|
1
|
Wang X, Rong C, Leng W, Niu P, He Z, Wang G, Qi X, Zhao D, Li J. Effect and mechanism of Dichloroacetate in the treatment of stroke and the resolution strategy for side effect. Eur J Med Res 2025; 30:148. [PMID: 40025562 PMCID: PMC11874805 DOI: 10.1186/s40001-025-02399-5] [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: 12/30/2024] [Accepted: 02/20/2025] [Indexed: 03/04/2025] Open
Abstract
Stroke is a serious disease that leads to high morbidity and mortality, and ischemic stroke accounts for more than 80% of strokes. At present, the only effective drug recombinant tissue plasminogen activator is limited by its indications, and its clinical application rate is not high. Therefore, it is urgent to develop effective new drugs according to the pathological mechanism. In the hypoxic state after ischemic stroke, anaerobic glycolysis has become the main way to provide energy to the brain. This process is essential for the maintenance of important brain functions and has important implications for recovery after stroke. However, acidosis caused by anaerobic glycolysis and lactic acid accumulation is an important pathological process after ischemic stroke. Dichloroacetate (DCA) is an orphan drug that has been used for decades to treat children with genetic mitochondrial diseases. Some studies have confirmed the role of DCA in stroke, but the conclusions are conflicting because some believe that DCA is not effective for ischemic stroke and may aggravate hemorrhagic stroke. This study reviews these studies and finds that DCA has a good effect on ischemic stroke. DCA can protect ischemic stroke by improving oxidative stress, reducing neuroinflammation, inhibiting apoptosis, protecting blood-brain barrier, and regulating metabolism. We also describe the differences in the outcomes of DCA in the treatment of ischemic stroke and the reasons why DCA aggravate hemorrhagic stroke. In addition, DCA, as a water disinfection byproduct, has been concerned about its toxicity. We describe the causes and solutions of peripheral neuropathy caused by DCA. In summary, this study analyzes the neuroprotective mechanism of DCA in ischemic stroke and the contradiction of the different research results, and discusses the causes and solutions of its adverse effects.
Collapse
Affiliation(s)
- Xu Wang
- Department of Encephalopathy, Hospital of Changchun University of Chinese Medicine, Changchun, 130021, Jilin, China
- School of Public Health, Jilin University, Changchun, 130021, Jilin, China
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, Jilin, China
| | - Chunshu Rong
- Department of Encephalopathy, Hospital of Changchun University of Chinese Medicine, Changchun, 130021, Jilin, China
| | - Wei Leng
- Department of Encephalopathy, Hospital of Changchun University of Chinese Medicine, Changchun, 130021, Jilin, China
| | - Ping Niu
- Department of Encephalopathy, Hospital of Changchun University of Chinese Medicine, Changchun, 130021, Jilin, China
| | - Ziqiao He
- School of Public Health, Jilin University, Changchun, 130021, Jilin, China
| | - Gaihua Wang
- School of Public Health, Jilin University, Changchun, 130021, Jilin, China
| | - Xin Qi
- School of Public Health, Jilin University, Changchun, 130021, Jilin, China
| | - Dexi Zhao
- Department of Encephalopathy, Hospital of Changchun University of Chinese Medicine, Changchun, 130021, Jilin, China.
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, Jilin, China.
| | - Jinhua Li
- School of Public Health, Jilin University, Changchun, 130021, Jilin, China.
| |
Collapse
|
|
2
|
Sun M, Wang K, Lu F, Yu D, Liu S. Regulatory role and therapeutic prospect of lactate modification in cancer. Front Pharmacol 2025; 16:1508552. [PMID: 40034817 PMCID: PMC11872897 DOI: 10.3389/fphar.2025.1508552] [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: 10/09/2024] [Accepted: 01/20/2025] [Indexed: 03/05/2025] Open
Abstract
Post-translational modifications (PTMs) of proteins refer to the process of adding chemical groups, sugars, or other molecules to specific residues of target proteins following their biosynthesis by ribosomes. PTMs play a crucial role in processes such as signal transduction, epigenetics, and disease development. Lactylation is a newly discovered PTM that, due to its close association with lactate-the end product of glycolytic metabolism-provides a new perspective on the connection between cellular metabolic reprogramming and epigenetic regulation. Studies have demonstrated that lactylation plays a significant role in tumor progression and is associated with poor clinical prognosis. Abnormal histone lactylation can influence gene expression in both tumor cells and immune cells, thereby regulating tumor progression and immunosuppression. Lactylation of non-histone proteins can also modulate processes such as tumor proliferation and drug resistance. This review summarizes the latest research progress in the field of lactylation, highlighting its roles and mechanisms in tumorigenesis, tumor development, the tumor microenvironment, and immunosuppression. It also explores the potential application value of lactylation in tumor-targeted therapy and combined immunotherapy.
Collapse
Affiliation(s)
- Mengdi Sun
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Kejing Wang
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Fang Lu
- Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Donghua Yu
- Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Shumin Liu
- Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| |
Collapse
|
|
3
|
Baber MA, Gough MD, Yeomans L, Giesler K, Muzzarelli K, Chen CJ, Assar Z, Toogood PL. Identification of a selective pyruvate dehydrogenase kinase 1 (PDHK1) chemical probe by virtual screening. Eur J Med Chem 2025; 284:117210. [PMID: 39742699 DOI: 10.1016/j.ejmech.2024.117210] [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: 11/09/2024] [Revised: 12/16/2024] [Accepted: 12/24/2024] [Indexed: 01/04/2025]
Abstract
PDHK1 is a non-canonical Ser/Thr kinase that negatively regulates the pyruvate dehydrogenase complex (PDC), restricting entry of acetyl-CoA into the tricarboxylic acid (TCA) cycle and downregulating oxidative phosphorylation. In many glycolytic tumors, PDHK1 is overexpressed to suppress activity of the PDC and cause a shift in metabolism toward an increased reliance on glycolysis (the Warburg effect). Genetic studies have shown that knockdown or knockout of PDHK1 reverts this phenotype and inhibits tumor growth in vitro and in vivo, but chemical tools to pharmacologically validate and build upon these data are lacking. We used AtomNet®, a deep convolutional neural network bioactivity predictor, to identify compound 7 as a potential inhibitor of PDHK1. During the process of hit validation, the active species was determined to be isomeric compound 10. Structure-activity studies based on 10 identified 17 as a low μM inhibitor of PDHK1 (IC50 = 1.5 ± 0.3 μM) that is selective against the other PDHK isoforms in both biochemical and cell-based assays. In A549 epithelial lung carcinoma cells, compound 17 inhibits phosphorylation of PDC E1α Ser232, a site that is specifically phosphorylated only by PDHK1, while minimally suppressing phosphorylation of Ser293, a site that is phosphorylated by all four PDHK isoforms. Altogether, these data identify 17 as a selective PDHK1 chemical probe useful for biochemical and cell-based studies.
Collapse
Affiliation(s)
- Mason A Baber
- Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Mya D Gough
- Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Larisa Yeomans
- Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
| | | | | | - Chih-Jung Chen
- Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Zahra Assar
- Cayman Chemical Company, Inc., Ann Arbor, MI, 48108, USA
| | - Peter L Toogood
- Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA; Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
| |
Collapse
|
|
4
|
Ma M, Zhang Y, Pu K, Tang W. Nanomaterial-enabled metabolic reprogramming strategies for boosting antitumor immunity. Chem Soc Rev 2025; 54:653-714. [PMID: 39620588 DOI: 10.1039/d4cs00679h] [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: 01/21/2025]
Abstract
Immunotherapy has become a crucial strategy in cancer treatment, but its effectiveness is often constrained. Most cancer immunotherapies focus on stimulating T-cell-mediated immunity by driving the cancer-immunity cycle, which includes tumor antigen release, antigen presentation, T cell activation, infiltration, and tumor cell killing. However, metabolism reprogramming in the tumor microenvironment (TME) supports the viability of cancer cells and inhibits the function of immune cells within this cycle, presenting clinical challenges. The distinct metabolic needs of tumor cells and immune cells require precise and selective metabolic interventions to maximize therapeutic outcomes while minimizing adverse effects. Recent advances in nanotherapeutics offer a promising approach to target tumor metabolism reprogramming and enhance the cancer-immunity cycle through tailored metabolic modulation. In this review, we explore cutting-edge nanomaterial strategies for modulating tumor metabolism to improve therapeutic outcomes. We review the design principles of nanoplatforms for immunometabolic modulation, key metabolic pathways and their regulation, recent advances in targeting these pathways for the cancer-immunity cycle enhancement, and future prospects for next-generation metabolic nanomodulators in cancer immunotherapy. We expect that emerging immunometabolic modulatory nanotechnology will establish a new frontier in cancer immunotherapy in the near future.
Collapse
Affiliation(s)
- Muye Ma
- Department of Diagnostic Radiology, Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore.
| | - Yongliang Zhang
- Department of Microbiology and Immunology, Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Dr 2, Singapore, 117545, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, 28 Medical Dr, Singapore, 117597, Singapore
| | - Kanyi Pu
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 70 Nanyang Drive, Singapore, 637457, Singapore.
- Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, Singapore, 636921, Singapore
| | - Wei Tang
- Department of Diagnostic Radiology, Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore.
- Department of Pharmacy and Pharmaceutic Sciences, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore
| |
Collapse
|
|
5
|
Luo L, Zhuang X, Fu L, Dong Z, Yi S, Wang K, Jiang Y, Zhao J, Yang X, Hei F. The role of the interplay between macrophage glycolytic reprogramming and NLRP3 inflammasome activation in acute lung injury/acute respiratory distress syndrome. Clin Transl Med 2024; 14:e70098. [PMID: 39623879 PMCID: PMC11612265 DOI: 10.1002/ctm2.70098] [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: 08/10/2024] [Revised: 10/26/2024] [Accepted: 11/04/2024] [Indexed: 12/06/2024] Open
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a severe respiratory condition associated with elevated morbidity and mortality. Understanding their complex pathophysiological mechanisms is crucial for developing new preventive and therapeutic strategies. Recent studies highlight the significant role of inflammation involved in ALI/ARDS, particularly the hyperactivation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome in macrophages. This activation drives pulmonary inflammation by releasing inflammatory signalling molecules and is linked to metabolic reprogramming, marked by increased glycolysis and reduced oxidative phosphorylation. However, the relationship between NLRP3 inflammasome activation and macrophage glycolytic reprogramming in ALI/ARDS, as well as the molecular mechanisms regulating these processes, remain elusive. This review provides a detailed description of the interactions and potential mechanisms linking NLRP3 inflammasome activation with macrophage glycolytic reprogramming, proposing that glycolytic reprogramming may represent a promising therapeutic target for mitigating inflammatory responses in ALI/ARDS. KEY POINTS: NLRP3 inflammasome activation is pivotal in mediating the excessive inflammatory response in ALI/ARDS. Glycolytic reprogramming regulates NLRP3 inflammasome activation. Therapeutic potential of targeting glycolytic reprogramming to inhibit NLRP3 inflammasome activation in ALI/ARDS.
