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Liu H, Wang S, Wang J, Guo X, Song Y, Fu K, Gao Z, Liu D, He W, Yang LL. Energy metabolism in health and diseases. Signal Transduct Target Ther 2025; 10:69. [PMID: 39966374 PMCID: PMC11836267 DOI: 10.1038/s41392-025-02141-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/08/2024] [Accepted: 12/25/2024] [Indexed: 02/20/2025] Open
Abstract
Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.
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Affiliation(s)
- Hui Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuo Wang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianhua Wang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xin Guo
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yujing Song
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kun Fu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenjie Gao
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Danfeng Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Wei He
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Lei-Lei Yang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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Hao ZN, Tan XP, Zhang Q, Li J, Xia R, Ma Z. Lactate and Lactylation: Dual Regulators of T-Cell-Mediated Tumor Immunity and Immunotherapy. Biomolecules 2024; 14:1646. [PMID: 39766353 PMCID: PMC11674224 DOI: 10.3390/biom14121646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 12/14/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
Lactate and its derivative, lactylation, play pivotal roles in modulating immune responses within the tumor microenvironment (TME), particularly in T-cell-mediated cancer immunotherapy. Elevated lactate levels, a hallmark of the Warburg effect, contribute to immune suppression through CD8+ T cell functionality and by promoting regulatory T cell (Treg) activity. Lactylation, a post-translational modification (PTM), alters histone and non-histone proteins, influencing gene expression and further reinforcing immune suppression. In the complex TME, lactate and its derivative, lactylation, are not only associated with immune suppression but can also, under certain conditions, exert immunostimulatory effects that enhance cytotoxic responses. This review describes the dual roles of lactate and lactylation in T-cell-mediated tumor immunity, analyzing how these factors contribute to immune evasion, therapeutic resistance, and immune activation. Furthermore, the article highlights emerging therapeutic strategies aimed at inhibiting lactate production or disrupting lactylation pathways to achieve a balanced regulation of these dual effects. These strategies offer new insights into overcoming tumor-induced immune suppression and hold the potential to improve the efficacy of cancer immunotherapies.
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Affiliation(s)
- Zhi-Nan Hao
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Xiao-Ping Tan
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
- The Third Clinical Medical College of Yangtze University, Jingzhou Hospital of Traditional Chinese Medicine, Jingzhou 434023, China
| | - Qing Zhang
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Jie Li
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Ruohan Xia
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China
| | - Zhaowu Ma
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China
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Wang M, Qu L, Du X, Song P, Ng JPL, Wong VKW, Law BYK, Fu X. Natural Products and Derivatives Targeting Metabolic Reprogramming in Colorectal Cancer: A Comprehensive Review. Metabolites 2024; 14:490. [PMID: 39330497 PMCID: PMC11433951 DOI: 10.3390/metabo14090490] [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: 07/17/2024] [Revised: 09/03/2024] [Accepted: 09/05/2024] [Indexed: 09/28/2024] Open
Abstract
Metabolic reprogramming is a critical pathogenesis of colorectal cancer (CRC), referring to metabolic disorders that cancer cells make in response to the stimulating pressure. Metabolic reprogramming induces changes in genetic material and promotes CRC progression and has been proven to be an efficient target of CRC. As natural products have garnered interest due to notable pharmacological effects and potential in counteracting chemoresistance, an increasing body of research is delving into the impact of these natural products on the metabolic reprogramming associated with CRC. In this review, we collected published data from the Web of Science and PubMed, covering the period from January 1980 to October 2023. This article focuses on five central facets of metabolic alterations in cancer cells, glucose metabolism, mitochondrial oxidative phosphorylation (OXPHOS), amino acid metabolism, fatty acid synthesis, and nucleotide metabolism, to provide an overview of recent advancements in natural product interventions targeting metabolic reprogramming in CRC. Our analysis underscores the potential of natural products in disrupting the metabolic pathways of CRC, suggesting promising therapeutic targets for CRC and expanding treatment options for metabolic-associated ailments.
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Affiliation(s)
- Mengyu Wang
- Nehr’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (M.W.)
- Research Institute for Marine Traditional Chinese Medicine, Key Laboratory of Marine Traditional Chinese Medicine in Shandong Universities, Shandong Engineering and Technology Research Center on Omics of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Liqun Qu
- Research Institute for Marine Traditional Chinese Medicine, Key Laboratory of Marine Traditional Chinese Medicine in Shandong Universities, Shandong Engineering and Technology Research Center on Omics of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
- Qingdao Academy of Chinese Medical Sciences Shandong University of Traditional Chinese Medicine, Qingdao Key Laboratory of Research in Marine Traditional Chinese Medicine, Qingdao Key Technology Innovation Center of Marine Traditional Chinese Medicine’s Deep Development and Industrialization, Qingdao 266114, China
| | - Xinying Du
- Research Institute for Marine Traditional Chinese Medicine, Key Laboratory of Marine Traditional Chinese Medicine in Shandong Universities, Shandong Engineering and Technology Research Center on Omics of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
- Qingdao Academy of Chinese Medical Sciences Shandong University of Traditional Chinese Medicine, Qingdao Key Laboratory of Research in Marine Traditional Chinese Medicine, Qingdao Key Technology Innovation Center of Marine Traditional Chinese Medicine’s Deep Development and Industrialization, Qingdao 266114, China
| | - Peng Song
- Nehr’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (M.W.)
- Research Institute for Marine Traditional Chinese Medicine, Key Laboratory of Marine Traditional Chinese Medicine in Shandong Universities, Shandong Engineering and Technology Research Center on Omics of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Jerome P. L. Ng
- Nehr’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (M.W.)
| | - Vincent Kam Wai Wong
- Nehr’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (M.W.)
| | - Betty Yuen Kwan Law
- Nehr’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (M.W.)
| | - Xianjun Fu
- Research Institute for Marine Traditional Chinese Medicine, Key Laboratory of Marine Traditional Chinese Medicine in Shandong Universities, Shandong Engineering and Technology Research Center on Omics of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
- Qingdao Academy of Chinese Medical Sciences Shandong University of Traditional Chinese Medicine, Qingdao Key Laboratory of Research in Marine Traditional Chinese Medicine, Qingdao Key Technology Innovation Center of Marine Traditional Chinese Medicine’s Deep Development and Industrialization, Qingdao 266114, China
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Sunita Prajapati K, Gupta S, Chaudhri S, Kumar S. Role of ONECUT family transcription factors in cancer and other diseases. Exp Cell Res 2024; 438:114035. [PMID: 38593917 DOI: 10.1016/j.yexcr.2024.114035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 04/04/2024] [Accepted: 04/06/2024] [Indexed: 04/11/2024]
Abstract
Members of ONECUT transcription factor play an essential role in several developmental processes, however, the atypical expression of ONECUT proteins lead to numerous diseases, including cancer. ONECUT family proteins promote cell proliferation, progression, invasion, metastasis, angiogenesis, and stemness. This family of proteins interacts with other proteins such as KLF4, TGF-β, VEGFA, PRC2, SMAD3 and alters their expression involved in the regulation of various signaling pathways including Jak/Stat3, Akt/Erk, TGF-β, Smad2/3, and HIF-1α. Furthermore, ONECUT proteins are proposed as predictive biomarkers for pancreatic and gastric cancers. The present review summarizes the involvement of ONECUT family proteins in the development and progression of various human cancers and other diseases.
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Affiliation(s)
- Kumari Sunita Prajapati
- Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Guddha, Bathinda, 151401, Punjab, India
| | - Sanjay Gupta
- Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA
| | - Smriti Chaudhri
- Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Guddha, Bathinda, 151401, Punjab, India
| | - Shashank Kumar
- Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Guddha, Bathinda, 151401, Punjab, India.
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Chiu PF, Chang CK, Huang PS, Lin YY, Lin CS, Yang HY, Hsu LC, Yu LCH, Liang PH. Design, Synthesis, and Evaluation of Glucose Transporter Inhibitor-SN38 Conjugates for Targeting Colorectal Cancer. J Med Chem 2023. [PMID: 37413981 DOI: 10.1021/acs.jmedchem.3c00476] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/08/2023]
Abstract
Irinotecan (1), a prodrug of SN38 (2) approved by the US Food and Drug Administration for treating colorectal cancer, lacks specificity and causes many side effects. To increase the selectivity and therapeutic efficacy of this drug, we designed and synthesized conjugates of SN38 and glucose transporter inhibitors (phlorizin (5) or phloretin (6)), which could be hydrolyzed by glutathione or cathepsin to release SN38 in the tumor microenvironment, as a proof of concept. These conjugates (8, 9, and 10) displayed better antitumor efficacy with lower systemic exposure to SN38 in an orthotopic colorectal cancer mouse model compared with irinotecan at the same dosage. Further, no major adverse effects of the conjugates were observed during treatment. Biodistribution studies showed that conjugate 10 could induce higher concentrations of free SN38 in tumor tissues than irinotecan at the same dosage. Thus, the developed conjugates exhibit potential for treating colorectal cancer.
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Affiliation(s)
- Pei-Fang Chiu
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Chun-Kai Chang
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Pin-Shuo Huang
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - You-Yu Lin
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Chung-Shun Lin
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Hui-Yi Yang
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Lih-Ching Hsu
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Linda Chia-Hui Yu
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei 100, Taiwan
| | - Pi-Hui Liang
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- The Genomics Research Center, Academia Sinica, Taipei 128, Taiwan
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Wang X, Zhao G, Ju C, Dong L, Liu Y, Ding Z, Li W, Peng Y, Zheng J. Reduction of emodin-8-O-ß-D-glucoside content participates in processing-based detoxification of polygoni multiflori radix. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 114:154750. [PMID: 36990007 DOI: 10.1016/j.phymed.2023.154750] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 02/13/2023] [Accepted: 03/06/2023] [Indexed: 06/19/2023]
Abstract
BACKGROUND The occurrence of severe liver injury by the herbal medicine Polygoni Multiflori Radix (PMR) has drawn significant attention. The fact that processing attenuates PMR-induced hepatotoxicity has been well accepted, but the mechanisms are still ambiguous. PURPOSE This study aimed to illuminate the mechanism of processing-based attenuation of PMR hepatotoxicity. METHODS The contents of emodin-8-O-β-d-glucoside (EG) and emodin (EMD) in raw and processed PMR were quantified. The difference in toxicokinetic behaviors of EG and EMD was determined in vivo, and the disposition properties of EG were investigated in vitro and in vivo. RESULTS Decreased EG content was found in processed (black bean) PMR. Processed PMR showed reduced adverse effects relative to raw PMR. In addition, less hepatic protein adduction derived from EMD was produced in mice after exposure to processed PMR than that in animals receiving raw PMR. Glucose transporters SGLT1 and GLUT2 participated in the absorption of EG, and effective hydrolysis of EG to EMD took place in the intestinal epithelial cells during the process of absorption. Cytosolic broad-specificity β-glucosidase and lactase phlorizin hydrolase, as well as intestinal flora, participated in the hydrolysis of EG. The circulated EMD resulting from the deglycosylation of EG executed the hepatotoxic action. CONCLUSION EG is a pre-toxin and can be metabolically activated to EMD participating in the hepatotoxic event. The reduction of EG content due to processing is a key mechanistic factor that initiates the detoxification of PMR.
