, Hexi District, Tianjin, 300060, PR China
| | - Xiaohan Hou
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China
| | - Shibo Fu
- Department of Biology, Gudui BioPharma Technology Inc., 5 Lanyuan Road, Huayuan Industrial Park, Tianjin, 300384, PR China
| | - Qingzhi Gao
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China.
| | - Shengnan Liu
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China.
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Chen X, Zhao Y, Lyu S, Gao G, Gao Y, Qi Y, Du J. Identification of novel inhibitors of GLUT1 by virtual screening and cell-based assays. Invest New Drugs 2021; 39:1242-1255. [PMID: 33900490 DOI: 10.1007/s10637-021-01109-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 03/22/2021] [Indexed: 12/14/2022]
Abstract
In order to fuel the uncontrolled cell proliferation and division, tumor cells reprogram the energy metabolism to Warburg effect, where glucose is preferably converted by glycolysis even in the presence of oxygen. However, the high energetic demand of tumor cells require upregulating the expression of glucose transporters, notably GLUT1, which substantially increases glucose uptake into cytoplasm. GLUT1 is overexpressed in a variety of tumor cells and is likely to be a potential drug target in the treatment of pan-cancers. Although many small molecules were reported to inhibit the glucose uptake function by various measurements, several shortcomings such as weak binding affinity, low specificity of the known inhibitors demand the identification of alternative inhibitors with novel scaffolds. In this study, we performed a virtual screening campaign by docking each compound from Chemdiv database to the glucose binding pocket based on the crystal structure of GLUT1 (PDB ID 4PYP) and four small molecules with novel scaffolds were identified to inhibit the glucose uptake of cancer cells at the sub-micromole level. The identified compounds may serve as starting points for the development of anti-cancer drugs via the manipulation of the energy metabolism.
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Affiliation(s)
- Xiaotong Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Yunshuo Zhao
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Sifan Lyu
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Guanfei Gao
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Yanfeng Gao
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China
| | - Yuanming Qi
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Jiangfeng Du
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
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50
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Chen X, Zhao Y, Gao Y, Qi Y, Du J. Outcomes in hepatocellular carcinoma patients undergoing sorafenib treatment: toxicities, cellular oxidative stress, treatment adherence, and quality of life: Erratum. Anticancer Drugs 2021; 32:345-364. [PMID: 33417326 DOI: 10.1097/cad.0000000000001029] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Xiaotong Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Yunshuo Zhao
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Yanfeng Gao
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Yuanming Qi
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Jiangfeng Du
- School of Life Sciences, Zhengzhou University, Zhengzhou
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