Collapse
Affiliation(s)
- Lan Luo
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Xiaoli Zhuang
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Lin Fu
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Ziyuan Dong
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Shuyuan Yi
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Kan Wang
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Yu Jiang
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Ju Zhao
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Xiaofang Yang
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Feilong Hei
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| |
Collapse
|
|
6
|
Cordani M, Michetti F, Zarrabi A, Zarepour A, Rumio C, Strippoli R, Marcucci F. The role of glycolysis in tumorigenesis: From biological aspects to therapeutic opportunities. Neoplasia 2024; 58:101076. [PMID: 39476482 PMCID: PMC11555605 DOI: 10.1016/j.neo.2024.101076] [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: 08/02/2024] [Revised: 10/13/2024] [Accepted: 10/17/2024] [Indexed: 11/11/2024]
Abstract
Glycolytic metabolism generates energy and intermediates for biomass production. Tumor-associated glycolysis is upregulated compared to normal tissues in response to tumor cell-autonomous or non-autonomous stimuli. The consequences of this upregulation are twofold. First, the metabolic effects of glycolysis become predominant over those mediated by oxidative metabolism. Second, overexpressed components of the glycolytic pathway (i.e. enzymes or metabolites) acquire new functions unrelated to their metabolic effects and which are referred to as "moonlighting" functions. These functions include induction of mutations and other tumor-initiating events, effects on cancer stem cells, induction of increased expression and/or activity of oncoproteins, epigenetic and transcriptional modifications, bypassing of senescence and induction of proliferation, promotion of DNA damage repair and prevention of DNA damage, antiapoptotic effects, inhibition of drug influx or increase of drug efflux. Upregulated metabolic functions and acquisition of new, non-metabolic functions lead to biological effects that support tumorigenesis: promotion of tumor initiation, stimulation of tumor cell proliferation and primary tumor growth, induction of epithelial-mesenchymal transition, autophagy and metastasis, immunosuppressive effects, induction of drug resistance and effects on tumor accessory cells. These effects have negative consequences on the prognosis of tumor patients. On these grounds, it does not come to surprise that tumor-associated glycolysis has become a target of interest in antitumor drug discovery. So far, however, clinical results with glycolysis inhibitors have fallen short of expectations. In this review we propose approaches that may allow to bypass some of the difficulties that have been encountered so far with the therapeutic use of glycolysis inhibitors.
Collapse
Affiliation(s)
- Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University of Madrid, Madrid 28040, Spain; Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid 28040, Spain
| | - Federica Michetti
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161, Italy; Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases L., Spallanzani, IRCCS, Via Portuense, 292, Rome 00149, Italy
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Türkiye; Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan 320315, Taiwan
| | - Atefeh Zarepour
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600 077, India
| | - Cristiano Rumio
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Trentacoste 2, Milan 20134, Italy
| | - Raffaele Strippoli
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161, Italy; Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases L., Spallanzani, IRCCS, Via Portuense, 292, Rome 00149, Italy.
| | - Fabrizio Marcucci
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Trentacoste 2, Milan 20134, Italy.
| |
Collapse
|
|
7
|
Kamble OS, Chatterjee R, Abishek KG, Chandra J, Alsayari A, Wahab S, Sahebkar A, Kesharwani P, Dandela R. Small molecules targeting mitochondria as an innovative approach to cancer therapy. Cell Signal 2024; 124:111396. [PMID: 39251050 DOI: 10.1016/j.cellsig.2024.111396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 09/03/2024] [Accepted: 09/06/2024] [Indexed: 09/11/2024]
Abstract
Cellular death evasion is a defining characteristic of human malignancies and a significant contributor to therapeutic inefficacy. As a result of oncogenic inhibition of cell death mechanisms, established therapeutic regimens seems to be ineffective. Mitochondria serve as the cellular powerhouses, but they also function as repositories of self-destructive weaponry. Changes in the structure and activities of mitochondria have been consistently documented in cancer cells. In recent years, there has been an increasing focus on using mitochondria as a targeted approach for treating cancer. Considerable attention has been devoted to the development of delivery systems that selectively aim to deliver small molecules called "mitocans" to mitochondria, with the ultimate goal of modulating the physiology of cancer cells. This review summarizes the rationale and mechanism of mitochondrial targeting with small molecules in the treatment of cancer, and their impact on the mitochondria. This paper provides a concise overview of the reasoning and mechanism behind directing treatment towards mitochondria in cancer therapy, with a particular focus on targeting using small molecules. This review also examines diverse small molecule types within each category as potential therapeutic agents for cancer.
Collapse
Affiliation(s)
- Omkar S Kamble
- Department of Industrial and Engineering Chemistry, Institute of Chemical Technology, Indian Oil Odisha Campus, Samantpuri, Bhubaneswar 751013, India
| | - Rana Chatterjee
- Department of Industrial and Engineering Chemistry, Institute of Chemical Technology, Indian Oil Odisha Campus, Samantpuri, Bhubaneswar 751013, India
| | - K G Abishek
- Department of Industrial and Engineering Chemistry, Institute of Chemical Technology, Indian Oil Odisha Campus, Samantpuri, Bhubaneswar 751013, India
| | - Jyoti Chandra
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Abdulrhman Alsayari
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
| | - Rambabu Dandela
- Department of Industrial and Engineering Chemistry, Institute of Chemical Technology, Indian Oil Odisha Campus, Samantpuri, Bhubaneswar 751013, India.
| |
Collapse
|
|
8
|
Sánchez-Castillo A, Savelkouls KG, Baldini A, Hounjet J, Sonveaux P, Verstraete P, De Keersmaecker K, Dewaele B, Björkblom B, Melin B, Wu WY, Sjöberg RL, Rouschop KMA, Broen MPG, Vooijs M, Kampen KR. Sertraline/chloroquine combination therapy to target hypoxic and immunosuppressive serine/glycine synthesis-dependent glioblastomas. Oncogenesis 2024; 13:39. [PMID: 39537592 PMCID: PMC11561346 DOI: 10.1038/s41389-024-00540-3] [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: 03/25/2024] [Revised: 10/29/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024] Open
Abstract
The serine/glycine (ser/gly) synthesis pathway branches from glycolysis and is hyperactivated in approximately 30% of cancers. In ~13% of glioblastoma cases, we observed frequent amplifications and rare mutations in the gene encoding the enzyme PSPH, which catalyzes the last step in the synthesis of serine. This urged us to unveil the relevance of PSPH genetic alterations and subsequent ser/gly metabolism deregulation in the pathogenesis of glioblastoma. Primary glioblastoma cells overexpressing PSPH and PSPHV116I showed an increased clonogenic capacity, cell proliferation, and migration, supported by elevated nucleotide synthesis and utilization of reductive NAD(P). We previously identified sertraline as an inhibitor of ser/gly synthesis and explored its efficacy at suboptimal dosages in combination with the clinically pretested chloroquine to target ser/glyhigh glioblastoma models. Interestingly, ser/glyhigh glioblastomas, including PSPHamp and PSPHV116I, displayed selective synergistic inhibition of proliferation in response to combination therapy. PSPH knockdown severely affected ser/glyhigh glioblastoma clonogenicity and proliferation, while simultaneously increasing its sensitivity to chloroquine treatment. Metabolite landscaping revealed that sertraline/chloroquine combination treatment blocks NADH and ATP generation and restricts nucleotide synthesis, thereby inhibiting glioblastoma proliferation. Our previous studies highlight ser/glyhigh cancer cell modulation of its microenvironment at the level of immune suppression. To this end, high PSPH expression predicts poor immune checkpoint therapy responses in glioblastoma patients. Interestingly, we show that PSPH amplifications in glioblastoma facilitate the expression of immune suppressor galectin-1, which can be inhibited by sertraline treatment. Collectively, we revealed that ser/glyhigh glioblastomas are characterized by enhanced clonogenicity, migration, and suppression of the immune system, which could be tackled using combined sertraline/chloroquine treatment, revealing novel therapeutic opportunities for this subgroup of GBM patients.
Collapse
Affiliation(s)
- Anaís Sánchez-Castillo
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Kim G Savelkouls
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Alessandra Baldini
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Judith Hounjet
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Pierre Sonveaux
- Pole of Pharmacology, Institut de Recherche Experimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Brussels, Belgium
- WEL Research Institute, WELBIO Department, Wavre, Belgium
| | - Paulien Verstraete
- Department of Oncology, Laboratory for Disease Mechanisms in Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Kim De Keersmaecker
- Department of Oncology, Laboratory for Disease Mechanisms in Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Barbara Dewaele
- Center for Human Genetics, Laboratory for Genetics of Malignant Disorders, University Hospitals Leuven and KU Leuven, Leuven, Belgium
| | | | - Beatrice Melin
- Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden
| | - Wendy Y Wu
- Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden
| | - Rickard L Sjöberg
- Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden
| | - Kasper M A Rouschop
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Martijn P G Broen
- Department of Neurology, GROW School for Oncology and Reproduction, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Marc Vooijs
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Kim R Kampen
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands.
- Department of Oncology, Laboratory for Disease Mechanisms in Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
| |
Collapse
|
|
9
|
Ronghe R, Tavares AAS. The skeleton: an overlooked regulator of systemic glucose metabolism in cancer? Front Oncol 2024; 14:1481241. [PMID: 39588310 PMCID: PMC11586348 DOI: 10.3389/fonc.2024.1481241] [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: 08/15/2024] [Accepted: 10/22/2024] [Indexed: 11/27/2024] Open
Abstract
Recent discoveries demonstrated the skeleton's role as an endocrine organ regulating whole-body glucose homeostasis. Glucose metabolism is critical for rapid cell proliferation and tumour growth through increasing glucose uptake and fermentation of glucose to lactate despite being in an aerobic environment. This hypothesis paper discusses emerging evidence on how bones can regulate whole-body glucose homeostasis with potential to impact on tumour growth and proliferation. Moreover, it proposes a clinical link between bone glucose metabolism and prognosis of cancer based on recent clinical trial data. Targeting metabolic pathways related with classic glucose metabolism and also bone metabolism, novel methods of cancer therapy and treatment could be developed. This paper objective is to highlight the need for future research on this altered metabolism with potential to change future management of cancer patients.
Collapse
Affiliation(s)
- Rucha Ronghe
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, United Kingdom
| | - Adriana A. S. Tavares
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Queens Medical Research Institute, Edinburgh, United Kingdom
- Edinburgh Imaging, The University of Edinburgh, Queens Medical Research Institute, Edinburgh, United Kingdom
| |
Collapse
|
|
10
|
Liu J, Zhao F, Qu Y. Lactylation: A Novel Post-Translational Modification with Clinical Implications in CNS Diseases. Biomolecules 2024; 14:1175. [PMID: 39334941 PMCID: PMC11430557 DOI: 10.3390/biom14091175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/06/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
Lactate, an important metabolic product, provides energy to neural cells during energy depletion or high demand and acts as a signaling molecule in the central nervous system. Recent studies revealed that lactate-mediated protein lactylation regulates gene transcription and influences cell fate, metabolic processes, inflammation, and immune responses. This review comprehensively examines the regulatory roles and mechanisms of lactylation in neurodevelopment, neuropsychiatric disorders, brain tumors, and cerebrovascular diseases. This analysis indicates that lactylation has multifaceted effects on central nervous system function and pathology, particularly in hypoxia-induced brain damage. Highlighting its potential as a novel therapeutic target, lactylation may play a significant role in treating neurological diseases. By summarizing current findings, this review aims to provide insights and guide future research and clinical strategies for central nervous system disorders.
Collapse
Affiliation(s)
- Junyan Liu
- Department of Pediatrics/Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education)/NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu 610041, China
- Neonatal Intensive Care Unit, Binzhou Medical University Hospital, Binzhou 256600, China
| | - Fengyan Zhao
- Department of Pediatrics/Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education)/NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Yi Qu
- Department of Pediatrics/Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education)/NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| |
Collapse
|
|
11
|
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.
Collapse
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.
| |
Collapse
|
|
12
|
ZHANG Q, CAO L, XU K. [Role and Mechanism of Lactylation in Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2024; 27:471-479. [PMID: 39026499 PMCID: PMC11258650 DOI: 10.3779/j.issn.1009-3419.2024.102.20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Indexed: 07/20/2024]
Abstract
Post translational modifications (PTMs) can change the properties of a protein by covalent addition of functional groups to one or more amino acids, and influence almost all aspects of normal cell biology and pathogenesis. Lactylation is a novel identified PTM, and has been found in both histone and non-histone proteins. Since associated with the end product of glycolysis-- lactate, lactylation modification could provide a new perspective for understanding the relationship between metabolic reprogramming and epigenetic modifications. Accumulated evidences suggest that lactylation play important roles in tumor progression and links to poor prognosis in clinical studies. Histone lactylation can affect gene expression in tumor cells and immunological cells, further promoting tumor progression and immune suppression. Lactylation on non-histone proteins can also regulate tumor progression and drug resistance. In this review, we aimed to summarize the roles of lactylation in cancer progression, microenvironment interactions and immune suppression, try to identify new molecular targets for cancer therapy and provide a new direction for combined targeted therapy and immunotherapy.
.