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Affiliation(s)
- Xu Wang
- Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Roa, Shenyang, Liaoning 110016, PR China
| | - Guode Zhao
- Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Roa, Shenyang, Liaoning 110016, PR China
| | - Chengguo Ju
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, Liaoning 116600, PR China
| | - Lingwen Dong
- Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Roa, Shenyang, Liaoning 110016, PR China
| | - Yuyang Liu
- Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Roa, Shenyang, Liaoning 110016, PR China
| | - Zifang Ding
- Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Roa, Shenyang, Liaoning 110016, PR China
| | - Weiwei Li
- State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province, Guizhou Medical University, 9 Beijing Road, Guiyang, Guizhou 550025, PR China; State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004 Guizhou, PR China.
| | - Ying Peng
- Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Roa, Shenyang, Liaoning 110016, PR China.
| | - Jiang Zheng
- Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Roa, Shenyang, Liaoning 110016, PR China; State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province, Guizhou Medical University, 9 Beijing Road, Guiyang, Guizhou 550025, PR China.
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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.
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De S, Paul S, Manna A, Majumder C, Pal K, Casarcia N, Mondal A, Banerjee S, Nelson VK, Ghosh S, Hazra J, Bhattacharjee A, Mandal SC, Pal M, Bishayee A. Phenolic Phytochemicals for Prevention and Treatment of Colorectal Cancer: A Critical Evaluation of In Vivo Studies. Cancers (Basel) 2023; 15:993. [PMID: 36765950 PMCID: PMC9913554 DOI: 10.3390/cancers15030993] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/30/2023] [Accepted: 01/30/2023] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed and second leading cause of cancer-related death worldwide. Limitations with existing treatment regimens have demanded the search for better treatment options. Different phytochemicals with promising anti-CRC activities have been reported, with the molecular mechanism of actions still emerging. This review aims to summarize recent progress on the study of natural phenolic compounds in ameliorating CRC using in vivo models. This review followed the guidelines of the Preferred Reporting Items for Systematic Reporting and Meta-Analysis. Information on the relevant topic was gathered by searching the PubMed, Scopus, ScienceDirect, and Web of Science databases using keywords, such as "colorectal cancer" AND "phenolic compounds", "colorectal cancer" AND "polyphenol", "colorectal cancer" AND "phenolic acids", "colorectal cancer" AND "flavonoids", "colorectal cancer" AND "stilbene", and "colorectal cancer" AND "lignan" from the reputed peer-reviewed journals published over the last 20 years. Publications that incorporated in vivo experimental designs and produced statistically significant results were considered for this review. Many of these polyphenols demonstrate anti-CRC activities by inhibiting key cellular factors. This inhibition has been demonstrated by antiapoptotic effects, antiproliferative effects, or by upregulating factors responsible for cell cycle arrest or cell death in various in vivo CRC models. Numerous studies from independent laboratories have highlighted different plant phenolic compounds for their anti-CRC activities. While promising anti-CRC activity in many of these agents has created interest in this area, in-depth mechanistic and well-designed clinical studies are needed to support the therapeutic use of these compounds for the prevention and treatment of CRC.
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Affiliation(s)
- Samhita De
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | - Sourav Paul
- Department of Biotechnology, National Institute of Technology, Durgapur 713 209, India
| | - Anirban Manna
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | | | - Koustav Pal
- Jawaharlal Institute Post Graduate Medical Education and Research, Puducherry 605 006, India
| | - Nicolette Casarcia
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| | - Arijit Mondal
- Department of Pharmaceutical Chemistry, M.R. College of Pharmaceutical Sciences and Research, Balisha 743 234, India
| | - Sabyasachi Banerjee
- Department of Pharmaceutical Chemistry, Gupta College of Technological Sciences, Asansol 713 301, India
| | - Vinod Kumar Nelson
- Department of Pharmacology, Raghavendra Institute of Pharmaceutical Education and Research, Anantapur 515 721, India
| | - Suvranil Ghosh
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | - Joyita Hazra
- Department of Biotechnology, Indian Institute of Technology, Chennai 600 036, India
| | - Ashish Bhattacharjee
- Department of Biotechnology, National Institute of Technology, Durgapur 713 209, India
| | | | - Mahadeb Pal
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
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Thilagavathi R, Priyankha S, Kannan M, Prakash M, Selvam C. Compounds from diverse natural origin against triple-negative breast cancer: A comprehensive review. Chem Biol Drug Des 2023; 101:218-243. [PMID: 36323650 DOI: 10.1111/cbdd.14172] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 10/25/2022] [Accepted: 10/29/2022] [Indexed: 11/05/2022]
Abstract
Triple-negative breast cancer (TNBC) is caused due to the lack of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor 2 (HER2) expression. Triple-negative breast cancer is the most aggressive heterogeneous disease that is capable of producing different clones and mutations. Tumorigenesis in TNBC is caused due to the mutation or overexpression of tumor suppressor genes. It is also associated with mutations in the BRCA gene which is linked to hereditary breast cancer. In addition, PARP proteins and checkpoint proteins also play a crucial function in causing TNBC. Many cell signaling pathways are dysregulated in TNBC. Even though chemotherapy and immunotherapy are good options for TNBC treatment, the response rates are still low in general. Many phytochemicals that are derived from natural compounds have shown very good inhibitions for TNBC. Natural compounds have the great advantage of being less toxic, having lesser side effects, and being easily available. The secondary metabolites such as alkaloids, terpenoids, steroids, and flavonoids in natural products make them promising inhibitors of TNBC. Their compositions also offer vital insights into inhibitory action, which could lead to new cancer-fighting strategies. This review can help in understanding how naturally occurring substances and medicinal herbs decrease specific tumors and pave the way for the development of novel and extremely efficient antitumor therapies.
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Affiliation(s)
- Ramasamy Thilagavathi
- Department of Biotechnology, Faculty of Engineering, Karpagam Academy of Higher Education, Coimbatore, India
| | - Sridhar Priyankha
- Department of Chemistry, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Chengalpattu, India
| | - Manivel Kannan
- Faculty of Pharmacy, Karpagam Academy of Higher Education, Coimbatore, India
| | - Muthuramalingam Prakash
- Department of Chemistry, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Chengalpattu, India
| | - Chelliah Selvam
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA
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Hytti M, Ruuth J, Kanerva I, Bhattarai N, Pedersen ML, Nielsen CU, Kauppinen A. Phloretin inhibits glucose transport and reduces inflammation in human retinal pigment epithelial cells. Mol Cell Biochem 2023; 478:215-227. [PMID: 35771396 PMCID: PMC9836970 DOI: 10.1007/s11010-022-04504-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 06/15/2022] [Indexed: 01/24/2023]
Abstract
During age-related macular degeneration (AMD), chronic inflammatory processes, possibly fueled by high glucose levels, cause a breakdown of the retinal pigment epithelium (RPE), leading to vision loss. Phloretin, a natural dihydroxychalcone found in apples, targets several anti-inflammatory signaling pathways and effectively inhibits transporter-mediated glucose uptake. It could potentially prevent inflammation and cell death of RPE cells through either direct regulation of inflammatory signaling pathways or through amelioration of high glucose levels. To test this hypothesis, ARPE-19 cells were incubated with or without phloretin for 1 h before exposure to lipopolysaccharide (LPS). Cell viability and the release of pro-inflammatory cytokines interleukin 6 (IL-6), IL-8 and vascular endothelial growth factor (VEGF) were measured. Glucose uptake was studied using isotope uptake studies. The nuclear levels of nuclear factor erythroid 2-related factor 2 (Nrf2) were determined alongside the phosphorylation levels of mitogen-activated protein kinases. Phloretin pretreatment reduced the LPS-induced release of IL-6 and IL-8 as well as VEGF. Phloretin increased intracellular levels of reactive oxygen species and nuclear translocation of Nrf2. It also inhibited glucose uptake into ARPE-19 cells and the phosphorylation of Jun-activated kinase (JNK). Subsequent studies revealed that Nrf2, but not the inhibition of glucose uptake or JNK phosphorylation, was the main pathway of phloretin's anti-inflammatory activities. Phloretin was robustly anti-inflammatory in RPE cells and reduced IL-8 secretion via activation of Nrf2 but the evaluation of its potential in the treatment or prevention of AMD requires further studies.
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Affiliation(s)
- Maria Hytti
- School of Pharmacy, Department of Health Sciences, University of Eastern Finland, Yliopistonranta 1 C, 70210 Kuopio, Finland
| | - Johanna Ruuth
- School of Pharmacy, Department of Health Sciences, University of Eastern Finland, Yliopistonranta 1 C, 70210 Kuopio, Finland ,School of Medicine, Department of Health Sciences, University of Eastern Finland, Yliopistonranta 1 C, 70210 Kuopio, Finland
| | - Iiris Kanerva
- School of Pharmacy, Department of Health Sciences, University of Eastern Finland, Yliopistonranta 1 C, 70210 Kuopio, Finland
| | - Niina Bhattarai
- School of Pharmacy, Department of Health Sciences, University of Eastern Finland, Yliopistonranta 1 C, 70210 Kuopio, Finland
| | - Maria L. Pedersen
- Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark
| | - Carsten U. Nielsen
- Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark
| | - Anu Kauppinen
- School of Pharmacy, Department of Health Sciences, University of Eastern Finland, Yliopistonranta 1 C, 70210 Kuopio, Finland
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11
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Tuli HS, Rath P, Chauhan A, Ramniwas S, Vashishth K, Varol M, Jaswal VS, Haque S, Sak K. Phloretin, as a Potent Anticancer Compound: From Chemistry to Cellular Interactions. Molecules 2022; 27:8819. [PMID: 36557950 PMCID: PMC9787340 DOI: 10.3390/molecules27248819] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 12/06/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022] Open
Abstract
Phloretin is a natural dihydrochalcone found in many fruits and vegetables, especially in apple tree leaves and the Manchurian apricots, exhibiting several therapeutic properties, such as antioxidant, antidiabetic, anti-inflammatory, and antitumor activities. In this review article, the diverse aspects of the anticancer potential of phloretin are addressed, presenting its antiproliferative, proapoptotic, antimetastatic, and antiangiogenic activities in many different preclinical cancer models. The fact that phloretin is a planar lipophilic polyphenol and, thus, a membrane-disrupting Pan-Assay Interference compound (PAIN) compromises the validity of the cell-based anticancer activities. Phloretin significantly reduces membrane dipole potential and, therefore, is expected to be able to activate a number of cellular signaling pathways in a non-specific way. In this way, the effects of this minor flavonoid on Bax and Bcl-2 proteins, caspases and MMPs, cytokines, and inflammatory enzymes are all analyzed in the current review. Moreover, besides the anticancer activities exerted by phloretin alone, its co-effects with conventional anticancer drugs are also under discussion. Therefore, this review presents a thorough overview of the preclinical anticancer potential of phloretin, allowing one to take the next steps in the development of novel drug candidates and move on to clinical trials.