Collapse
|
|
13
|
Koltai T, Fliegel L. Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts. Pharmaceuticals (Basel) 2024; 17:744. [PMID: 38931411 PMCID: PMC11206832 DOI: 10.3390/ph17060744] [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: 03/28/2024] [Revised: 05/23/2024] [Accepted: 06/04/2024] [Indexed: 06/28/2024] Open
Abstract
Rarely has a chemical elicited as much controversy as dichloroacetate (DCA). DCA was initially considered a dangerous toxic industrial waste product, then a potential treatment for lactic acidosis. However, the main controversies started in 2008 when DCA was found to have anti-cancer effects on experimental animals. These publications showed contradictory results in vivo and in vitro such that a thorough consideration of this compound's in cancer is merited. Despite 50 years of experimentation, DCA's future in therapeutics is uncertain. Without adequate clinical trials and health authorities' approval, DCA has been introduced in off-label cancer treatments in alternative medicine clinics in Canada, Germany, and other European countries. The lack of well-planned clinical trials and its use by people without medical training has discouraged consideration by the scientific community. There are few thorough clinical studies of DCA, and many publications are individual case reports. Case reports of DCA's benefits against cancer have been increasing recently. Furthermore, it has been shown that DCA synergizes with conventional treatments and other repurposable drugs. Beyond the classic DCA target, pyruvate dehydrogenase kinase, new target molecules have also been recently discovered. These findings have renewed interest in DCA. This paper explores whether existing evidence justifies further research on DCA for cancer treatment and it explores the role DCA may play in it.
Collapse
Affiliation(s)
- Tomas Koltai
- Hospital del Centro Gallego de Buenos Aires, Buenos Aires 2199, Argentina
| | - Larry Fliegel
- Department of Biochemistry, University Alberta, Edmonton, AB T6G 2H7, Canada;
| |
Collapse
|
|
14
|
Chen S, Xu Y, Zhuo W, Zhang L. The emerging role of lactate in tumor microenvironment and its clinical relevance. Cancer Lett 2024; 590:216837. [PMID: 38548215 DOI: 10.1016/j.canlet.2024.216837] [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: 01/28/2024] [Revised: 03/16/2024] [Accepted: 03/25/2024] [Indexed: 04/12/2024]
Abstract
In recent years, the significant impact of lactate in the tumor microenvironment has been greatly documented. Acting not only as an energy substance in tumor metabolism, lactate is also an imperative signaling molecule. It plays key roles in metabolic remodeling, protein lactylation, immunosuppression, drug resistance, epigenetics and tumor metastasis, which has a tight relation with cancer patients' poor prognosis. This review illustrates the roles lactate plays in different aspects of tumor progression and drug resistance. From the comprehensive effects that lactate has on tumor metabolism and tumor immunity, the therapeutic targets related to it are expected to bring new hope for cancer therapy.
Collapse
Affiliation(s)
- Sihan Chen
- Department of Cell Biology and Department of Colorectal Surgery and Oncology, Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China; Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Yining Xu
- Department of Cell Biology and Department of Colorectal Surgery and Oncology, Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China; Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Wei Zhuo
- Department of Cell Biology and Department of Colorectal Surgery and Oncology, Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China; Institute of Gastroenterology, Zhejiang University, Hangzhou, China.
| | - Lu Zhang
- Department of Cell Biology and Department of Colorectal Surgery and Oncology, Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China; Institute of Gastroenterology, Zhejiang University, Hangzhou, China.
| |
Collapse
|
|
15
|
Carswell G, Chamberlin J, Bennett BD, Bushel PR, Chorley BN. Persistent gene expression and DNA methylation alterations linked to carcinogenic effects of dichloroacetic acid. Front Oncol 2024; 14:1389634. [PMID: 38764585 PMCID: PMC11099211 DOI: 10.3389/fonc.2024.1389634] [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: 02/22/2024] [Accepted: 04/18/2024] [Indexed: 05/21/2024] Open
Abstract
Background Mechanistic understanding of transient exposures that lead to adverse health outcomes will enhance our ability to recognize biological signatures of disease. Here, we measured the transcriptomic and epigenomic alterations due to exposure to the metabolic reprogramming agent, dichloroacetic acid (DCA). Previously, we showed that exposure to DCA increased liver tumor incidence in B6C3F1 mice after continuous or early life exposures significantly over background level. Methods Using archived formalin-fixed liver samples, we utilized modern methodologies to measure gene expression and DNA methylation levels to link to previously generated phenotypic measures. Gene expression was measured by targeted RNA sequencing (TempO-seq 1500+ toxicity panel: 2754 total genes) in liver samples collected from 10-, 32-, 57-, and 78-week old mice exposed to deionized water (controls), 3.5 g/L DCA continuously in drinking water ("Direct" group), or DCA for 10-, 32-, or 57-weeks followed by deionized water until sample collection ("Stop" groups). Genome-scaled alterations in DNA methylation were measured by Reduced Representation Bisulfite Sequencing (RRBS) in 78-week liver samples for control, Direct, 10-week Stop DCA exposed mice. Results Transcriptomic changes were most robust with concurrent or adjacent timepoints after exposure was withdrawn. We observed a similar pattern with DNA methylation alterations where we noted attenuated differentially methylated regions (DMRs) in the 10-week Stop DCA exposure groups compared to the Direct group at 78-weeks. Gene pathway analysis indicated cellular effects linked to increased oxidative metabolism, a primary mechanism of action for DCA, closer to exposure windows especially early in life. Conversely, many gene signatures and pathways reversed patterns later in life and reflected more pro-tumorigenic patterns for both current and prior DCA exposures. DNA methylation patterns correlated to early gene pathway perturbations, such as cellular signaling, regulation and metabolism, suggesting persistence in the epigenome and possible regulatory effects. Conclusion Liver metabolic reprogramming effects of DCA interacted with normal age mechanisms, increasing tumor burden with both continuous and prior DCA exposure in the male B6C3F1 rodent model.
Collapse
Affiliation(s)
- Gleta Carswell
- Center for Computational Toxicology and Exposure, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States
| | - John Chamberlin
- Center for Computational Toxicology and Exposure, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States
- Oak Ridge Institute for Science and Education, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States
| | - Brian D. Bennett
- Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, United States
| | - Pierre R. Bushel
- Massive Genome Informatics Group, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, United States
- Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, United States
| | - Brian N. Chorley
- Center for Computational Toxicology and Exposure, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States
| |
Collapse
|
|
16
|
Zhang Y, Sun M, Zhao H, Wang Z, Shi Y, Dong J, Wang K, Wang X, Li X, Qi H, Zhao X. Neuroprotective Effects and Therapeutic Potential of Dichloroacetate: Targeting Metabolic Disorders in Nervous System Diseases. Int J Nanomedicine 2023; 18:7559-7581. [PMID: 38106446 PMCID: PMC10725694 DOI: 10.2147/ijn.s439728] [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: 09/15/2023] [Accepted: 11/28/2023] [Indexed: 12/19/2023] Open
Abstract
Dichloroacetate (DCA) is an investigational drug used to treat lactic acidosis and malignant tumours. It works by inhibiting pyruvate dehydrogenase kinase and increasing the rate of glucose oxidation. Some studies have documented the neuroprotective benefits of DCA. By reviewing these studies, this paper shows that DCA has multiple pharmacological activities, including regulating metabolism, ameliorating oxidative stress, attenuating neuroinflammation, inhibiting apoptosis, decreasing autophagy, protecting the blood‒brain barrier, improving the function of endothelial progenitor cells, improving mitochondrial dynamics, and decreasing amyloid β-protein. In addition, DCA inhibits the enzyme that metabolizes it, which leads to peripheral neurotoxicity due to drug accumulation that may be solved by individualized drug delivery and nanovesicle delivery. In summary, in this review, we analyse the mechanisms of neuroprotection by DCA in different diseases and discuss the causes of and solutions to its adverse effects.
Collapse
Affiliation(s)
- Yue Zhang
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Meiyan Sun
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Hongxiang Zhao
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Zhengyan Wang
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Yanan Shi
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Jianxin Dong
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Kaifang Wang
- Department of Anesthesia, Tangdu Hospital, Fourth Military Medical University, Xian, Shanxi Province, People’s Republic of China
| | - Xi Wang
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China
| | - Xingyue Li
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
| | - Haiyan Qi
- Department of Anesthesiology, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, People’s Republic of China
| | - Xiaoyong Zhao
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China
- Department of Anesthesiology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China
| |
Collapse
|
|
17
|
Stacpoole PW. Clinical physiology and pharmacology of GSTZ1/MAAI. Biochem Pharmacol 2023; 217:115818. [PMID: 37742772 DOI: 10.1016/j.bcp.2023.115818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 09/05/2023] [Accepted: 09/21/2023] [Indexed: 09/26/2023]
Abstract
Herein I summarize the physiological chemistry and pharmacology of the bifunctional enzyme glutathione transferase zeta 1 (GSTZ1)/ maleylacetoacetate isomerase (MAAI) relevant to human physiology, drug metabolism and disease. MAAI is integral to the catabolism of the amino acids phenylalanine and tyrosine. Genetic or pharmacological inhibition of MAAI can be pathological in animals. However, to date, no clinical disease consequences are unequivocally attributable to inborn errors of this enzyme. MAAI is identical to the zeta 1 family isoform of GST, which biotransforms the investigational drug dichloroacetate (DCA) to the endogenous compound glyoxylate. DCA is a mechanism-based inhibitor of GSTZ1 that significantly reduces its rate of metabolism and increases accumulation of potentially harmful tyrosine intermediates and of the heme precursor δ-aminolevulinic acid (δ-ALA). GSTZ1 is most abundant in rodent and human liver, with its concentration several fold higher in cytoplasm than in mitochondria. Its activity and protein expression are dependent on the age of the host and the intracellular level of chloride ions. Gene association studies have linked GSTZ1 or its protein product to various physiological traits and pathologies. Haplotype variations in GSTZ1 influence the rate of DCA metabolism, enabling a genotyping strategy to allow potentially safe, precision-based drug dosing in clinical trials.
Collapse
Affiliation(s)
- Peter W Stacpoole
- Departments of Medicine and Biochemistry and Molecular Biology, University of Florida, College of Medicine, Gainesville, FL 32601, USA.
| |
Collapse
|
|
18
|
Schoenmann N, Tannenbaum N, Hodgeman RM, Raju RP. Regulating mitochondrial metabolism by targeting pyruvate dehydrogenase with dichloroacetate, a metabolic messenger. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166769. [PMID: 37263447 PMCID: PMC10776176 DOI: 10.1016/j.bbadis.2023.166769] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/20/2023] [Accepted: 05/26/2023] [Indexed: 06/03/2023]
Abstract
Dichloroacetate (DCA) is a naturally occurring xenobiotic that has been used as an investigational drug for over 50 years. Originally found to lower blood glucose levels and alter fat metabolism in diabetic rats, this small molecule was found to serve primarily as a pyruvate dehydrogenase kinase inhibitor. Pyruvate dehydrogenase kinase inhibits pyruvate dehydrogenase complex, the catalyst for oxidative decarboxylation of pyruvate to produce acetyl coenzyme A. Several congenital and acquired disease states share a similar pathobiology with respect to glucose homeostasis under distress that leads to a preferential shift from the more efficient oxidative phosphorylation to glycolysis. By reversing this process, DCA can increase available energy and reduce lactic acidosis. The purpose of this review is to examine the literature surrounding this metabolic messenger as it presents exciting opportunities for future investigation and clinical application in therapy including cancer, metabolic disorders, cerebral ischemia, trauma, and sepsis.