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Affiliation(s)
- Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala 133207, India
| | - Prangya Rath
- Amity Institute of Environmental Sciences, Amity University, Noida 201303, India
| | - Abhishek Chauhan
- Amity Institute of Environmental Toxicology, Safety and Management, Amity University, Noida 201303, India
| | - Seema Ramniwas
- University Centre for Research & Development, University Institute of Pharmaceutical Sciences, Chandigarh University, Gharuan, Mohali 140413, India
| | - Kanupriya Vashishth
- Advance Cardiac Centre Department of Cardiology, Post Graduate Institute of Medical Education and Research (PGIMER) Chandigarh, Chandigarh 160012, India
| | - Mehmet Varol
- Department of Molecular Biology and Genetics, Faculty of Science, Kotekli Campus, Mugla Sitki Kocman University, Mugla 48000, Turkey
| | - Vivek Sheel Jaswal
- Department of Chemistry and Chemical Science, School of Physical & Material Sciences, Central University of Himachal Pradesh, Dharamshala 176206, India
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan 45142, Saudi Arabia
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12
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Velázquez D, Průša V, Masrati G, Yariv E, Sychrova H, Ben‐Tal N, Zimmermannova O. Allosteric links between the hydrophilic N-terminus and transmembrane core of human Na + /H + antiporter NHA2. Protein Sci 2022; 31:e4460. [PMID: 36177733 PMCID: PMC9667825 DOI: 10.1002/pro.4460] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 09/16/2022] [Accepted: 09/25/2022] [Indexed: 12/13/2022]
Abstract
The human Na+ /H+ antiporter NHA2 (SLC9B2) transports Na+ or Li+ across the plasma membrane in exchange for protons, and is implicated in various pathologies. It is a 537 amino acids protein with an 82 residues long hydrophilic cytoplasmic N-terminus followed by a transmembrane part comprising 14 transmembrane helices. We optimized the functional expression of HsNHA2 in the plasma membrane of a salt-sensitive Saccharomyces cerevisiae strain and characterized in vivo a set of mutated or truncated versions of HsNHA2 in terms of their substrate specificity, transport activity, localization, and protein stability. We identified a highly conserved proline 246, located in the core of the protein, as being crucial for ion selectivity. The replacement of P246 with serine or threonine resulted in antiporters with altered substrate specificity that were not only highly active at acidic pH 4.0 (like the native antiporter), but also at neutral pH. P246T/S versions also exhibited increased resistance to the HsNHA2-specific inhibitor phloretin. We experimentally proved that a putative salt bridge between E215 and R432 is important for antiporter function, but also structural integrity. Truncations of the first 50-70 residues of the N-terminus doubled the transport activity of HsNHA2, while changes in the charge at positions E47, E56, K57, or K58 decreased the antiporter's transport activity. Thus, the hydrophilic N-terminal part of the protein appears to allosterically auto-inhibit cation transport of HsNHA2. Our data also show this in vivo approach to be useful for a rapid screening of SNP's effect on HsNHA2 activity.
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Affiliation(s)
- Diego Velázquez
- Laboratory of Membrane TransportInstitute of Physiology of the Czech Academy of SciencesPragueCzech Republic
| | - Vojtěch Průša
- Laboratory of Membrane TransportInstitute of Physiology of the Czech Academy of SciencesPragueCzech Republic
| | - Gal Masrati
- Department of Biochemistry and Molecular BiologyGeorge S. Wise Faculty of Life Sciences, Tel‐Aviv UniversityTel‐AvivIsrael
| | - Elon Yariv
- Department of Biochemistry and Molecular BiologyGeorge S. Wise Faculty of Life Sciences, Tel‐Aviv UniversityTel‐AvivIsrael
| | - Hana Sychrova
- Laboratory of Membrane TransportInstitute of Physiology of the Czech Academy of SciencesPragueCzech Republic
| | - Nir Ben‐Tal
- Department of Biochemistry and Molecular BiologyGeorge S. Wise Faculty of Life Sciences, Tel‐Aviv UniversityTel‐AvivIsrael
| | - Olga Zimmermannova
- Laboratory of Membrane TransportInstitute of Physiology of the Czech Academy of SciencesPragueCzech Republic
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13
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Temre MK, Kumar A, Singh SM. An appraisal of the current status of inhibition of glucose transporters as an emerging antineoplastic approach: Promising potential of new pan-GLUT inhibitors. Front Pharmacol 2022; 13:1035510. [PMID: 36386187 PMCID: PMC9663470 DOI: 10.3389/fphar.2022.1035510] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/18/2022] [Indexed: 07/23/2023] Open
Abstract
Neoplastic cells displayed altered metabolism with accelerated glycolysis. Therefore, these cells need a mammoth supply of glucose for which they display an upregulated expression of various glucose transporters (GLUT). Thus, novel antineoplastic strategies focus on inhibiting GLUT to intersect the glycolytic lifeline of cancer cells. This review focuses on the current status of various GLUT inhibition scenarios. The GLUT inhibitors belong to both natural and synthetic small inhibitory molecules category. As neoplastic cells express multiple GLUT isoforms, it is necessary to use pan-GLUT inhibitors. Nevertheless, it is also necessary that such pan-GLUT inhibitors exert their action at a low concentration so that normal healthy cells are left unharmed and minimal injury is caused to the other vital organs and systems of the body. Moreover, approaches are also emerging from combining GLUT inhibitors with other chemotherapeutic agents to potentiate the antineoplastic action. A new pan-GLUT inhibitor named glutor, a piperazine-one derivative, has shown a potent antineoplastic action owing to its inhibitory action exerted at nanomolar concentrations. The review discusses the merits and limitations of the existing GLUT inhibitory approach with possible future outcomes.
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Affiliation(s)
- Mithlesh Kumar Temre
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Ajay Kumar
- Deparment of Zoology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Sukh Mahendra Singh
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
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14
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Carecho R, Figueira I, Terrasso AP, Godinho‐Pereira J, de Oliveira Sequeira C, Pereira SA, Milenkovic D, Leist M, Brito C, Nunes dos Santos C. Circulating (Poly)phenol Metabolites: Neuroprotection in a 3D Cell Model of Parkinson's Disease. Mol Nutr Food Res 2022; 66:e2100959. [PMID: 34964254 PMCID: PMC9788306 DOI: 10.1002/mnfr.202100959] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/10/2021] [Indexed: 12/30/2022]
Abstract
SCOPE Diets rich in (poly)phenols have been associated with positive effects on neurodegenerative disorders, such as Parkinson's disease (PD). Several low-molecular weight (poly)phenol metabolites (LMWPM) are found in the plasma after consumption of (poly)phenol-rich food. It is expected that LMWPM, upon reaching the brain, may have beneficial effects against both oxidative stress and neuroinflammation, and possibly attenuate cell death mechanisms relate to the loss of dopaminergic neurons in PD. METHODS AND RESULTS This study investigates the neuroprotective potential of two blood-brain barrier permeant LMWPM, catechol-O-sulfate (cat-sulf), and pyrogallol-O-sulfate (pyr-sulf), in a human 3D cell model of PD. Neurospheroids were generated from LUHMES neuronal precursor cells and challenged by 1-methyl-4-phenylpyridinium (MPP+ ) to induce neuronal stress. LMWPM pretreatments were differently neuroprotective towards MPP+ insult, presenting distinct effects on the neuronal transcriptome. Particularly, cat-sulf pretreatment appeared to boost counter-regulatory defense mechanisms (preconditioning). When MPP+ is applied, both LMWPM positively modulated glutathione metabolism and heat-shock response, as also favorably shifting the balance of pro/anti-apoptotic proteins. CONCLUSIONS Our findings point to the potential of LMWPM to trigger molecular mechanisms that help dopaminergic neurons to cope with a subsequent toxic insult. They are promising molecules to be further explored in the context of preventing and attenuating parkinsonian neurodegeneration.
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Affiliation(s)
- Rafael Carecho
- CEDOCNOVA Medical SchoolFaculdade de Ciências MédicasUniversidade NOVA de Lisboa1150‐082LisboaPortugal
- ITQBInstituto de Tecnologia Química e Biológica António XavierUniversidade Nova de Lisboa2780‐157OeirasPortugal
| | - Inês Figueira
- CEDOCNOVA Medical SchoolFaculdade de Ciências MédicasUniversidade NOVA de Lisboa1150‐082LisboaPortugal
| | - Ana Paula Terrasso
- ITQBInstituto de Tecnologia Química e Biológica António XavierUniversidade Nova de Lisboa2780‐157OeirasPortugal
- iBETInstituto de Biologia Experimental e Tecnológica2781–901OeirasPortugal
| | - Joana Godinho‐Pereira
- ITQBInstituto de Tecnologia Química e Biológica António XavierUniversidade Nova de Lisboa2780‐157OeirasPortugal
- iBETInstituto de Biologia Experimental e Tecnológica2781–901OeirasPortugal
| | | | - Sofia Azeredo Pereira
- CEDOCNOVA Medical SchoolFaculdade de Ciências MédicasUniversidade NOVA de Lisboa1150‐082LisboaPortugal
| | - Dragan Milenkovic
- INRAEUNHUniversité Clermont Auvergne63122St Genes ChampanelleFrance
- Department of NutritionUniversity of California Davis95616DavisCAUSA
| | - Marcel Leist
- In‐vitro Toxicology and BiomedicineUniversity of Konstanz78457ConstanceGermany
| | - Catarina Brito
- ITQBInstituto de Tecnologia Química e Biológica António XavierUniversidade Nova de Lisboa2780‐157OeirasPortugal
- iBETInstituto de Biologia Experimental e Tecnológica2781–901OeirasPortugal
| | - Cláudia Nunes dos Santos
- CEDOCNOVA Medical SchoolFaculdade de Ciências MédicasUniversidade NOVA de Lisboa1150‐082LisboaPortugal
- ITQBInstituto de Tecnologia Química e Biológica António XavierUniversidade Nova de Lisboa2780‐157OeirasPortugal
- iBETInstituto de Biologia Experimental e Tecnológica2781–901OeirasPortugal
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15
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Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies. Cancers (Basel) 2022; 14:cancers14194568. [PMID: 36230492 PMCID: PMC9559313 DOI: 10.3390/cancers14194568] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/14/2022] [Accepted: 09/16/2022] [Indexed: 11/24/2022] Open
Abstract
Simple Summary Reprogramming of glucose metabolism is a hallmark of cancer and can be targeted by therapeutic agents. Some metabolism regulators, such as ivosidenib and enasidenib, have been approved for cancer treatment. Currently, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Furthermore, some natural products have shown efficacy in killing tumor cells by regulating glucose metabolism, offering novel therapeutic opportunities in cancer. However, most of them have failed to be translated into clinical applications due to low selectivity, high toxicity, and side effects. Recent studies suggest that combining glucose metabolism modulators with chemotherapeutic drugs, immunotherapeutic drugs, and other conventional anticancer drugs may be a future direction for cancer treatment. Abstract Reprogramming of glucose metabolism provides sufficient energy and raw materials for the proliferation, metastasis, and immune escape of cancer cells, which is enabled by glucose metabolism-related enzymes that are abundantly expressed in a broad range of cancers. Therefore, targeting glucose metabolism enzymes has emerged as a promising strategy for anticancer drug development. Although several glucose metabolism modulators have been approved for cancer treatment in recent years, some limitations exist, such as a short half-life, poor solubility, and numerous adverse effects. With the rapid development of medicinal chemicals, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Additionally, several studies have found that some natural products can suppress cancer progression by regulating glucose metabolism enzymes. In this review, we summarize the mechanisms underlying the reprogramming of glucose metabolism and present enzymes that could serve as therapeutic targets. In addition, we systematically review the existing drugs targeting glucose metabolism enzymes, including small-molecule modulators and natural products. Finally, the opportunities and challenges for glucose metabolism enzyme-targeted anticancer drugs are also discussed. In conclusion, combining glucose metabolism modulators with conventional anticancer drugs may be a promising cancer treatment strategy.