Collapse
Affiliation(s)
- Nick Schoenmann
- Department of Emergency Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Nicholas Tannenbaum
- Department of Emergency Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Ryan M Hodgeman
- Department of Emergency Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Raghavan Pillai Raju
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States of America.
| |
Collapse
|
|
19
|
Denisova OV, Merisaari J, Huhtaniemi R, Qiao X, Yetukuri L, Jumppanen M, Kaur A, Pääkkönen M, von Schantz‐Fant С, Ohlmeyer M, Wennerberg K, Kauko O, Koch R, Aittokallio T, Taipale M, Westermarck J. PP2A-based triple-strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells. Mol Oncol 2023; 17:1803-1820. [PMID: 37458534 PMCID: PMC10483611 DOI: 10.1002/1878-0261.13488] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 05/08/2023] [Accepted: 07/13/2023] [Indexed: 07/27/2023] Open
Abstract
Mitochondrial glycolysis and hyperactivity of the phosphatidylinositol 3-kinase-protein kinase B (AKT) pathway are hallmarks of malignant brain tumors. However, kinase inhibitors targeting AKT (AKTi) or the glycolysis master regulator pyruvate dehydrogenase kinase (PDKi) have failed to provide clinical benefits for brain tumor patients. Here, we demonstrate that heterogeneous glioblastoma (GB) and medulloblastoma (MB) cell lines display only cytostatic responses to combined AKT and PDK targeting. Biochemically, the combined AKT and PDK inhibition resulted in the shutdown of both target pathways and priming to mitochondrial apoptosis but failed to induce apoptosis. In contrast, all tested brain tumor cell models were sensitive to a triplet therapy, in which AKT and PDK inhibition was combined with the pharmacological reactivation of protein phosphatase 2A (PP2A) by NZ-8-061 (also known as DT-061), DBK-1154, and DBK-1160. We also provide proof-of-principle evidence for in vivo efficacy in the intracranial GB and MB models by the brain-penetrant triplet therapy (AKTi + PDKi + PP2A reactivator). Mechanistically, PP2A reactivation converted the cytostatic AKTi + PDKi response to cytotoxic apoptosis, through PP2A-elicited shutdown of compensatory mitochondrial oxidative phosphorylation and by increased proton leakage. These results encourage the development of triple-strike strategies targeting mitochondrial metabolism to overcome therapy tolerance in brain tumors.
Collapse
Affiliation(s)
- Oxana V. Denisova
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
| | - Joni Merisaari
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
- Institute of BiomedicineUniversity of TurkuFinland
| | - Riikka Huhtaniemi
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
| | - Xi Qiao
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
| | - Laxman Yetukuri
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
- Institute for Molecular Medicine Finland (FIMM), HiLIFEUniversity of HelsinkiFinland
- Centre for Biostatistics and Epidemiology (OCBE)University of OsloNorway
| | - Mikael Jumppanen
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
| | - Amanpreet Kaur
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
| | - Mirva Pääkkönen
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
| | | | - Michael Ohlmeyer
- Icahn School of Medicine at Mount SinaiNew YorkNYUSA
- Atux Iskay LLCPlainsboroNJUSA
| | - Krister Wennerberg
- Institute for Molecular Medicine Finland (FIMM), HiLIFEUniversity of HelsinkiFinland
- Biotech Research & Innovation CentreUniversity of CopenhagenDenmark
| | - Otto Kauko
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
| | | | - Tero Aittokallio
- Institute for Molecular Medicine Finland (FIMM), HiLIFEUniversity of HelsinkiFinland
- Centre for Biostatistics and Epidemiology (OCBE)University of OsloNorway
- Institute for Cancer ResearchOslo University HospitalNorway
| | - Mikko Taipale
- Donnelly Centre for Cellular and Biomolecular ResearchUniversity of TorontoCanada
| | - Jukka Westermarck
- Turku Bioscience CentreUniversity of Turku and Åbo Akademi UniversityFinland
- Institute of BiomedicineUniversity of TurkuFinland
| |
Collapse
|
|
20
|
Su J, Zheng Z, Bian C, Chang S, Bao J, Yu H, Xin Y, Jiang X. Functions and mechanisms of lactylation in carcinogenesis and immunosuppression. Front Immunol 2023; 14:1253064. [PMID: 37646027 PMCID: PMC10461103 DOI: 10.3389/fimmu.2023.1253064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 07/31/2023] [Indexed: 09/01/2023] Open
Abstract
As critical executors regulating many cellular operations, proteins determine whether living activities can be performed in an orderly and efficient manner. Precursor proteins are inert and must be modified posttranslationally to enable a wide range of protein types and functions. Protein posttranslational modifications (PTMs) are well recognized as being directly associated with carcinogenesis and immune modulation and have emerged as important targets for cancer detection and treatment. Lactylation (Kla), a novel PTM associated with cellular metabolism found in a wide range of cells, interacts with both histone and nonhistone proteins. Unlike other epigenetic changes, Kla has been linked to poor tumor prognosis in all current studies. Histone Kla can affect gene expression in tumors and immunological cells, thereby promoting malignancy and immunosuppression. Nonhistone proteins can also regulate tumor progression and treatment resistance through Kla. In this review, we aimed to summarize the role of Kla in the onset and progression of cancers, metabolic reprogramming, immunosuppression, and intestinal flora regulation to identify new molecular targets for cancer therapy and provide a new direction for combined targeted therapy and immunotherapy.
Collapse
Affiliation(s)
- Jing Su
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China
- NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, China
| | - Zhuangzhuang Zheng
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China
- NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, China
| | - Chenbin Bian
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China
- NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, China
| | - Sitong Chang
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China
- NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, China
| | - Jindian Bao
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China
- NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, China
| | - Huiyuan Yu
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China
- NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, China
| | - Ying Xin
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Xin Jiang
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China
- NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, China
| |
Collapse
|
|
21
|
Martell E, Kuzmychova H, Senthil H, Kaul E, Chokshi CR, Venugopal C, Anderson CM, Singh SK, Sharif T. Compensatory cross-talk between autophagy and glycolysis regulates senescence and stemness in heterogeneous glioblastoma tumor subpopulations. Acta Neuropathol Commun 2023; 11:110. [PMID: 37420311 PMCID: PMC10327182 DOI: 10.1186/s40478-023-01604-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 06/16/2023] [Indexed: 07/09/2023] Open
Abstract
Despite tremendous research efforts, successful targeting of aberrant tumor metabolism in clinical practice has remained elusive. Tumor heterogeneity and plasticity may play a role in the clinical failure of metabolism-targeting interventions for treating cancer patients. Moreover, compensatory growth-related processes and adaptive responses exhibited by heterogeneous tumor subpopulations to metabolic inhibitors are poorly understood. Here, by using clinically-relevant patient-derived glioblastoma (GBM) cell models, we explore the cross-talk between glycolysis, autophagy, and senescence in maintaining tumor stemness. We found that stem cell-like GBM tumor subpopulations possessed higher basal levels of glycolytic activity and increased expression of several glycolysis-related enzymes including, GLUT1/SLC2A1, PFKP, ALDOA, GAPDH, ENO1, PKM2, and LDH, compared to their non-stem-like counterparts. Importantly, bioinformatics analysis also revealed that the mRNA expression of glycolytic enzymes positively correlates with stemness markers (CD133/PROM1 and SOX2) in patient GBM tumors. While treatment with glycolysis inhibitors induced senescence in stem cell-like GBM tumor subpopulations, as evidenced by increased β-galactosidase staining and upregulation of the cell cycle regulators p21Waf1/Cip1/CDKN1A and p16INK4A/CDKN2A, these cells maintained their aggressive stemness features and failed to undergo apoptotic cell death. Using various techniques including autophagy flux and EGFP-MAP1LC3B+ puncta formation analysis, we determined that inhibition of glycolysis led to the induction of autophagy in stem cell-like GBM tumor subpopulations, but not in their non-stem-like counterparts. Similarly, blocking autophagy in stem cell-like GBM tumor subpopulations induced senescence-associated growth arrest without hampering stemness capacity or inducing apoptosis while reciprocally upregulating glycolytic activity. Combinatorial treatment of stem cell-like GBM tumor subpopulations with autophagy and glycolysis inhibitors blocked the induction of senescence while drastically impairing their stemness capacity which drove cells towards apoptotic cell death. These findings identify a novel and complex compensatory interplay between glycolysis, autophagy, and senescence that helps maintain stemness in heterogeneous GBM tumor subpopulations and provides a survival advantage during metabolic stress.
Collapse
Affiliation(s)
- Emma Martell
- Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Helgi Kuzmychova
- Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Harshal Senthil
- Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Esha Kaul
- Faculty of Science, University of Manitoba, Winnipeg, MB, Canada
| | - Chirayu R Chokshi
- Department of Biochemistry, McMaster University, Hamilton, ON, Canada
| | - Chitra Venugopal
- Department of Surgery, McMaster University, Hamilton, ON, Canada
| | - Christopher M Anderson
- Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Health Sciences Centre, Winnipeg, MB, Canada
| | - Sheila K Singh
- Department of Biochemistry, McMaster University, Hamilton, ON, Canada
- Department of Surgery, McMaster University, Hamilton, ON, Canada
| | - Tanveer Sharif
- Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
| |
Collapse
|
|
22
|
Lei P, Wang W, Sheldon M, Sun Y, Yao F, Ma L. Role of Glucose Metabolic Reprogramming in Breast Cancer Progression and Drug Resistance. Cancers (Basel) 2023; 15:3390. [PMID: 37444501 PMCID: PMC10341343 DOI: 10.3390/cancers15133390] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/26/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
The involvement of glucose metabolic reprogramming in breast cancer progression, metastasis, and therapy resistance has been increasingly appreciated. Studies in recent years have revealed molecular mechanisms by which glucose metabolic reprogramming regulates breast cancer. To date, despite a few metabolism-based drugs being tested in or en route to clinical trials, no drugs targeting glucose metabolism pathways have yet been approved to treat breast cancer. Here, we review the roles and mechanisms of action of glucose metabolic reprogramming in breast cancer progression and drug resistance. In addition, we summarize the currently available metabolic inhibitors targeting glucose metabolism and discuss the challenges and opportunities in targeting this pathway for breast cancer treatment.
Collapse
Affiliation(s)
- Pan Lei
- Hubei Hongshan Laboratory, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China; (P.L.); (W.W.)
- Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Wenzhou Wang
- Hubei Hongshan Laboratory, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China; (P.L.); (W.W.)
| | - Marisela Sheldon
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Yutong Sun
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Fan Yao
- Hubei Hongshan Laboratory, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China; (P.L.); (W.W.)
- Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural University, Shenzhen 518000, China
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518000, China
| | - Li Ma
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston TX 77030, USA
| |
Collapse
|
|
23
|
The "Superoncogene" Myc at the Crossroad between Metabolism and Gene Expression in Glioblastoma Multiforme. Int J Mol Sci 2023; 24:ijms24044217. [PMID: 36835628 PMCID: PMC9966483 DOI: 10.3390/ijms24044217] [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: 12/30/2022] [Revised: 02/10/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
The concept of the Myc (c-myc, n-myc, l-myc) oncogene as a canonical, DNA-bound transcription factor has consistently changed over the past few years. Indeed, Myc controls gene expression programs at multiple levels: directly binding chromatin and recruiting transcriptional coregulators; modulating the activity of RNA polymerases (RNAPs); and drawing chromatin topology. Therefore, it is evident that Myc deregulation in cancer is a dramatic event. Glioblastoma multiforme (GBM) is the most lethal, still incurable, brain cancer in adults, and it is characterized in most cases by Myc deregulation. Metabolic rewiring typically occurs in cancer cells, and GBM undergoes profound metabolic changes to supply increased energy demand. In nontransformed cells, Myc tightly controls metabolic pathways to maintain cellular homeostasis. Consistently, in Myc-overexpressing cancer cells, including GBM cells, these highly controlled metabolic routes are affected by enhanced Myc activity and show substantial alterations. On the other hand, deregulated cancer metabolism impacts Myc expression and function, placing Myc at the intersection between metabolic pathway activation and gene expression. In this review paper, we summarize the available information on GBM metabolism with a specific focus on the control of the Myc oncogene that, in turn, rules the activation of metabolic signals, ensuring GBM growth.
Collapse
|
|
24
|
Marco-Brualla J, de Miguel D, Martínez-Lostao L, Anel A. DR5 Up-Regulation Induced by Dichloroacetate Sensitizes Tumor Cells to Lipid Nanoparticles Decorated with TRAIL. J Clin Med 2023; 12:jcm12020608. [PMID: 36675536 PMCID: PMC9864242 DOI: 10.3390/jcm12020608] [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: 12/13/2022] [Revised: 01/04/2023] [Accepted: 01/10/2023] [Indexed: 01/14/2023] Open
Abstract
Cancer resistance to treatments is a challenge that researchers constantly seek to overcome. For instance, TNF-related apoptosis-inducing ligand (TRAIL) is a potential good prospect as an anti-cancer therapy, as it attacks tumor cells but not normal cells. However, treatments based in soluble TRAIL provided incomplete clinical results and diverse formulations have been developed to improve its bioactivity. In previous works, we generated a new TRAIL formulation based in its attachment to the surface of unilamellar nanoliposomes (LUV-TRAIL). This formulation greatly increased apoptosis in a wide selection of tumor cell types, albeit a few of them remained resistant. On the other hand, it has been described that a metabolic shift in cancer cells can also alter its sensitivity to other treatments. In this work, we sought to increase the sensitivity of several tumor cell types resistant to LUV-TRAIL by previous exposure to the metabolic drug dichloroacetate (DCA), which forces oxidative phosphorylation. Results showed that DCA + LUV-TRAIL had a synergistic effect on both lung adenocarcinoma A549, colorectal HT29, and breast cancer MCF7 cells. Despite DCA inducing intracellular changes in a cell-type specific way, the increase in cell death by apoptosis was clearly correlated with an increase in death receptor 5 (DR5) surface expression in all cell lines. Therefore, DCA-induced metabolic shift emerges as a suitable option to overcome TRAIL resistance in cancer cells.
Collapse
Affiliation(s)
- Joaquín Marco-Brualla
- Apoptosis, Immunity and Cancer Group, Department of Biochemistry and Molecular and Cell Biology, Aragon Health Research Institute (IIS-Aragón) & University of Zaragoza, 50009 Zargoza, Spain
| | - Diego de Miguel
- Apoptosis, Immunity and Cancer Group, Department of Biochemistry and Molecular and Cell Biology, Aragon Health Research Institute (IIS-Aragón) & University of Zaragoza, 50009 Zargoza, Spain
| | | | - Alberto Anel
- Apoptosis, Immunity and Cancer Group, Department of Biochemistry and Molecular and Cell Biology, Aragon Health Research Institute (IIS-Aragón) & University of Zaragoza, 50009 Zargoza, Spain
- Correspondence:
| |
Collapse
|
|
25
|
Pal S, Sharma A, Mathew SP, Jaganathan BG. Targeting cancer-specific metabolic pathways for developing novel cancer therapeutics. Front Immunol 2022; 13:955476. [PMID: 36618350 PMCID: PMC9815821 DOI: 10.3389/fimmu.2022.955476] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 10/20/2022] [Indexed: 12/24/2022] Open
Abstract
Cancer is a heterogeneous disease characterized by various genetic and phenotypic aberrations. Cancer cells undergo genetic modifications that promote their proliferation, survival, and dissemination as the disease progresses. The unabated proliferation of cancer cells incurs an enormous energy demand that is supplied by metabolic reprogramming. Cancer cells undergo metabolic alterations to provide for increased energy and metabolite requirement; these alterations also help drive the tumor progression. Dysregulation in glucose uptake and increased lactate production via "aerobic glycolysis" were described more than 100 years ago, and since then, the metabolic signature of various cancers has been extensively studied. However, the extensive research in this field has failed to translate into significant therapeutic intervention, except for treating childhood-ALL with amino acid metabolism inhibitor L-asparaginase. Despite the growing understanding of novel metabolic alterations in tumors, the therapeutic targeting of these tumor-specific dysregulations has largely been ineffective in clinical trials. This chapter discusses the major pathways involved in the metabolism of glucose, amino acids, and lipids and highlights the inter-twined nature of metabolic aberrations that promote tumorigenesis in different types of cancer. Finally, we summarise the therapeutic interventions which can be used as a combinational therapy to target metabolic dysregulations that are unique or common in blood, breast, colorectal, lung, and prostate cancer.
Collapse
Affiliation(s)
- Soumik Pal
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Amit Sharma
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Sam Padalumavunkal Mathew
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Bithiah Grace Jaganathan
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India,Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati, Assam, India,*Correspondence: Bithiah Grace Jaganathan,
| |
Collapse
|
|
26
|
Chae HS, Hong ST. Overview of Cancer Metabolism and Signaling Transduction. Int J Mol Sci 2022; 24:12. [PMID: 36613455 PMCID: PMC9819818 DOI: 10.3390/ijms24010012] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/13/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
Despite the remarkable progress in cancer treatment up to now, we are still far from conquering the disease. The most substantial change after the malignant transformation of normal cells into cancer cells is the alteration in their metabolism. Cancer cells reprogram their metabolism to support the elevated energy demand as well as the acquisition and maintenance of their malignancy, even in nutrient-poor environments. The metabolic alterations, even under aerobic conditions, such as the upregulation of the glucose uptake and glycolysis (the Warburg effect), increase the ROS (reactive oxygen species) and glutamine dependence, which are the prominent features of cancer metabolism. Among these metabolic alterations, high glutamine dependency has attracted serious attention in the cancer research community. In addition, the oncogenic signaling pathways of the well-known important genetic mutations play important regulatory roles, either directly or indirectly, in the central carbon metabolism. The identification of the convergent metabolic phenotypes is crucial to the targeting of cancer cells. In this review, we investigate the relationship between cancer metabolism and the signal transduction pathways, and we highlight the recent developments in anti-cancer therapy that target metabolism.
Collapse
Affiliation(s)
- Hee-Suk Chae
- Department of Obstetrics and Gynecology, Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju 561-712, Jeonnbuk, Republic of Korea
| | - Seong-Tshool Hong
- Department of Biomedical Sciences, Jeonbuk National University Medical School, Jeonju 561-712, Jeonnbuk, Republic of Korea
| |
Collapse
|
|
27
|
Memon AA, Vats S, Sundquist J, Li Y, Sundquist K. Mitochondrial DNA Copy Number: Linking Diabetes and Cancer. Antioxid Redox Signal 2022; 37:1168-1190. [PMID: 36169625 DOI: 10.1089/ars.2022.0100] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Recent Advances: Various studies have suggested that mitochondrial DNA copy number (mtDNA-CN), a surrogate biomarker of mitochondrial dysfunction, is an easily quantifiable biomarker for chronic diseases, including diabetes and cancer. However, current knowledge is limited, and the results are controversial. This has been attributed mainly to methodology and study design. Critical Issues: The incidence of diabetes and cancer has increased significantly in recent years. Moreover, type 2 diabetes (T2D) has been shown to be a risk factor for cancer. mtDNA-CN has been associated with both T2D and cancer. However, it is not known whether mtDNA-CN plays any role in the association between T2D and cancer. Significance: In this review, we have discussed mtDNA-CN in diabetes and cancer, and reviewed the literature and methodology used in published studies so far. Based on the literature review, we have speculated how mtDNA-CN may act as a link between diabetes and cancer. Furthermore, we have provided some recommendations for reliable translation of mtDNA-CN as a biomarker. Future Directions: Further research is required to elucidate the role of mtDNA-CN in the association between T2D and cancer. If established, early lifestyle interventions, such as physical activity and diet control that improve mitochondrial function, may help preventing cancer in patients with T2D. Antioxid. Redox Signal. 37, 1168-1190.
Collapse
Affiliation(s)
- Ashfaque A Memon
- Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden
| | - Sakshi Vats
- Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden
| | - Jan Sundquist
- Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden
| | - Yanni Li
- Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden
| | - Kristina Sundquist
- Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden
| |
Collapse
|
|
28
|
Abstract
Significance: Cancer-associated tissue-specific lactic acidosis stimulates and mediates tumor invasion and metastasis and is druggable. Rarely, malignancy causes systemic lactic acidosis, the role of which is poorly understood. Recent Advances: The understanding of the role of lactate has shifted dramatically since its discovery. Long recognized as only a waste product, lactate has become known as an alternative metabolism substrate and a secreted nutrient that is exchanged between the tumor and the microenvironment. Tissue-specific lactic acidosis is targeted to improve the host body's anticancer defense and serves as a tool that allows the targeting of anticancer compounds. Systemic lactic acidosis is associated with poor survival. In patients with solid cancer, systemic lactic acidosis is associated with an extremely poor prognosis, as revealed by the analysis of 57 published cases in this study. Although it is considered a pathology worth treating, targeting systemic lactic acidosis in patients with solid cancer is usually inefficient. Critical Issues: Research gaps include simple questions, such as the unknown nuclear pH of the cancer cells and its effects on chemotherapy outcomes, pH sensitivity of glycosylation in cancer cells, in vivo mechanisms of response to acidosis in the absence of lactate, and overinterpretation of in vitro results that were obtained by using cells that were not preadapted to acidic environments. Future Directions: Numerous metabolism-targeting anticancer compounds induce lactatemia, lactic acidosis, or other types of acidosis. Their potential to induce acidic environments is largely overlooked, although the acidosis might contribute to a substantial portion of the observed clinical effects. Antioxid. Redox Signal. 37, 1130-1152.
Collapse
Affiliation(s)
- Petr Heneberg
- Third Faculty of Medicine, Charles University, Prague, Czech Republic
| |
Collapse
|
|
29
|
Cunha A, Rocha AC, Barbosa F, Baião A, Silva P, Sarmento B, Queirós O. Glycolytic Inhibitors Potentiated the Activity of Paclitaxel and Their Nanoencapsulation Increased Their Delivery in a Lung Cancer Model. Pharmaceutics 2022; 14:pharmaceutics14102021. [PMID: 36297455 PMCID: PMC9611291 DOI: 10.3390/pharmaceutics14102021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 11/17/2022] Open
Abstract
Antiglycolytic agents inhibit cell metabolism and modify the tumor’s microenvironment, affecting chemotherapy resistance mechanisms. In this work, we studied the effect of the glycolytic inhibitors 3-bromopyruvate (3BP), dichloroacetate (DCA) and 2-deoxyglucose (2DG) on cancer cell properties and on the multidrug resistance phenotype, using lung cancer cells as a model. All compounds led to the loss of cell viability, with different effects on the cell metabolism, migration and proliferation, depending on the drug and cell line assayed. DCA was the most promising compound, presenting the highest inhibitory effect on cell metabolism and proliferation. DCA treatment led to decreased glucose consumption and ATP and lactate production in both A549 and NCI-H460 cell lines. Furthermore, the DCA pretreatment sensitized the cancer cells to Paclitaxel (PTX), a conventional chemotherapeutic drug, with a 2.7-fold and a 10-fold decrease in PTX IC50 values in A549 and NCI-H460 cell lines, respectively. To increase the intracellular concentration of DCA, thereby potentiating its effect, DCA-loaded poly(lactic-co-glycolic acid) nanoparticles were produced. At higher DCA concentrations, encapsulation was found to increase its toxicity. These results may help find a new treatment strategy through combined therapy, which could open doors to new treatment approaches.
Collapse
Affiliation(s)
- Andrea Cunha
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
| | - Ana Catarina Rocha
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
- DCM—Departamento de Ciências Médicas, Universidade de Aveiro, 3810-193 Aveiro, Portugal
| | - Flávia Barbosa
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
- DCM—Departamento de Ciências Médicas, Universidade de Aveiro, 3810-193 Aveiro, Portugal
| | - Ana Baião
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- INEB—Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
- ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal
| | - Patrícia Silva
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
- TOXRUN—Toxicology Research Unit, University Institute of Health Sciences (IUCS), CESPU, 3810-193 Gandra, Portugal
| | - Bruno Sarmento
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- INEB—Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
| | - Odília Queirós
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
- Correspondence:
| |
Collapse
|
|
30
|
Li X, Yang Y, Zhang B, Lin X, Fu X, An Y, Zou Y, Wang JX, Wang Z, Yu T. Lactate metabolism in human health and disease. Signal Transduct Target Ther 2022; 7:305. [PMID: 36050306 PMCID: PMC9434547 DOI: 10.1038/s41392-022-01151-3] [Citation(s) in RCA: 404] [Impact Index Per Article: 134.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 07/17/2022] [Accepted: 08/09/2022] [Indexed: 12/29/2022] Open
Abstract
The current understanding of lactate extends from its origins as a byproduct of glycolysis to its role in tumor metabolism, as identified by studies on the Warburg effect. The lactate shuttle hypothesis suggests that lactate plays an important role as a bridging signaling molecule that coordinates signaling among different cells, organs and tissues. Lactylation is a posttranslational modification initially reported by Professor Yingming Zhao’s research group in 2019. Subsequent studies confirmed that lactylation is a vital component of lactate function and is involved in tumor proliferation, neural excitation, inflammation and other biological processes. An indispensable substance for various physiological cellular functions, lactate plays a regulatory role in different aspects of energy metabolism and signal transduction. Therefore, a comprehensive review and summary of lactate is presented to clarify the role of lactate in disease and to provide a reference and direction for future research. This review offers a systematic overview of lactate homeostasis and its roles in physiological and pathological processes, as well as a comprehensive overview of the effects of lactylation in various diseases, particularly inflammation and cancer.