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16
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Kim JL, Lee DH, Pan CH, Park S, Oh SC, Lee SY. Role of phloretin as a sensitizer to TRAIL‑induced apoptosis in colon cancer. Oncol Lett 2022; 24:321. [PMID: 35949608 PMCID: PMC9353883 DOI: 10.3892/ol.2022.13441] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 04/06/2022] [Indexed: 11/06/2022] Open
Abstract
Phloretin is one of the apple polyphenols with anticancer activities. Since tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) serves important roles in inducing apoptosis, the present study examined the effect of phloretin on TRAIL-induced apoptosis in colon cancer cells. Treatment with both phloretin and TRAIL markedly suppressed the survival of cancer cells from several colon cancer cell lines compared with that of cells treated with either TRAIL or phloretin. Additionally, decreased numbers of colonies were observed following addition of phloretin and TRAIL. Furthermore, TRAIL- and phloretin-treated HT-29-Luc cells exhibited decreased luciferase activity. Increased apoptosis was observed in phloretin- and TRAIL-treated HT-29-Luc colon cancer cells, accompanying elevated levels of cleaved poly(ADP-ribose) polymerase, and caspase-3, −8 and −9. The expression levels of MCL1 apoptosis regulator BCL2 family member (Mcl-1) were decreased following addition of phloretin in colon cancer cells. In addition, overexpression of Mcl-1 in phloretin- and TRAIL-treated HT-29-Luc cells resulted in increased cell survival. Treatment of HT-29-Luc cells with a combination of cycloheximide (CHX) and phloretin led to a more prominent decrease in Mcl-1 expression compared with that in cells treated with CHX alone, while Mcl-1 expression was recovered by treatment with MG132. Binding of ubiquitin with Mcl-1 was verified using immunoprecipitation. Intraperitoneal injection of both TRAIL and phloretin into tumor xenografts was associated with a decreased tumor volume compared with that following injection with either TRAIL or phloretin. Overall, the present results suggest a synergistic effect of phloretin on TRAIL-induced apoptosis in colon cancer cells.
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Affiliation(s)
- Jung-Lim Kim
- Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University, Seoul 08308, Republic of Korea
| | - Dae-Hee Lee
- Department of Marine Food Science and Technology, Gangneung‑Wonju National University, Gangneung, Gangwon 25457, Republic of Korea
| | - Cheol-Ho Pan
- Natural Product Informatics Research Center, Korea Institute of Science and Technology Gangneung Institute of Natural Products, Gangneung, Gangwon 25451, Republic of Korea
| | - Su Park
- Department of Surgery, Wonkwang University Sanbon Hospital, Gyeonggi 15865, Republic of Korea
| | - Sang-Cheul Oh
- Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University, Seoul 08308, Republic of Korea
| | - Suk-Young Lee
- Division of Hemato‑Oncology, Department of Internal Medicine, School of Medicine, Wonkwang University Sanbon Hospital, Gunpo, Gyeonggi 15865, Republic of Korea
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17
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Huang T, Che Q, Chen X, Chen D, Yu B, He J, Chen H, Yan H, Zheng P, Luo Y, Huang Z. Apple Polyphenols Improve Intestinal Antioxidant Capacity and Barrier Function by Activating the Nrf2/Keap1 Signaling Pathway in a Pig Model. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:7576-7585. [PMID: 35679090 DOI: 10.1021/acs.jafc.2c02495] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
In recent years, the function of plant polyphenols to improve the intestinal barrier has been fully demonstrated. However, the exact mechanisms linking plant polyphenols with the intestinal barrier function have not yet been established. Apple polyphenols (APs) are safe and healthy nutrients, which are extracted from apples and their byproducts. Using pig and IPEC-J2 cell models, this study investigated the effects of dietary AP supplementation on intestinal antioxidant capacity and barrier function. Then, we further explored the role of the Nrf2/Keap1 signaling pathway in maintaining intestinal antioxidant capacity and barrier function. Our study found that dietary AP supplementation improved the intestinal mechanical barrier by promoting the intestinal morphology and intestinal tight junction protein expression, improved the intestinal immune barrier by increasing intestinal secretory immunoglobulin A production, and improved the intestinal biological barrier by increasing probiotics and decreasing the Escherichia coli population. Further research found that dietary AP supplementation increased the intestinal antioxidant capacity and activated the Nrf2/Keap1 signaling pathway. Finally, after treatment with Nrf2-specific inhibitor ML-385, the upregulation effect of APs on antioxidant capacity and tight junction protein expression was reduced in IPEC-J2 cells. Our results suggested that APs promoted intestinal antioxidant capacity and barrier function via the Nrf2/Keap1 signaling pathway.
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Affiliation(s)
- Tengteng Huang
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan 611130, P. R. China
| | - Qiangjun Che
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan 611130, P. R. China
| | - Xiaoling Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan 611130, P. R. China
| | - Daiwen Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan 611130, P. R. China
| | - Bing Yu
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan 611130, P. R. China
| | - Jun He
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan 611130, P. R. China
| | - Hong Chen
- College of Food Science, Sichuan Agricultural University, Yaan, Sichuan 625014, P. R. China
| | - Hui Yan
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan 611130, P. R. China
| | - Ping Zheng
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan 611130, P. R. China
| | - Yuheng Luo
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan 611130, P. R. China
| | - Zhiqing Huang
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan 611130, P. R. China
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18
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Kubik J, Humeniuk E, Adamczuk G, Madej-Czerwonka B, Korga-Plewko A. Targeting Energy Metabolism in Cancer Treatment. Int J Mol Sci 2022; 23:ijms23105572. [PMID: 35628385 PMCID: PMC9146201 DOI: 10.3390/ijms23105572] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/12/2022] [Accepted: 05/15/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer is the second most common cause of death worldwide after cardiovascular diseases. The development of molecular and biochemical techniques has expanded the knowledge of changes occurring in specific metabolic pathways of cancer cells. Increased aerobic glycolysis, the promotion of anaplerotic responses, and especially the dependence of cells on glutamine and fatty acid metabolism have become subjects of study. Despite many cancer treatment strategies, many patients with neoplastic diseases cannot be completely cured due to the development of resistance in cancer cells to currently used therapeutic approaches. It is now becoming a priority to develop new treatment strategies that are highly effective and have few side effects. In this review, we present the current knowledge of the enzymes involved in the different steps of glycolysis, the Krebs cycle, and the pentose phosphate pathway, and possible targeted therapies. The review also focuses on presenting the differences between cancer cells and normal cells in terms of metabolic phenotype. Knowledge of cancer cell metabolism is constantly evolving, and further research is needed to develop new strategies for anti-cancer therapies.
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Affiliation(s)
- Joanna Kubik
- Independent Medical Biology Unit, Faculty of Pharmacy, Medical University of Lublin, 20-093 Lublin, Poland; (J.K.); (G.A.); (A.K.-P.)
| | - Ewelina Humeniuk
- Independent Medical Biology Unit, Faculty of Pharmacy, Medical University of Lublin, 20-093 Lublin, Poland; (J.K.); (G.A.); (A.K.-P.)
- Correspondence: ; Tel.: +48-81-448-65-20
| | - Grzegorz Adamczuk
- Independent Medical Biology Unit, Faculty of Pharmacy, Medical University of Lublin, 20-093 Lublin, Poland; (J.K.); (G.A.); (A.K.-P.)
| | - Barbara Madej-Czerwonka
- Human Anatomy Department, Faculty of Medicine, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Agnieszka Korga-Plewko
- Independent Medical Biology Unit, Faculty of Pharmacy, Medical University of Lublin, 20-093 Lublin, Poland; (J.K.); (G.A.); (A.K.-P.)
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19
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Oyenihi AB, Belay ZA, Mditshwa A, Caleb OJ. "An apple a day keeps the doctor away": The potentials of apple bioactive constituents for chronic disease prevention. J Food Sci 2022; 87:2291-2309. [PMID: 35502671 PMCID: PMC9321083 DOI: 10.1111/1750-3841.16155] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 03/04/2022] [Accepted: 03/27/2022] [Indexed: 11/30/2022]
Abstract
Apples are rich sources of selected micronutrients (e.g., iron, zinc, vitamins C and E) and polyphenols (e.g., procyanidins, phloridzin, 5′‐caffeoylquinic acid) that can help in mitigating micronutrient deficiencies (MNDs) and chronic diseases. This review provides an up‐to‐date overview of the significant bioactive compounds in apples together with their reported pharmacological actions against chronic diseases such as diabetes, cancer, and cardiovascular diseases. For consumers to fully gain these health benefits, it is important to ensure an all‐year‐round supply of highly nutritious and good‐quality apples. Therefore, after harvest, the physicochemical and nutritional quality attributes of apples are maintained by applying various postharvest treatments and hurdle techniques. The impact of these postharvest practices on the safety of apples during storage is also highlighted. This review emphasizes that advancements in postharvest management strategies that extend the storage life of apples should be optimized to better preserve the bioactive components crucial to daily dietary needs and this can help improve the overall health of consumers.
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Affiliation(s)
- Ayodeji B Oyenihi
- Functional Foods Research Unit, Faculty of Applied Sciences, Cape Peninsula University of Technology, Bellville, South Africa
| | - Zinash A Belay
- Agri-Food Systems & Omics Laboratory, Post-Harvest and Agro-Processing Technologies (PHATs), Agricultural Research Council (ARC) Infruitec-Nietvoorbij, Stellenbosch, South Africa
| | - Asanda Mditshwa
- School of Agriculture, Earth and Environmental Sciences, College of Agriculture, Engineering and Science, University of KwaZulu-Natal (PMB-Campus), Scottsville, South Africa
| | - Oluwafemi J Caleb
- Department of Food Science, Faculty of AgriSciences, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa.,SARChI Postharvest Technology Laboratory, African Institute for Postharvest Technology, Faculty of AgriSciences, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa
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20
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Losurdo G, Gravina AG, Maroni L, Gabrieletto EM, Ianiro G, Ferrarese A. Future challenges in gastroenterology and hepatology, between innovations and unmet needs: A SIGE Young Editorial Board's perspective. Dig Liver Dis 2022; 54:583-597. [PMID: 34509394 DOI: 10.1016/j.dld.2021.08.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 08/09/2021] [Accepted: 08/12/2021] [Indexed: 02/08/2023]
Abstract
Gastroenterology, Digestive Endoscopy and Hepatology have faced significant improvements in terms of diagnosis and therapy in the last decades. However, many fields still remain poorly explored, and many questions unanswered. Moreover, basic-science, as well as translational and clinical discoveries, together with technology advancement will determine further steps toward a better, refined care for many gastroenterological disorders in the future. Therefore, the Young Investigators of the Italian Society of Gastroenterology (SIGE) joined together, offering a perspective on major future innovations in some hot clinical topics in Gastroenterology, Endoscopy, and Hepatology, as well as the current pitfalls and the grey zones.
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Affiliation(s)
- Giuseppe Losurdo
- Gastroenterology Unit, Department of Emergency and Organ Transplantation, University 'Aldo Moro' of Bari; PhD Course in Organs and Tissues Transplantation and Cellular Therapies, Department of Emergency and Organ Transplantation, University 'Aldo Moro' of Bari.
| | - Antonietta Gerarda Gravina
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Luca Maroni
- Department of Gastroenterology, Marche Polytechnic University, Ancona, Italy
| | | | - Gianluca Ianiro
- Digestive Disease Center, Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Alberto Ferrarese
- Gastroenterology and Hepatology, Azienda Ospedaliera Universitaria Integrata, Ospedale Borgo Trento, Verona, Italy
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21
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Arif MU, Khan MKI, Riaz S, Nazir A, Maan AA, Amin U, Saeed F, Afzaal M. Role of fruits in aging and age-related disorders. Exp Gerontol 2022; 162:111763. [DOI: 10.1016/j.exger.2022.111763] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 02/04/2022] [Accepted: 02/27/2022] [Indexed: 11/24/2022]
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Effects of Annurca Flesh Apple Polyphenols in Human Thyroid Cancer Cell Lines. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:6268755. [PMID: 35222800 PMCID: PMC8872649 DOI: 10.1155/2022/6268755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 01/14/2022] [Accepted: 01/25/2022] [Indexed: 11/24/2022]
Abstract
Among natural macromolecules, the polyphenol extract from Annurca flesh (AFPE) apple could play a potential therapeutic role for a large spectrum of human cancer also by exerting antioxidant properties. Thyroid cancer is a common neoplasia in women, and it is in general responsive to treatments although patients may relapse and metastasize or therapy-related side effects could occur. In this study, we explored the effects of AFPE on papillary (TPC-1) and anaplastic (CAL62) thyroid cancer cell line proliferation and viability. We found that AFPE exposure induced a reduction of cell proliferation and cell viability in dose-dependent manner. The effect was associated with the reduction of phosphorylation of Rb protein. To study the mechanisms underlying the biological effects of AFPE treatment in thyroid cancer cells, we investigated the modulation of miRNA (miR) expression. We found that AFPE treatment increased the expression of the miR-141, miR-145, miR-200a-5p, miR-425, and miR-551b-5p. Additionally, since natural polyphenols could exert their beneficial effects through the antioxidant properties, we investigated this aspect, and we found that AFPE treatment reduced the production of reactive oxygen species (ROS) in CAL62 cells. Moreover, AFPE pretreatment protects against hydrogen peroxide-induced oxidative stress in thyroid cancer cell lines. Taken together, our findings suggest that AFPE, by acting at micromolar concentration in thyroid cancer cell lines, may be considered a promising adjuvant natural agent for thyroid cancer treatment approach.
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23
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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: 16] [Impact Index Per Article: 4.0] [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.
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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
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24
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Casado-Díaz A, Rodríguez-Ramos Á, Torrecillas-Baena B, Dorado G, Quesada-Gómez JM, Gálvez-Moreno MÁ. Flavonoid Phloretin Inhibits Adipogenesis and Increases OPG Expression in Adipocytes Derived from Human Bone-Marrow Mesenchymal Stromal-Cells. Nutrients 2021; 13:4185. [PMID: 34836440 PMCID: PMC8623874 DOI: 10.3390/nu13114185] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 12/20/2022] Open
Abstract
Phloretin (a flavonoid abundant in apple), has antioxidant, anti-inflammatory, and glucose-transporter inhibitory properties. Thus, it has interesting pharmacological and nutraceutical potential. Bone-marrow mesenchymal stem cells (MSC) have high differentiation capacity, being essential for maintaining homeostasis and regenerative capacity in the organism. Yet, they preferentially differentiate into adipocytes instead of osteoblasts with aging. This has a negative impact on bone turnover, remodeling, and formation. We have evaluated the effects of phloretin on human adipogenesis, analyzing MSC induced to differentiate into adipocytes. Expression of adipogenic genes, as well as genes encoding OPG and RANKL (involved in osteoclastogenesis), protein synthesis, lipid-droplets formation, and apoptosis, were studied. Results showed that 10 and 20 µM phloretin inhibited adipogenesis. This effect was mediated by increasing beta-catenin, as well as increasing apoptosis in adipocytes, at late stages of differentiation. In addition, this chemical increased OPG gene expression and OPG/RANKL ratio in adipocytes. These results suggest that this flavonoid (including phloretin-rich foods) has interesting potential for clinical and regenerative-medicine applications. Thus, such chemicals could be used to counteract obesity and prevent bone-marrow adiposity. That is particularly useful to protect bone mass and treat diseases like osteoporosis, which is an epidemic worldwide.
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Affiliation(s)
- Antonio Casado-Díaz
- Unidad de Gestión Clínica de Endocrinología y Nutrición—GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, CIBERFES, 14004 Córdoba, Spain; (Á.R.-R.); (B.T.-B.); (J.M.Q.-G.); (M.Á.G.-M.)
| | - Ángel Rodríguez-Ramos
- Unidad de Gestión Clínica de Endocrinología y Nutrición—GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, CIBERFES, 14004 Córdoba, Spain; (Á.R.-R.); (B.T.-B.); (J.M.Q.-G.); (M.Á.G.-M.)
| | - Bárbara Torrecillas-Baena
- Unidad de Gestión Clínica de Endocrinología y Nutrición—GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, CIBERFES, 14004 Córdoba, Spain; (Á.R.-R.); (B.T.-B.); (J.M.Q.-G.); (M.Á.G.-M.)
| | - Gabriel Dorado
- Dep. Bioquímica y Biología Molecular, Campus Rabanales C6-1-E17, Campus de Excelencia Internacional Agroalimentario (ceiA3), Universidad de Córdoba, CIBERFES, 14071 Córdoba, Spain;
| | - José Manuel Quesada-Gómez
- Unidad de Gestión Clínica de Endocrinología y Nutrición—GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, CIBERFES, 14004 Córdoba, Spain; (Á.R.-R.); (B.T.-B.); (J.M.Q.-G.); (M.Á.G.-M.)
| | - María Ángeles Gálvez-Moreno
- Unidad de Gestión Clínica de Endocrinología y Nutrición—GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, CIBERFES, 14004 Córdoba, Spain; (Á.R.-R.); (B.T.-B.); (J.M.Q.-G.); (M.Á.G.-M.)
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25
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Nezbedova L, McGhie T, Christensen M, Heyes J, Nasef NA, Mehta S. Onco-Preventive and Chemo-Protective Effects of Apple Bioactive Compounds. Nutrients 2021; 13:4025. [PMID: 34836282 PMCID: PMC8618396 DOI: 10.3390/nu13114025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/31/2021] [Accepted: 11/03/2021] [Indexed: 01/16/2023] Open
Abstract
Cancer is one of the leading causes of death globally. Epidemiological studies have strongly linked a diet high in fruits to a lower incidence of cancer. Furthermore, extensive research shows that secondary plant metabolites known as phytochemicals, which are commonly found in fruits, have onco-preventive and chemo-protective effects. Apple is a commonly consumed fruit worldwide that is available all year round and is a rich source of phytochemicals. In this review, we summarize the association of apple consumption with cancer incidence based on findings from epidemiological and cohort studies. We further provide a comprehensive review of the main phytochemical patterns observed in apples and their bioavailability after consumption. Finally, we report on the latest findings from in vitro and in vivo studies highlighting some of the key molecular mechanisms targeted by apple phytochemicals in relation to inhibiting multiple 'hallmarks of cancer' that are important in the progression of cancer.
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Affiliation(s)
- Linda Nezbedova
- School of Food and Advanced Technology, Massey University, Palmerston North 4442, New Zealand; (L.N.); (J.H.)