Collapse
Affiliation(s)
- Xiaolu Li
- Center for Regenerative Medicine, Institute for Translational Medicine, The Affiliated Hospital of Qingdao University; Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266000, China
| | - Yanyan Yang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Bei Zhang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Xiaotong Lin
- Department of Respiratory Medicine, Qingdao Municipal Hospital, Qingdao, 266011, China
| | - Xiuxiu Fu
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266000, China
| | - Yi An
- Department of Cardiology, The Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Qingdao, 266555, China
| | - Yulin Zou
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266000, China
| | - Jian-Xun Wang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Zhibin Wang
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266000, China.
| | - Tao Yu
- Center for Regenerative Medicine, Institute for Translational Medicine, The Affiliated Hospital of Qingdao University; Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266000, China.
| |
Collapse
|
|
31
|
Hossain M, Roth S, Dimmock JR, Das U. Cytotoxic derivatives of dichloroacetic acid and some metal complexes. Arch Pharm (Weinheim) 2022; 355:e2200236. [DOI: 10.1002/ardp.202200236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 07/27/2022] [Accepted: 07/30/2022] [Indexed: 11/12/2022]
Affiliation(s)
| | - Shayne Roth
- School of Sciences Indiana University Kokomo Kokomo Indiana USA
| | - Jonathan R. Dimmock
- Drug Discovery and Development Research Cluster University of Saskatchewan Saskatoon Saskatchewan Canada
| | - Umashankar Das
- Drug Discovery and Development Research Cluster University of Saskatchewan Saskatoon Saskatchewan Canada
| |
Collapse
|
|
32
|
Development of actionable targets of multi-kinase inhibitors (AToMI) screening platform to dissect kinase targets of staurosporines in glioblastoma cells. Sci Rep 2022; 12:13796. [PMID: 35963891 PMCID: PMC9376105 DOI: 10.1038/s41598-022-18118-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 08/05/2022] [Indexed: 11/08/2022] Open
Abstract
Therapeutic resistance to kinase inhibitors constitutes a major unresolved clinical challenge in cancer and especially in glioblastoma. Multi-kinase inhibitors may be used for simultaneous targeting of multiple target kinases and thereby potentially overcome kinase inhibitor resistance. However, in most cases the identification of the target kinases mediating therapeutic effects of multi-kinase inhibitors has been challenging. To tackle this important problem, we developed an actionable targets of multi-kinase inhibitors (AToMI) strategy and used it for characterization of glioblastoma target kinases of staurosporine derivatives displaying synergy with protein phosphatase 2A (PP2A) reactivation. AToMI consists of interchangeable modules combining drug-kinase interaction assay, siRNA high-throughput screening, bioinformatics analysis, and validation screening with more selective target kinase inhibitors. As a result, AToMI analysis revealed AKT and mitochondrial pyruvate dehydrogenase kinase PDK1 and PDK4 as kinase targets of staurosporine derivatives UCN-01, CEP-701, and K252a that synergized with PP2A activation across heterogeneous glioblastoma cells. Based on these proof-of-principle results, we propose that the application and further development of AToMI for clinically applicable multi-kinase inhibitors could provide significant benefits in overcoming the challenge of lack of knowledge of the target specificity of multi-kinase inhibitors.
Collapse
|
|
33
|
Refining the Role of Pyruvate Dehydrogenase Kinases in Glioblastoma Development. Cancers (Basel) 2022; 14:cancers14153769. [PMID: 35954433 PMCID: PMC9367285 DOI: 10.3390/cancers14153769] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/20/2022] [Accepted: 07/25/2022] [Indexed: 12/07/2022] Open
Abstract
Glioblastoma (GB) are the most frequent brain cancers. Aggressive growth and limited treatment options induce a median survival of 12–15 months. In addition to highly proliferative and invasive properties, GB cells show cancer-associated metabolic characteristics such as increased aerobic glycolysis. Pyruvate dehydrogenase (PDH) is a key enzyme complex at the crossroads between lactic fermentation and oxidative pathways, finely regulated by PDH kinases (PDHKs). PDHKs are often overexpressed in cancer cells to facilitate high glycolytic flux. We hypothesized that targeting PDHKs, by disturbing cancer metabolic homeostasis, would alter GB progression and render cells vulnerable to additional cancer treatment. Using patient databases, distinct expression patterns of PDHK1 and PDHK2 in GB tissues were obvious. To disturb protumoral glycolysis, we modulated PDH activity through the genetic or pharmacological inhibition of PDHK in patient-derived stem-like spheroids. Striking effects of PDHKs inhibition using dichloroacetate were observed in vitro on cell morphology and metabolism, resulting in increased intracellular ROS levels and decreased proliferation and invasion. In vivo findings confirmed a reduction in tumor size and better survival of mice implanted with PDHK1 and PDHK2 knockout cells. Adding a radiotherapeutic protocol further resulted in a reduction in tumor size and improved mouse survival in our model.
Collapse
|
|
34
|
Tyagi A, Wu SY, Watabe K. Metabolism in the progression and metastasis of brain tumors. Cancer Lett 2022; 539:215713. [PMID: 35513201 PMCID: PMC9999298 DOI: 10.1016/j.canlet.2022.215713] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 04/21/2022] [Accepted: 04/22/2022] [Indexed: 01/30/2023]
Abstract
Malignant brain tumors and metastases pose significant health problems and cause substantial morbidity and mortality in children and adults. Based on epidemiological evidence, gliomas comprise 30% and 80% of primary brain tumors and malignant tumors, respectively. Brain metastases affect 15-30% of cancer patients, particularly primary tumors of the lung, breast, colon, and kidney, and melanoma. Despite advancements in multimodal molecular targeted therapy and immunotherapy that do not ensure long-term treatment, malignant brain tumors and metastases contribute significantly to cancer related mortality. Recent studies have shown that metastatic cancer cells possess distinct metabolic traits to adapt and survive in new environment that differs significantly from the primary site in both nutrient composition and availability. As metabolic regulation lies at the intersection of many research areas, concerted efforts to understand the metabolic mechanism(s) driving malignant brain tumors and metastases may reveal novel therapeutic targets to prevent or reduce metastasis and predict biomarkers for the treatment of this aggressive disease. This review focuses on various aspects of metabolic signaling, interface between metabolic regulators and cellular processes, and implications of their dysregulation in the context of brain tumors and metastases.
Collapse
Affiliation(s)
- Abhishek Tyagi
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Shih-Ying Wu
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Kounosuke Watabe
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
| |
Collapse
|
|
35
|
Tiersma JF, Evers B, Bakker BM, Jalving M, de Jong S. Pyruvate Dehydrogenase Kinase Inhibition by Dichloroacetate in Melanoma Cells Unveils Metabolic Vulnerabilities. Int J Mol Sci 2022; 23:ijms23073745. [PMID: 35409102 PMCID: PMC8999016 DOI: 10.3390/ijms23073745] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/21/2022] [Accepted: 03/25/2022] [Indexed: 12/03/2022] Open
Abstract
Melanoma is characterized by high glucose uptake, partially mediated through elevated pyruvate dehydrogenase kinase (PDK), making PDK a potential treatment target in melanoma. We aimed to reduce glucose uptake in melanoma cell lines through PDK inhibitors dichloroacetate (DCA) and AZD7545 and through PDK knockdown, to inhibit cell growth and potentially unveil metabolic co-vulnerabilities resulting from PDK inhibition. MeWo cells were most sensitive to DCA, while SK-MEL-2 was the least sensitive, with IC50 values ranging from 13.3 to 27.0 mM. DCA strongly reduced PDH phosphorylation and increased the oxygen consumption rate:extracellular acidification rate (OCR:ECAR) ratio up to 6-fold. Knockdown of single PDK isoforms had similar effects on PDH phosphorylation and OCR:ECAR ratio as DCA but did not influence sensitivity to DCA. Growth inhibition by DCA was synergistic with the glutaminase inhibitor CB-839 (2- to 5-fold sensitization) and with diclofenac, known to inhibit monocarboxylate transporters (MCTs) (3- to 8-fold sensitization). CB-839 did not affect the OCR:ECAR response to DCA, whereas diclofenac strongly inhibited ECAR and further increased the OCR:ECAR ratio. We conclude that in melanoma cell lines, DCA reduces proliferation through reprogramming of cellular metabolism and synergizes with other metabolically targeted drugs.
Collapse
Affiliation(s)
- Jiske F. Tiersma
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
| | - Bernard Evers
- Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signalling, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands; (B.E.); (B.M.B.)
| | - Barbara M. Bakker
- Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signalling, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands; (B.E.); (B.M.B.)
| | - Mathilde Jalving
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
- Correspondence: (M.J.); (S.d.J.); Tel.: +31-50-3615692 (M.J.); +31-50-3612964 (S.d.J.)
| | - Steven de Jong
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
- Correspondence: (M.J.); (S.d.J.); Tel.: +31-50-3615692 (M.J.); +31-50-3612964 (S.d.J.)
| |
Collapse
|
|
36
|
Phase II study of dichloroacetate, an inhibitor of pyruvate dehydrogenase, in combination with chemoradiotherapy for unresected, locally advanced head and neck squamous cell carcinoma. Invest New Drugs 2022; 40:622-633. [DOI: 10.1007/s10637-022-01235-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 03/11/2022] [Indexed: 12/14/2022]
|
|
37
|
Bazanov DR, Maximova NA, Seliverstov MY, Zefirov NA, Sosonyuk SE, Lozinskaya NA. Synthesis of Covalent Conjugates of Dichloroacetic Acid with Polyfunctional Compounds. RUSSIAN JOURNAL OF ORGANIC CHEMISTRY 2021. [DOI: 10.1134/s107042802111004x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
|
|
38
|
Kaur J, Bhattacharyya S. Cancer Stem Cells: Metabolic Characterization for Targeted Cancer Therapy. Front Oncol 2021; 11:756888. [PMID: 34804950 PMCID: PMC8602811 DOI: 10.3389/fonc.2021.756888] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/18/2021] [Indexed: 02/02/2023] Open
Abstract
The subpopulation of cancer stem cells (CSCs) within tumor bulk are known for tumor recurrence and metastasis. CSCs show intrinsic resistance to conventional therapies and phenotypic plasticity within the tumor, which make these a difficult target for conventional therapies. CSCs have different metabolic phenotypes based on their needs as compared to the bulk cancer cells. CSCs show metabolic plasticity and constantly alter their metabolic state between glycolysis and oxidative metabolism (OXPHOS) to adapt to scarcity of nutrients and therapeutic stress. The metabolic characteristics of CSCs are distinct compared to non-CSCs and thus provide an opportunity to devise more effective strategies to target CSCs. Mechanism for metabolic switch in CSCs is still unravelled, however existing evidence suggests that tumor microenvironment affects the metabolic phenotype of cancer cells. Understanding CSCs metabolism may help in discovering new and effective clinical targets to prevent cancer relapse and metastasis. This review summarises the current knowledge of CSCs metabolism and highlights the potential targeted treatment strategies.