- Riddet Institute, Massey University, Palmerston North 4442, New Zealand;
| | - Tony McGhie
- The New Zealand Institute for Plant and Food Research Limited, Palmerston North 4442, New Zealand;
| | - Mark Christensen
- Heritage Food Crops Research Trust, Whanganui 4501, New Zealand;
| | - Julian Heyes
- School of Food and Advanced Technology, Massey University, Palmerston North 4442, New Zealand; (L.N.); (J.H.)
| | - Noha Ahmed Nasef
- Riddet Institute, Massey University, Palmerston North 4442, New Zealand;
| | - Sunali Mehta
- Pathology Department, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand
- Maurice Wilkins Centre for Biodiscovery, University of Otago, Dunedin 9054, New Zealand
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Apple Polyphenols Extract (APE) Alleviated Dextran Sulfate Sodium Induced Acute Ulcerative Colitis and Accompanying Neuroinflammation via Inhibition of Apoptosis and Pyroptosis. Foods 2021; 10:foods10112711. [PMID: 34828992 PMCID: PMC8619666 DOI: 10.3390/foods10112711] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/01/2021] [Accepted: 11/02/2021] [Indexed: 12/15/2022] Open
Abstract
The main aim of this study was to investigate the potent anti-apoptosis and anti-pyroptosis effects of apple polyphenols extract (APE) on dextran sulfate sodium model group (DSS)-induced acute ulcerative colitis (UC) and the protective effect of APE against acute UC-related neuroinflammation and synapse damage. Forty-three C57BL/6 male mice were randomly divided into a control group (CON), a 3% DSS model group (DSS), a 500 mg/(kg·bw·d) APE group (HAP), and a 125 (LD) or 500 (HD) mg/(kg·bw·d) APE treatment concomitantly with DSS treatment group. The results showed that APE significantly ameliorated DSS-induced acute UC through inhibiting intestinal epithelial cell (IEC) apoptosis and the Caspase-1/Caspase-11-dependent pyroptosis pathway, with increased BCL-2 protein expression and decreased protein levels of NLRP3, ASC, Caspase-1/11, and GSDND. Furthermore, APE significantly reduced acute UC-related neuroinflammation and synapse damage, supported by decreased mRNA levels of hypothalamus Cox-2 and hippocampus Gfap and also increased the mRNA levels of hypothalamus Psd-95. The increased protein expression of ZO-1 and Occludin improved the intestinal barrier integrity and improved the function of goblet cells by upregulating the protein level of MUC-2 and TTF3 accounted for the beneficial effects of APE on UC-associated neuroinflammation. Therefore, APE might be a safe and effective agent for the management of acute UC.
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27
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Identification of new GLUT2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems. Sci Rep 2021; 11:13751. [PMID: 34215797 PMCID: PMC8253845 DOI: 10.1038/s41598-021-93063-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 06/14/2021] [Indexed: 01/07/2023] Open
Abstract
Glucose is an essential energy source for cells. In humans, its passive diffusion through the cell membrane is facilitated by members of the glucose transporter family (GLUT, SLC2 gene family). GLUT2 transports both glucose and fructose with low affinity and plays a critical role in glucose sensing mechanisms. Alterations in the function or expression of GLUT2 are involved in the Fanconi-Bickel syndrome, diabetes, and cancer. Distinguishing GLUT2 transport in tissues where other GLUTs coexist is challenging due to the low affinity of GLUT2 for glucose and fructose and the scarcity of GLUT-specific modulators. By combining in silico ligand screening of an inward-facing conformation model of GLUT2 and glucose uptake assays in a hexose transporter-deficient yeast strain, in which the GLUT1-5 can be expressed individually, we identified eleven new GLUT2 inhibitors (IC50 ranging from 0.61 to 19.3 µM). Among them, nine were GLUT2-selective, one inhibited GLUT1-4 (pan-Class I GLUT inhibitor), and another inhibited GLUT5 only. All these inhibitors dock to the substrate cavity periphery, close to the large cytosolic loop connecting the two transporter halves, outside the substrate-binding site. The GLUT2 inhibitors described here have various applications; GLUT2-specific inhibitors can serve as tools to examine the pathophysiological role of GLUT2 relative to other GLUTs, the pan-Class I GLUT inhibitor can block glucose entry in cancer cells, and the GLUT2/GLUT5 inhibitor can reduce the intestinal absorption of fructose to combat the harmful effects of a high-fructose diet.
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28
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Dias AS, Helguero L, Almeida CR, Duarte IF. Natural Compounds as Metabolic Modulators of the Tumor Microenvironment. Molecules 2021; 26:molecules26123494. [PMID: 34201298 PMCID: PMC8228554 DOI: 10.3390/molecules26123494] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/03/2021] [Accepted: 06/04/2021] [Indexed: 02/07/2023] Open
Abstract
The tumor microenvironment (TME) is a heterogenous assemblage of malignant and non-malignant cells, including infiltrating immune cells and other stromal cells, together with extracellular matrix and a variety of soluble factors. This complex and dynamic milieu strongly affects tumor differentiation, progression, immune evasion, and response to therapy, thus being an important therapeutic target. The phenotypic and functional features of the various cell types present in the TME are largely dependent on their ability to adopt different metabolic programs. Hence, modulating the metabolism of the cells in the TME, and their metabolic crosstalk, has emerged as a promising strategy in the context of anticancer therapies. Natural compounds offer an attractive tool in this respect as their multiple biological activities can potentially be harnessed to ‘(re)-educate’ TME cells towards antitumoral roles. The present review discusses how natural compounds shape the metabolism of stromal cells in the TME and how this may impact tumor development and progression.
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Affiliation(s)
- Ana S. Dias
- Department of Chemistry, CICECO—Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal;
- Department of Medical Sciences, iBiMED—Institute of Biomedicine, University of Aveiro, 3810-193 Aveiro, Portugal; (L.H.); (C.R.A.)
| | - Luisa Helguero
- Department of Medical Sciences, iBiMED—Institute of Biomedicine, University of Aveiro, 3810-193 Aveiro, Portugal; (L.H.); (C.R.A.)
| | - Catarina R. Almeida
- Department of Medical Sciences, iBiMED—Institute of Biomedicine, University of Aveiro, 3810-193 Aveiro, Portugal; (L.H.); (C.R.A.)
| | - Iola F. Duarte
- Department of Chemistry, CICECO—Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal;
- Correspondence: ; Tel.: +351-234-401-418
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29
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Chen H, Yang J, Yang Y, Zhang J, Xu Y, Lu X. The Natural Products and Extracts: Anti-Triple-Negative Breast Cancer in Vitro. Chem Biodivers 2021; 18:e2001047. [PMID: 34000082 DOI: 10.1002/cbdv.202001047] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 05/17/2021] [Indexed: 11/10/2022]
Abstract
Triple-negative breast cancer (TNBC) makes up 15 % to 20 % of all breast cancer (BC) cases, and represents one of the most challenging malignancies to treat. For many years, chemotherapy has been the main treatment option for TNBC. Natural products isolated from marine organisms and terrestrial organisms with great structural diversity and high biochemical specificity form a compound library for the assessment and discovery of new drugs. In this review, we mainly focused on natural compounds and extracts (from marine and terrestrial environments) with strong anti-TNBC activities (IC50 <100 μM) and their possible mechanisms reported in the past six years (2015-2021).
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Affiliation(s)
- Han Chen
- College of Basic Medical Sciences, Department of Biochemistry and Molecular Biology, Naval Medical University, Xiangyin Road 800, Shanghai, 200433, P. R. China
| | - Jiaping Yang
- College of Basic Medical Sciences, Department of Biochemistry and Molecular Biology, Naval Medical University, Xiangyin Road 800, Shanghai, 200433, P. R. China
| | - Yanlong Yang
- School of Traditional Chinese Medicine, Naval Medical University, 200433, Shanghai, P. R. China
| | - Jianpeng Zhang
- College of Basic Medical Sciences, Department of Biochemistry and Molecular Biology, Naval Medical University, Xiangyin Road 800, Shanghai, 200433, P. R. China
| | - Yao Xu
- College of Basic Medical Sciences, Department of Biochemistry and Molecular Biology, Naval Medical University, Xiangyin Road 800, Shanghai, 200433, P. R. China
| | - Xiaoling Lu
- College of Basic Medical Sciences, Department of Biochemistry and Molecular Biology, Naval Medical University, Xiangyin Road 800, Shanghai, 200433, P. R. China
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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.
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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
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Mabate B, Daub CD, Malgas S, Edkins AL, Pletschke BI. Fucoidan Structure and Its Impact on Glucose Metabolism: Implications for Diabetes and Cancer Therapy. Mar Drugs 2021; 19:md19010030. [PMID: 33440853 PMCID: PMC7826564 DOI: 10.3390/md19010030] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 12/31/2020] [Accepted: 01/07/2021] [Indexed: 12/16/2022] Open
Abstract
Fucoidans are complex polysaccharides derived from brown seaweeds which consist of considerable proportions of L-fucose and other monosaccharides, and sulphated ester residues. The search for novel and natural bioproduct drugs (due to toxicity issues associated with chemotherapeutics) has led to the extensive study of fucoidan due to reports of it having several bioactive characteristics. Among other fucoidan bioactivities, antidiabetic and anticancer properties have received the most research attention in the past decade. However, the elucidation of the fucoidan structure and its biological activity is still vague. In addition, research has suggested that there is a link between diabetes and cancer; however, limited data exist where dual chemotherapeutic efforts are elucidated. This review provides an overview of glucose metabolism, which is the central process involved in the progression of both diseases. We also highlight potential therapeutic targets and show the relevance of fucoidan and its derivatives as a candidate for both cancer and diabetes therapy.
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Affiliation(s)
- Blessing Mabate
- Enzyme Science Programme (ESP), Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6140, South Africa; (B.M.); (C.D.D.); (S.M.)
| | - Chantal Désirée Daub
- Enzyme Science Programme (ESP), Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6140, South Africa; (B.M.); (C.D.D.); (S.M.)
| | - Samkelo Malgas
- Enzyme Science Programme (ESP), Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6140, South Africa; (B.M.); (C.D.D.); (S.M.)
| | - Adrienne Lesley Edkins
- Biomedical Biotechnology Research Unit, Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6140, South Africa;
| | - Brett Ivan Pletschke
- Enzyme Science Programme (ESP), Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6140, South Africa; (B.M.); (C.D.D.); (S.M.)
- Correspondence: ; Tel.: +27-46-603-8081; Fax: +27-46-603-7576
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Chen M, Gowd V, Wang M, Chen F, Cheng KW. The apple dihydrochalcone phloretin suppresses growth and improves chemosensitivity of breast cancer cells via inhibition of cytoprotective autophagy. Food Funct 2021; 12:177-190. [PMID: 33291138 DOI: 10.1039/d0fo02362k] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The inhibitory effect and mechanism of the apple dihydrochalcone, phloretin, on breast cancer cell growth were evaluated in in vitro conditions simulating complete nutrition and glucose-restriction, respectively. In two breast cancer cell lines with different histological backgrounds, phloretin consistently exhibited much stronger activity against cell growth in glucose-limiting than in full media. RNA-seq analysis showed that key autophagy-related genes were downregulated upon phloretin treatment in both estrogen-receptor-positive MCF7 and triple-negative MDA-MB-231 cells. Immunoblotting verified significantly decreased expression of LC3B-II by phloretin in low-glucose and glucose-free media, but not in full medium. Together with the use of two pharmacological autophagy inhibitors, chloroquine and 3-methyladenine, and confocal microscopy of breast cancer cell lines transfected with GFP-LC3B, phloretin demonstrated a strong capability to suppress autophagic flux, which was likely mediated through downregulation of mTOR/ULK1 signaling, whereas the expression of canonical autophagy regulators ATG5 and ATG7 was not significantly affected. Phloretin also reversed tamoxifen- and doxorubicin-induced cytoprotective autophagy in the breast cancer cell lines, and this was manifested in its synergistic growth inhibitory effect with these chemotherapeutic agents. Furthermore, it was able to restore or enhance the chemosensitivity of a tamoxifen-resistant cell line. Taken together, our study has, for the first time, revealed that phloretin could effectively suppress glucose-starvation- and chemotherapeutic-induced cytoprotective autophagy in breast cancer cell lines likely through downregulation of mTOR/ULK1 signaling.