Collapse
Affiliation(s)
- Jasmeet Kaur
- Department of Biophysics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Shalmoli Bhattacharyya
- Department of Biophysics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| |
Collapse
|
|
39
|
Lajin B, Braeuer S, Borovička J, Goessler W. Is the water disinfection by-product dichloroacetic acid biosynthesized in the edible mushroom Russula nigricans? CHEMOSPHERE 2021; 281:130819. [PMID: 33991903 DOI: 10.1016/j.chemosphere.2021.130819] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/05/2021] [Accepted: 05/05/2021] [Indexed: 06/12/2023]
Abstract
We report the first halogen speciation analysis study by high performance liquid chromatography coupled with inductively coupled plasma tandem mass spectrometry (HPLC-ICPMS/MS) in the fruiting bodies of various mushroom species. Non-targeted speciation analysis revealed the occurrence of dichloroacetic acid (DCAA) in the edible mushroom Russula nigricans. Multiple samples of this mushroom (n = 5) collected from different geographic non-industrial regions in two different countries confirmed the consistent presence of this species at a relatively narrow concentration range (23-37 mg kg-1), whereas no other chlorinated acetic acid (e.g. chloroacetic acid and trichloroacetic acid) was detected. Neither DCAA nor any other chlorinated acetic acid were detected in any of the other mushroom species investigated in the present study, including seven different mushroom species of the same genus Russula, even though all mushrooms were collected from the same non-industrial geographic regions. Together with the previously reported biological activities of DCAA, these findings collectively suggest biosynthesis of this compound as an explanation for its dominant presence in R. nigricans, and constitute the first example of the dominant natural occurrence of this compound over other chlorinated acetic acids in a living organism. This may warrant a change in our view of the occurrence of dichloroacetic acid in nature, where primarily considered as a pollutant arising from water disinfection.
Collapse
Affiliation(s)
- Bassam Lajin
- Institute of Chemistry, University of Graz, Universitaetsplatz 1, 8010, Graz, Austria.
| | - Simone Braeuer
- Institute of Chemistry, University of Graz, Universitaetsplatz 1, 8010, Graz, Austria; Atomic & Mass Spectrometry Research Unit, Department of Chemistry, Ghent University, Krijgslaan 281-S12, 9000, Ghent, Belgium
| | - Jan Borovička
- Nuclear Physics Institute of the Czech Academy of Sciences, Hlavní 130, 25068, Husinec-Řež, Czech Republic; Institute of Geology of the Czech Academy of Sciences, Rozvojová 269, 16500, Prague 6, Czech Republic
| | - Walter Goessler
- Institute of Chemistry, University of Graz, Universitaetsplatz 1, 8010, Graz, Austria
| |
Collapse
|
|
40
|
Targeting Glucose Metabolism of Cancer Cells with Dichloroacetate to Radiosensitize High-Grade Gliomas. Int J Mol Sci 2021; 22:7265. [PMID: 34298883 PMCID: PMC8305417 DOI: 10.3390/ijms22147265;] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
As the cornerstone of high-grade glioma (HGG) treatment, radiotherapy temporarily controls tumor cells via inducing oxidative stress and subsequent DNA breaks. However, almost all HGGs recur within months. Therefore, it is important to understand the underlying mechanisms of radioresistance, so that novel strategies can be developed to improve the effectiveness of radiotherapy. While currently poorly understood, radioresistance appears to be predominantly driven by altered metabolism and hypoxia. Glucose is a central macronutrient, and its metabolism is rewired in HGG cells, increasing glycolytic flux to produce energy and essential metabolic intermediates, known as the Warburg effect. This altered metabolism in HGG cells not only supports cell proliferation and invasiveness, but it also contributes significantly to radioresistance. Several metabolic drugs have been used as a novel approach to improve the radiosensitivity of HGGs, including dichloroacetate (DCA), a small molecule used to treat children with congenital mitochondrial disorders. DCA reverses the Warburg effect by inhibiting pyruvate dehydrogenase kinases, which subsequently activates mitochondrial oxidative phosphorylation at the expense of glycolysis. This effect is thought to block the growth advantage of HGGs and improve the radiosensitivity of HGG cells. This review highlights the main features of altered glucose metabolism in HGG cells as a contributor to radioresistance and describes the mechanism of action of DCA. Furthermore, we will summarize recent advances in DCA's pre-clinical and clinical studies as a radiosensitizer and address how these scientific findings can be translated into clinical practice to improve the management of HGG patients.
Collapse
|
|
41
|
Cook KM, Shen H, McKelvey KJ, Gee HE, Hau E. Targeting Glucose Metabolism of Cancer Cells with Dichloroacetate to Radiosensitize High-Grade Gliomas. Int J Mol Sci 2021; 22:ijms22147265. [PMID: 34298883 PMCID: PMC8305417 DOI: 10.3390/ijms22147265] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/30/2021] [Accepted: 07/01/2021] [Indexed: 02/06/2023] Open
Abstract
As the cornerstone of high-grade glioma (HGG) treatment, radiotherapy temporarily controls tumor cells via inducing oxidative stress and subsequent DNA breaks. However, almost all HGGs recur within months. Therefore, it is important to understand the underlying mechanisms of radioresistance, so that novel strategies can be developed to improve the effectiveness of radiotherapy. While currently poorly understood, radioresistance appears to be predominantly driven by altered metabolism and hypoxia. Glucose is a central macronutrient, and its metabolism is rewired in HGG cells, increasing glycolytic flux to produce energy and essential metabolic intermediates, known as the Warburg effect. This altered metabolism in HGG cells not only supports cell proliferation and invasiveness, but it also contributes significantly to radioresistance. Several metabolic drugs have been used as a novel approach to improve the radiosensitivity of HGGs, including dichloroacetate (DCA), a small molecule used to treat children with congenital mitochondrial disorders. DCA reverses the Warburg effect by inhibiting pyruvate dehydrogenase kinases, which subsequently activates mitochondrial oxidative phosphorylation at the expense of glycolysis. This effect is thought to block the growth advantage of HGGs and improve the radiosensitivity of HGG cells. This review highlights the main features of altered glucose metabolism in HGG cells as a contributor to radioresistance and describes the mechanism of action of DCA. Furthermore, we will summarize recent advances in DCA’s pre-clinical and clinical studies as a radiosensitizer and address how these scientific findings can be translated into clinical practice to improve the management of HGG patients.
Collapse
Affiliation(s)
- Kristina M. Cook
- Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney 2006, Australia; (H.S.); (K.J.M.); (H.E.G.); (E.H.)
- Correspondence: ; Tel.: +61-286274858
| | - Han Shen
- Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney 2006, Australia; (H.S.); (K.J.M.); (H.E.G.); (E.H.)
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead 2145, Australia
| | - Kelly J. McKelvey
- Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney 2006, Australia; (H.S.); (K.J.M.); (H.E.G.); (E.H.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, University of Sydney, St. Leonards 2065, Australia
| | - Harriet E. Gee
- Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney 2006, Australia; (H.S.); (K.J.M.); (H.E.G.); (E.H.)
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead 2145, Australia
- Sydney West Radiation Oncology Network, University of Sydney, Sydney 2006, Australia
- Children’s Medical Research Institute, Westmead 2145, Australia
| | - Eric Hau
- Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney 2006, Australia; (H.S.); (K.J.M.); (H.E.G.); (E.H.)
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead 2145, Australia
- Sydney West Radiation Oncology Network, University of Sydney, Sydney 2006, Australia
| |
Collapse
|
|
42
|
Wu D, Dasgupta A, Read AD, Bentley RET, Motamed M, Chen KH, Al-Qazazi R, Mewburn JD, Dunham-Snary KJ, Alizadeh E, Tian L, Archer SL. Oxygen sensing, mitochondrial biology and experimental therapeutics for pulmonary hypertension and cancer. Free Radic Biol Med 2021; 170:150-178. [PMID: 33450375 PMCID: PMC8217091 DOI: 10.1016/j.freeradbiomed.2020.12.452] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/24/2020] [Accepted: 12/30/2020] [Indexed: 02/06/2023]
Abstract
The homeostatic oxygen sensing system (HOSS) optimizes systemic oxygen delivery. Specialized tissues utilize a conserved mitochondrial sensor, often involving NDUFS2 in complex I of the mitochondrial electron transport chain, as a site of pO2-responsive production of reactive oxygen species (ROS). These ROS are converted to a diffusible signaling molecule, hydrogen peroxide (H2O2), by superoxide dismutase (SOD2). H2O2 exits the mitochondria and regulates ion channels and enzymes, altering plasma membrane potential, intracellular Ca2+ and Ca2+-sensitization and controlling acute, adaptive, responses to hypoxia that involve changes in ventilation, vascular tone and neurotransmitter release. Subversion of this O2-sensing pathway creates a pseudohypoxic state that promotes disease progression in pulmonary arterial hypertension (PAH) and cancer. Pseudohypoxia is a state in which biochemical changes, normally associated with hypoxia, occur despite normal pO2. Epigenetic silencing of SOD2 by DNA methylation alters H2O2 production, activating hypoxia-inducible factor 1α, thereby disrupting mitochondrial metabolism and dynamics, accelerating cell proliferation and inhibiting apoptosis. Other epigenetic mechanisms, including dysregulation of microRNAs (miR), increase pyruvate dehydrogenase kinase and pyruvate kinase muscle isoform 2 expression in both diseases, favoring uncoupled aerobic glycolysis. This Warburg metabolic shift also accelerates cell proliferation and impairs apoptosis. Disordered mitochondrial dynamics, usually increased mitotic fission and impaired fusion, promotes disease progression in PAH and cancer. Epigenetic upregulation of dynamin-related protein 1 (Drp1) and its binding partners, MiD49 and MiD51, contributes to the pathogenesis of PAH and cancer. Finally, dysregulation of intramitochondrial Ca2+, resulting from impaired mitochondrial calcium uniporter complex (MCUC) function, links abnormal mitochondrial metabolism and dynamics. MiR-mediated decreases in MCUC function reduce intramitochondrial Ca2+, promoting Warburg metabolism, whilst increasing cytosolic Ca2+, promoting fission. Epigenetically disordered mitochondrial O2-sensing, metabolism, dynamics, and Ca2+ homeostasis offer new therapeutic targets for PAH and cancer. Promoting glucose oxidation, restoring the fission/fusion balance, and restoring mitochondrial calcium regulation are promising experimental therapeutic strategies.
Collapse
Affiliation(s)
- Danchen Wu
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Asish Dasgupta
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Austin D Read
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Rachel E T Bentley
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Mehras Motamed
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Kuang-Hueih Chen
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Ruaa Al-Qazazi
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Jeffrey D Mewburn
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Kimberly J Dunham-Snary
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Elahe Alizadeh
- Queen's Cardiopulmonary Unit (QCPU), Department of Medicine, Queen's University, 116 Barrie Street, Kingston, ON, K7L 3J9, Canada
| | - Lian Tian
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK
| | - Stephen L Archer
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada.
| |
Collapse
|
|
43
|
Abstract
In this review, Shen and Kang provide an overview of the tumor-intrinsic and microenvironment- and treatment-induced stresses that tumor cells encounter in the metastatic cascade and the molecular pathways they develop to relieve these stresses. Metastasis is the ultimate “survival of the fittest” test for cancer cells, as only a small fraction of disseminated tumor cells can overcome the numerous hurdles they encounter during the transition from the site of origin to a distinctly different distant organ in the face of immune and therapeutic attacks and various other stresses. During cancer progression, tumor cells develop a variety of mechanisms to cope with the stresses they encounter, and acquire the ability to form metastases. Restraining these stress-releasing pathways could serve as potentially effective strategies to prevent or reduce metastasis and improve the survival of cancer patients. Here, we provide an overview of the tumor-intrinsic, microenvironment- and treatment-induced stresses that tumor cells encounter in the metastatic cascade and the molecular pathways they develop to relieve these stresses. We also summarize the preclinical and clinical studies that evaluate the potential therapeutic benefit of targeting these stress-relieving pathways.
Collapse
Affiliation(s)
- Minhong Shen
- Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
| |
Collapse
|
|
44
|
Sun L, Zhang H, Gao P. Metabolic reprogramming and epigenetic modifications on the path to cancer. Protein Cell 2021; 13:877-919. [PMID: 34050894 PMCID: PMC9243210 DOI: 10.1007/s13238-021-00846-7] [Citation(s) in RCA: 287] [Impact Index Per Article: 71.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023] Open
Abstract
Metabolic rewiring and epigenetic remodeling, which are closely linked and reciprocally regulate each other, are among the well-known cancer hallmarks. Recent evidence suggests that many metabolites serve as substrates or cofactors of chromatin-modifying enzymes as a consequence of the translocation or spatial regionalization of enzymes or metabolites. Various metabolic alterations and epigenetic modifications also reportedly drive immune escape or impede immunosurveillance within certain contexts, playing important roles in tumor progression. In this review, we focus on how metabolic reprogramming of tumor cells and immune cells reshapes epigenetic alterations, in particular the acetylation and methylation of histone proteins and DNA. We also discuss other eminent metabolic modifications such as, succinylation, hydroxybutyrylation, and lactylation, and update the current advances in metabolism- and epigenetic modification-based therapeutic prospects in cancer.
Collapse
Affiliation(s)
- Linchong Sun
- Guangzhou First People's Hospital, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, 510006, China.
| | - Huafeng Zhang
- The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230027, China. .,CAS Centre for Excellence in Cell and Molecular Biology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
| | - Ping Gao
- Guangzhou First People's Hospital, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, 510006, China. .,School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 510006, China. .,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510005, China.
| |
Collapse
|
|
45
|
Anwar S, Shamsi A, Mohammad T, Islam A, Hassan MI. Targeting pyruvate dehydrogenase kinase signaling in the development of effective cancer therapy. Biochim Biophys Acta Rev Cancer 2021; 1876:188568. [PMID: 34023419 DOI: 10.1016/j.bbcan.2021.188568] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/06/2021] [Accepted: 05/11/2021] [Indexed: 02/06/2023]
Abstract
Pyruvate is irreversibly decarboxylated to acetyl coenzyme A by mitochondrial pyruvate dehydrogenase complex (PDC). Decarboxylation of pyruvate is considered a crucial step in cell metabolism and energetics. The cancer cells prefer aerobic glycolysis rather than mitochondrial oxidation of pyruvate. This attribute of cancer cells allows them to sustain under indefinite proliferation and growth. Pyruvate dehydrogenase kinases (PDKs) play critical roles in many diseases because they regulate PDC activity. Recent findings suggest an altered metabolism of cancer cells is associated with impaired mitochondrial function due to PDC inhibition. PDKs inhibit the PDC activity via phosphorylation of the E1a subunit and subsequently cause a glycolytic shift. Thus, inhibition of PDK is an attractive strategy in anticancer therapy. This review highlights that PDC/PDK axis could be implicated in cancer's therapeutic management by developing potential small-molecule PDK inhibitors. In recent years, a dramatic increase in the targeting of the PDC/PDK axis for cancer treatment gained an attention from the scientific community. We further discuss breakthrough findings in the PDC-PDK axis. In addition, structural features, functional significance, mechanism of activation, involvement in various human pathologies, and expression of different forms of PDKs (PDK1-4) in different types of cancers are discussed in detail. We further emphasized the gene expression profiling of PDKs in cancer patients to prognosis and therapeutic manifestations. Additionally, inhibition of the PDK/PDC axis by small molecule inhibitors and natural compounds at different clinical evaluation stages has also been discussed comprehensively.
Collapse
Affiliation(s)
- Saleha Anwar
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Anas Shamsi
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Taj Mohammad
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Asimul Islam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
| |
Collapse
|
|
46
|
PDK2: An Underappreciated Regulator of Liver Metabolism. LIVERS 2021. [DOI: 10.3390/livers1020008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Pyruvate metabolism is critical for all mammalian cells. The pyruvate dehydrogenase complex couples the pyruvate formed as the primary product of glycolysis to the formation of acetyl-CoA required as the primary substrate of the citric acid cycle. Dysregulation of this coupling contributes to alterations in metabolic flexibility in obesity, diabetes, cancer, and more. The pyruvate dehydrogenase kinase family of isozymes phosphorylate and inactive the pyruvate dehydrogenase complex in the mitochondria. This function makes them critical mediators of mitochondrial metabolism and drug targets in a number of disease states. The liver expresses multiple PDKs, predominantly PDK1 and PDK2 in the fed state and PDK1, PDK2, and PDK4 in the starved and diabetic states. PDK4 undergoes substantial transcriptional regulation in response to a diverse array of stimuli in most tissues. PDK2 has received less attention than PDK4 potentially due to the dramatic changes in transcriptional gene regulation. However, PDK2 is more responsive than the other PDKs to feedforward and feedback regulation by substrates and products of the pyruvate dehydrogenase complex. Although underappreciated, this makes PDK2 particularly important for the minute-to-minute fine control of the pyruvate dehydrogenase complex and a major contributor to metabolic flexibility. The purpose of this review is to characterize the underappreciated role of PDK2 in liver metabolism. We will focus on known biological actions and physiological roles as well as what roles PDK2 may play in disease states. We will also define current inhibitors and address their potential as therapeutic agents in the future.
Collapse
|
|
47
|
Parczyk J, Ruhnau J, Pelz C, Schilling M, Wu H, Piaskowski NN, Eickholt B, Kühn H, Danker K, Klein A. Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines. BMC Cancer 2021; 21:481. [PMID: 33931028 PMCID: PMC8086110 DOI: 10.1186/s12885-021-08186-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 04/14/2021] [Indexed: 02/08/2023] Open
Abstract
Background One key approach for anticancer therapy is drug combination. Drug combinations can help reduce doses and thereby decrease side effects. Furthermore, the likelihood of drug resistance is reduced. Distinct alterations in tumor metabolism have been described in past decades, but metabolism has yet to be targeted in clinical cancer therapy. Recently, we found evidence for synergism between dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, and the HIF-1α inhibitor PX-478. In this study, we aimed to analyse this synergism in cell lines of different cancer types and to identify the underlying biochemical mechanisms. Methods The dose-dependent antiproliferative effects of the single drugs and their combination were assessed using SRB assays. FACS, Western blot and HPLC analyses were performed to investigate changes in reactive oxygen species levels, apoptosis and the cell cycle. Additionally, real-time metabolic analyses (Seahorse) were performed with DCA-treated MCF-7 cells. Results The combination of DCA and PX-478 produced synergistic effects in all eight cancer cell lines tested, including colorectal, lung, breast, cervical, liver and brain cancer. Reactive oxygen species generation and apoptosis played important roles in this synergism. Furthermore, cell proliferation was inhibited by the combination treatment. Conclusions Here, we found that these tumor metabolism-targeting compounds exhibited a potent synergism across all tested cancer cell lines. Thus, we highly recommend the combination of these two compounds for progression to in vivo translational and clinical trials. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08186-9.
Collapse
Affiliation(s)
- Jonas Parczyk
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.
| | - Jérôme Ruhnau
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.
| | - Carsten Pelz
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
| | - Max Schilling
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
| | - Hao Wu
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
| | - Nicole Nadine Piaskowski
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
| | - Britta Eickholt
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
| | - Hartmut Kühn
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
| | - Kerstin Danker
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
| | - Andreas Klein
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
| |
Collapse
|
|
48
|
Schiliro C, Firestein BL. Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation. Cells 2021; 10:cells10051056. [PMID: 33946927 PMCID: PMC8146072 DOI: 10.3390/cells10051056] [Citation(s) in RCA: 270] [Impact Index Per Article: 67.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer cells alter metabolic processes to sustain their characteristic uncontrolled growth and proliferation. These metabolic alterations include (1) a shift from oxidative phosphorylation to aerobic glycolysis to support the increased need for ATP, (2) increased glutaminolysis for NADPH regeneration, (3) altered flux through the pentose phosphate pathway and the tricarboxylic acid cycle for macromolecule generation, (4) increased lipid uptake, lipogenesis, and cholesterol synthesis, (5) upregulation of one-carbon metabolism for the production of ATP, NADH/NADPH, nucleotides, and glutathione, (6) altered amino acid metabolism, (7) metabolism-based regulation of apoptosis, and (8) the utilization of alternative substrates, such as lactate and acetate. Altered metabolic flux in cancer is controlled by tumor-host cell interactions, key oncogenes, tumor suppressors, and other regulatory molecules, including non-coding RNAs. Changes to metabolic pathways in cancer are dynamic, exhibit plasticity, and are often dependent on the type of tumor and the tumor microenvironment, leading in a shift of thought from the Warburg Effect and the “reverse Warburg Effect” to metabolic plasticity. Understanding the complex nature of altered flux through these multiple pathways in cancer cells can support the development of new therapies.
Collapse
Affiliation(s)
- Chelsea Schiliro
- Cell and Developmental Biology Graduate Program and Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854, USA;
| | - Bonnie L. Firestein
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854, USA
- Correspondence: ; Tel.: +1-848-445-8045
| |
Collapse
|
|
49
|
Pyruvate dehydrogenase kinases (PDKs): an overview toward clinical applications. Biosci Rep 2021; 41:228121. [PMID: 33739396 PMCID: PMC8026821 DOI: 10.1042/bsr20204402] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 03/12/2021] [Accepted: 03/17/2021] [Indexed: 01/01/2023] Open
Abstract
Pyruvate dehydrogenase kinase (PDK) can regulate the catalytic activity of pyruvate decarboxylation oxidation via the mitochondrial pyruvate dehydrogenase complex, and it further links glycolysis with the tricarboxylic acid cycle and ATP generation. This review seeks to elucidate the regulation of PDK activity in different species, mainly mammals, and the role of PDK inhibitors in preventing increased blood glucose, reducing injury caused by myocardial ischemia, and inducing apoptosis of tumor cells. Regulations of PDKs expression or activity represent a very promising approach for treatment of metabolic diseases including diabetes, heart failure, and cancer. The future research and development could be more focused on the biochemical understanding of the diseases, which would help understand the cellular energy metabolism and its regulation by pharmacological effectors of PDKs.
Collapse
|
|
50
|
McKelvey KJ, Wilson EB, Short S, Melcher AA, Biggs M, Diakos CI, Howell VM. Glycolysis and Fatty Acid Oxidation Inhibition Improves Survival in Glioblastoma. Front Oncol 2021; 11:633210. [PMID: 33854970 PMCID: PMC8039392 DOI: 10.3389/fonc.2021.633210] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 02/10/2021] [Indexed: 01/18/2023] Open
Abstract
Glioblastoma (GBM) is the most aggressive adult glioma with a median survival of 14 months. While standard treatments (safe maximal resection, radiation, and temozolomide chemotherapy) have increased the median survival in favorable O(6)-methylguanine-DNA methyltransferase (MGMT)-methylated GBM (~21 months), a large proportion of patients experience a highly debilitating and rapidly fatal disease. This study examined GBM cellular energetic pathways and blockade using repurposed drugs: the glycolytic inhibitor, namely dicholoroacetate (DCA), and the partial fatty acid oxidation (FAO) inhibitor, namely ranolazine (Rano). Gene expression data show that GBM subtypes have similar glucose and FAO pathways, and GBM tumors have significant upregulation of enzymes in both pathways, compared to normal brain tissue (p < 0.01). DCA and the DCA/Rano combination showed reduced colony-forming activity of GBM and increased oxidative stress, DNA damage, autophagy, and apoptosis in vitro. In the orthotopic Gl261 and CT2A syngeneic murine models of GBM, DCA, Rano, and DCA/Rano increased median survival and induced focal tumor necrosis and hemorrhage. In conclusion, dual targeting of glycolytic and FAO metabolic pathways provides a viable treatment that warrants further investigation concurrently or as an adjuvant to standard chemoradiation for GBM.
Collapse
Affiliation(s)
- Kelly J. McKelvey
- Bill Walsh Translational Cancer Research Laboratory, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Erica B. Wilson
- Translational Neuro-Oncology, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | - Susan Short
- Translational Neuro-Oncology, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | - Alan A. Melcher
- Translational Immunotherapy, Division of Radiotherapy and Imaging, Institute for Cancer Research, London, United Kingdom
| | - Michael Biggs
- Department of Neurosurgery, North Shore Private Hospital, St Leonards, NSW, Australia
| | - Connie I. Diakos
- Bill Walsh Translational Cancer Research Laboratory, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
- Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, St Leonards, NSW, Australia
- Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Viive M. Howell
- Bill Walsh Translational Cancer Research Laboratory, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| |
Collapse
|