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Affiliation(s)
- Ming Chen
- Shenzhen Key Laboratory of Marine Microbiome Engineering, Institute for Advanced Study, Shenzhen University, Shenzhen 518060, China. and Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China
| | - Vemana Gowd
- Shenzhen Key Laboratory of Marine Microbiome Engineering, Institute for Advanced Study, Shenzhen University, Shenzhen 518060, China. and Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China
| | - Mingfu Wang
- Shenzhen Key Laboratory of Marine Microbiome Engineering, Institute for Advanced Study, Shenzhen University, Shenzhen 518060, China. and School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong 999077, P.R. China
| | - Feng Chen
- Shenzhen Key Laboratory of Marine Microbiome Engineering, Institute for Advanced Study, Shenzhen University, Shenzhen 518060, China. and Institute for Innovative Development of Food Industry, Shenzhen University, Shenzhen 518060, China and Institute for Food and Bioresource Engineering, College of Engineering, Peking University, Beijing 100871, China
| | - Ka-Wing Cheng
- Shenzhen Key Laboratory of Marine Microbiome Engineering, Institute for Advanced Study, Shenzhen University, Shenzhen 518060, China. and Institute for Innovative Development of Food Industry, Shenzhen University, Shenzhen 518060, China
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Zhang S, Hu C, Guo Y, Wang X, Meng Y. Polyphenols in fermented apple juice: Beneficial effects on human health. J Funct Foods 2021. [DOI: 10.1016/j.jff.2020.104294] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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Aghakhani S, Zerrouk N, Niarakis A. Metabolic Reprogramming of Fibroblasts as Therapeutic Target in Rheumatoid Arthritis and Cancer: Deciphering Key Mechanisms Using Computational Systems Biology Approaches. Cancers (Basel) 2020; 13:E35. [PMID: 33374292 PMCID: PMC7795338 DOI: 10.3390/cancers13010035] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/12/2020] [Accepted: 12/17/2020] [Indexed: 12/29/2022] Open
Abstract
Fibroblasts, the most abundant cells in the connective tissue, are key modulators of the extracellular matrix (ECM) composition. These spindle-shaped cells are capable of synthesizing various extracellular matrix proteins and collagen. They also provide the structural framework (stroma) for tissues and play a pivotal role in the wound healing process. While they are maintainers of the ECM turnover and regulate several physiological processes, they can also undergo transformations responding to certain stimuli and display aggressive phenotypes that contribute to disease pathophysiology. In this review, we focus on the metabolic pathways of glucose and highlight metabolic reprogramming as a critical event that contributes to the transition of fibroblasts from quiescent to activated and aggressive cells. We also cover the emerging evidence that allows us to draw parallels between fibroblasts in autoimmune disorders and more specifically in rheumatoid arthritis and cancer. We link the metabolic changes of fibroblasts to the toxic environment created by the disease condition and discuss how targeting of metabolic reprogramming could be employed in the treatment of such diseases. Lastly, we discuss Systems Biology approaches, and more specifically, computational modeling, as a means to elucidate pathogenetic mechanisms and accelerate the identification of novel therapeutic targets.
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Affiliation(s)
- Sahar Aghakhani
- GenHotel, University of Evry, University of Paris-Saclay, Genopole, 91000 Evry, France; (S.A.); (N.Z.)
- Lifeware Group, Inria Saclay, 91120 Palaiseau, France
| | - Naouel Zerrouk
- GenHotel, University of Evry, University of Paris-Saclay, Genopole, 91000 Evry, France; (S.A.); (N.Z.)
| | - Anna Niarakis
- GenHotel, University of Evry, University of Paris-Saclay, Genopole, 91000 Evry, France; (S.A.); (N.Z.)
- Lifeware Group, Inria Saclay, 91120 Palaiseau, France
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Jung EJ, Lee WS, Paramanantham A, Kim HJ, Shin SC, Kim GS, Jung JM, Ryu CH, Hong SC, Chung KH, Kim CW. p53 Enhances Artemisia annua L. Polyphenols-Induced Cell Death Through Upregulation of p53-Dependent Targets and Cleavage of PARP1 and Lamin A/C in HCT116 Colorectal Cancer Cells. Int J Mol Sci 2020; 21:ijms21239315. [PMID: 33297377 PMCID: PMC7730414 DOI: 10.3390/ijms21239315] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/04/2020] [Accepted: 12/05/2020] [Indexed: 12/11/2022] Open
Abstract
Plant-derived natural polyphenols exhibit anticancer activity without showing any noticeable toxicities to normal cells. The aim of this study was to investigate the role of p53 on the anticancer effect of polyphenols isolated from Korean Artemisia annua L. (pKAL) in HCT116 human colorectal cancer cells. We confirmed that pKAL induced reactive oxygen species (ROS) production, propidium iodide (PI) uptake, nuclear structure change, and acidic vesicles in a p53-independent manner in p53-null HCT116 cells through fluorescence microscopy analysis of DCF/PI-, DAPI-, and AO-stained cells. The pKAL-induced anticancer effects were found to be significantly higher in p53-wild HCT116 cells than in p53-null by hematoxylin staining, CCK-8 assay, Western blot, and flow cytometric analysis of annexin V/PI-stained cells. In addition, expression of ectopic p53 in p53-null cells was upregulated by pKAL in both the nucleus and cytoplasm, increasing pKAL-induced cell death. Moreover, Western bot analysis revealed that pKAL-induced cell death was associated with upregulation of p53-dependent targets such as p21, Bax and DR5 and cleavage of PARP1 and lamin A/C in p53-wild HCT116 cells, but not in p53-null. Taken together, these results indicate that p53 plays an important role in enhancing the anticancer effects of pKAL by upregulating p53 downstream targets and inducing intracellular cell death processes.
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Affiliation(s)
- Eun Joo Jung
- Departments of Biochemistry, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 52727, Korea; (E.J.J.); (C.W.K.)
| | - Won Sup Lee
- Departments of Internal Medicine, Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju 52727, Korea;
- Correspondence: ; Tel.: +82-55-750-8733; Fax: +82-55-758-9122
| | - Anjugam Paramanantham
- Departments of Internal Medicine, Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju 52727, Korea;
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea;
| | - Hye Jung Kim
- Departments of Pharmacology, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 52727, Korea;
| | - Sung Chul Shin
- Department of Chemistry, Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea;
| | - Gon Sup Kim
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea;
| | - Jin-Myung Jung
- Departments of Neurosurgery, Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju 52727, Korea;
| | - Chung Ho Ryu
- Department of Food Technology, Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea;
| | - Soon Chan Hong
- Departments of Surgery, Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju 52727, Korea;
| | - Ky Hyun Chung
- Departments of Urology, Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju 52727, Korea;
| | - Choong Won Kim
- Departments of Biochemistry, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 52727, Korea; (E.J.J.); (C.W.K.)
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Tilekar K, Upadhyay N, Iancu CV, Pokrovsky V, Choe JY, Ramaa CS. Power of two: combination of therapeutic approaches involving glucose transporter (GLUT) inhibitors to combat cancer. Biochim Biophys Acta Rev Cancer 2020; 1874:188457. [PMID: 33096154 PMCID: PMC7704680 DOI: 10.1016/j.bbcan.2020.188457] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/16/2020] [Accepted: 10/16/2020] [Indexed: 12/20/2022]
Abstract
Cancer research of the Warburg effect, a hallmark metabolic alteration in tumors, focused attention on glucose metabolism whose targeting uncovered several agents with promising anticancer effects at the preclinical level. These agents' monotherapy points to their potential as adjuvant combination therapy to existing standard chemotherapy in human trials. Accordingly, several studies on combining glucose transporter (GLUT) inhibitors with chemotherapeutic agents, such as doxorubicin, paclitaxel, and cytarabine, showed synergistic or additive anticancer effects, reduced chemo-, radio-, and immuno-resistance, and reduced toxicity due to lowering the therapeutic doses required for desired chemotherapeutic effects, as compared with monotherapy. The combinations have been specifically effective in treating cancer glycolytic phenotypes, such as pancreatic and breast cancers. Even combining GLUT inhibitors with other glycolytic inhibitors and energy restriction mimetics seems worthwhile. Though combination clinical trials are in the early phase, initial results are intriguing. The various types of GLUTs, their role in cancer progression, GLUT inhibitors, and their anticancer mechanism of action have been reviewed several times. However, utilizing GLUT inhibitors as combination therapeutics has received little attention. We consider GLUT inhibitors agents that directly affect glucose transporters by binding to them or indirectly alter glucose transport by changing the transporters' expression level. This review mainly focuses on summarizing the effects of various combinations of GLUT inhibitors with other anticancer agents and providing a perspective on the current status.
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Affiliation(s)
- Kalpana Tilekar
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, Maharashtra, India
| | - Neha Upadhyay
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, Maharashtra, India
| | - Cristina V. Iancu
- East Carolina Diabetes and Obesity Institute, Department of Chemistry, East Carolina University, Greenville, North Carolina, USA
| | - Vadim Pokrovsky
- Laboratory of Combined Therapy, N.N. Blokhin Cancer Research Center, Moscow, Russia
- Department of Biochemistry, People’s Friendship University, Moscow, Russia
| | - Jun-yong Choe
- East Carolina Diabetes and Obesity Institute, Department of Chemistry, East Carolina University, Greenville, North Carolina, USA
| | - C. S. Ramaa
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, Maharashtra, India
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Regioselective Hydroxylation of Phloretin, a Bioactive Compound from Apples, by Human Cytochrome P450 Enzymes. Pharmaceuticals (Basel) 2020; 13:ph13110330. [PMID: 33105851 PMCID: PMC7690628 DOI: 10.3390/ph13110330] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/17/2020] [Accepted: 10/21/2020] [Indexed: 01/15/2023] Open
Abstract
Phloretin, the major polyphenol compound in apples and apple products, is interesting because it shows beneficial effects on human health. It is mainly found as a form of glucoside, phlorizin. However, the metabolic pathway of phloretin in humans has not been reported. Therefore, identifying phloretin metabolites made in human liver microsomes and the human cytochrome P450 (P450) enzymes to make them is interesting. In this study, the roles of human liver P450s for phloretin oxidation were examined using human liver microsomes and recombinant human liver P450s. One major metabolite of phloretin in human liver microsomes was 3-OH phloretin, which is the same product of a bacterial CYP102A1-catalyzed reaction of phloretin. CYP3A4 and CYP2C19 showed kcat values of 3.1 and 5.8 min-1, respectively. However, CYP3A4 has a 3.3-fold lower Km value than CYP2C19. The catalytic efficiency of a CYP3A4-catalyzed reaction is 1.8-fold higher than a reaction catalyzed by CYP2C19. Whole-cell biotransformation with CYP3A4 was achieved 0.16 mM h-1 productivity for 3-OH phlorein from 8 mM phloretin at optimal condition. Phloretin was a potent inhibitor of CYP3A4-catalyzed testosterone 6β-hydroxylation activity. Antibodies against CYP3A4 inhibited up to 90% of the microsomal activity of phloretin 3-hydroxylation. The immunoinhibition effect of anti-2C19 is much lower than that of anti-CYP3A4. Thus, CYP3A4 majorly contributes to the human liver microsomal phloretin 3-hydroxylation, and CYP2C19 has a minor role.
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Sayed AM, Hassanein EH, Salem SH, Hussein OE, Mahmoud AM. Flavonoids-mediated SIRT1 signaling activation in hepatic disorders. Life Sci 2020; 259:118173. [DOI: 10.1016/j.lfs.2020.118173] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 07/18/2020] [Accepted: 07/27/2020] [Indexed: 02/07/2023]
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Zhu X, Chen HH, Gao CY, Zhang XX, Jiang JX, Zhang Y, Fang J, Zhao F, Chen ZG. Energy metabolism in cancer stem cells. World J Stem Cells 2020; 12:448-461. [PMID: 32742562 PMCID: PMC7360992 DOI: 10.4252/wjsc.v12.i6.448] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/09/2020] [Accepted: 05/19/2020] [Indexed: 02/06/2023] Open
Abstract
Normal cells mainly rely on oxidative phosphorylation as an effective energy source in the presence of oxygen. In contrast, most cancer cells use less efficient glycolysis to produce ATP and essential biomolecules. Cancer cells gain the characteristics of metabolic adaptation by reprogramming their metabolic mechanisms to meet the needs of rapid tumor growth. A subset of cancer cells with stem characteristics and the ability to regenerate exist throughout the tumor and are therefore called cancer stem cells (CSCs). New evidence indicates that CSCs have different metabolic phenotypes compared with differentiated cancer cells. CSCs can dynamically transform their metabolic state to favor glycolysis or oxidative metabolism. The mechanism of the metabolic plasticity of CSCs has not been fully elucidated, and existing evidence indicates that the metabolic phenotype of cancer cells is closely related to the tumor microenvironment. Targeting CSC metabolism may provide new and effective methods for the treatment of tumors. In this review, we summarize the metabolic characteristics of cancer cells and CSCs and the mechanisms of the metabolic interplay between the tumor microenvironment and CSCs, and discuss the clinical implications of targeting CSC metabolism.
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Affiliation(s)
- Xuan Zhu
- Department of Radiation Oncology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Hui-Hui Chen
- The Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Chen-Yi Gao
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Xin-Xin Zhang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Jing-Xin Jiang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Yi Zhang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Jun Fang
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Feng Zhao
- Department of Radiation Oncology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Zhi-Gang Chen
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China.
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40
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Influence of different cooking methods on the nutritional and potentially harmful components of peanuts. Food Chem 2020; 316:126269. [DOI: 10.1016/j.foodchem.2020.126269] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 01/15/2020] [Accepted: 01/17/2020] [Indexed: 01/22/2023]
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Bars-Cortina D, Martínez-Bardají A, Macià A, Motilva MJ, Piñol-Felis C. Consumption evaluation of one apple flesh a day in the initial phases prior to adenoma/adenocarcinoma in an azoxymethane rat colon carcinogenesis model. J Nutr Biochem 2020; 83:108418. [PMID: 32592950 DOI: 10.1016/j.jnutbio.2020.108418] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 03/17/2020] [Accepted: 04/24/2020] [Indexed: 01/03/2023]
Abstract
Colorectal cancer (CRC) is the fourth cancer with the most new cases reported in 2018 worldwide. Consumption of fruit and vegetables is a protective factor against the risk of CRC. Beyond this, flavonoids could orchestrate these healthy effects. Apart from containing the typical apple flavonoids, red-fleshed apples also contain anthocyanins, mainly cyanidin-3-O-galactoside (Cy3Gal). Through an azoxymethane rat carcinogenesis model, a study was carried out in order to assess the possible protective effects of apple polyphenols, with special attention to anthocyanins. In addition, apart from negative and positive controls, a group with chemotherapy with 5-fluorouracil (5FU) was included to compare their performance against the output collected from the animal treatments with white-fleshed apple (WF), red-fleshed apple (RF) and Cy3Gal (AE). Although the 5FU group presented the best performance towards aberrant crypt foci (ACF) inhibition (70.1%), rats fed with white-fleshed apples ('Golden Smoothee') were able to achieve 41.3% ACF inhibition, while none of the challenged treatments (WF, RF and AE) suffered mucin depletion in their colonocytes. Expression changes of 17 genes related to CRC were assessed. In detail, the ACF inhibition phenotype detected in 5FU and WF groups could be explained through the expression changes detected in the apoptosis-related genes of Aurka, p53 and Cox2. Moreover, in the apple consumption groups (WF and RF), a reduced protein expression of matrix metalloproteinases with gelatinase activity (MMP-2 and 9) was detected. Overall, our study suggests an effect of apple polyphenols and apple anthocyanin Cy3Gal against colon carcinogenesis, retarding/diminishing the appearance of the precancerous markers studied.
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Affiliation(s)
- David Bars-Cortina
- Food Technology Department, XaRTA-TPV, Agrotecnio Center, Escola Tècnica Superior d'Enginyeria Agrària, Universitat de Lleida, Lleida, Catalonia, Spain; Department of Medicine, Universitat de Lleida, Lleida, Catalonia, Spain.
| | | | - Alba Macià
- Food Technology Department, XaRTA-TPV, Agrotecnio Center, Escola Tècnica Superior d'Enginyeria Agrària, Universitat de Lleida, Lleida, Catalonia, Spain
| | - María-Jose Motilva
- Instituto de Ciencias de la Vid y del Vino (ICVV) (Consejo Superior de Investigaciones Científicas-CSIC, Universidad de la Rioja, Gobierno de la Rioja), Logroño, La Rioja, Spain.
| | - Carme Piñol-Felis
- Department of Medicine, Universitat de Lleida, Lleida, Catalonia, Spain; Institut de Recerca Biomèdica de Lleida, Fundació Dr. Pifarré-IRBLleida, Lleida, Catalonia, Spain.
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Moorthy M, Chaiyakunapruk N, Jacob SA, Palanisamy UD. Prebiotic potential of polyphenols, its effect on gut microbiota and anthropometric/clinical markers: A systematic review of randomised controlled trials. Trends Food Sci Technol 2020. [DOI: 10.1016/j.tifs.2020.03.036] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Sato J, Nakayama M, Tomita A, Sonoda T, Miyamoto T. Difference in the antibacterial action of epigallocatechin gallate and theaflavin 3,3'-di-O-gallate on Bacillus coagulans. J Appl Microbiol 2020; 129:601-611. [PMID: 32281733 DOI: 10.1111/jam.14662] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 03/11/2020] [Accepted: 03/29/2020] [Indexed: 11/28/2022]
Abstract
AIMS To study the mechanism of the antibacterial action of tea polyphenols such as catechins and theaflavins against Bacillus coagulans, and the interaction of epigallocatechin gallate (EGCg) or theaflavin 3,3'-di-O-gallate (TFDG) with the surface of B. coagulans cells was investigated. METHODS AND RESULTS The antibacterial activities of EGCg and TFDG against B. coagulans cells were measured by counting of the viable cells after the mixing with each polyphenol. Bactericidal effect of TFDG was shown at the concentration of greater than or equal to 62·5 mg l-1 ; however, at the same concentration, EGCg did not. According to the results of two dimensional (2D)-electrophoresis analysis, TFDG seemed to interact with cytoplasmic membrane proteins. The activity of the glucose transporters of the cells decreased 40% following the treatment with TFDG of 62·5 mg l-1 ; however, this decrease was only slight in case of EGCg. This result was in accordance with the strength of their bactericidal activities. CONCLUSION Our results suggest that the direct interaction between membrane proteins and TFDG is an important factor in the antibacterial activity of polymerized catechins, affecting their functions and leading to cell death. SIGNIFICANCE AND IMPACT OF THE STUDY Tea polyphenols can effectively use the prevention of product spoilage in the food and beverage industry.
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Affiliation(s)
- J Sato
- Safety Science Research, R&D, Kao Corporation, Ichikai, Tochigi, Japan.,Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Nishi-ku, Fukuoka, Japan
| | - M Nakayama
- Safety Science Research, R&D, Kao Corporation, Ichikai, Tochigi, Japan
| | - A Tomita
- Safety Science Research, R&D, Kao Corporation, Ichikai, Tochigi, Japan
| | - T Sonoda
- Safety Science Research, R&D, Kao Corporation, Ichikai, Tochigi, Japan
| | - T Miyamoto
- Division of Food Science & Biotechnology, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Nishi-ku, Fukuoka, Japan
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Tamura Y, Tomiya S, Takegaki J, Kouzaki K, Tsutaki A, Nakazato K. Apple polyphenols induce browning of white adipose tissue. J Nutr Biochem 2020; 77:108299. [DOI: 10.1016/j.jnutbio.2019.108299] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 10/09/2019] [Accepted: 11/12/2019] [Indexed: 12/11/2022]
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Martínez-Rodríguez OP, Thompson-Bonilla MDR, Jaramillo-Flores ME. Association between obesity and breast cancer: Molecular bases and the effect of flavonoids in signaling pathways. Crit Rev Food Sci Nutr 2020; 60:3770-3792. [PMID: 31899947 DOI: 10.1080/10408398.2019.1708262] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Obesity is an abnormal or excessive accumulation of fat that leads to different health problems, such as cancer, where the adipocytes promote the proliferation, migration, and invasion of cancer cells, especially in the breast, where the epithelial cells are immersed in a fatty environment, and the interactions between these two types of cells involve, not only adipokines but also local pro-inflammatory mechanisms and hypoxic processes generating anti-apoptotic signals, which are a common result in leptin signaling. The expression of the Vascular Endothelial Growth Factor (VEGF) and cyclin D1, results in the decrease in phosphorylation of AMPK, increasing the activity of the aromatase enzyme; alternatively, the adiponectin activates AMPK to reduce inflammation. Nevertheless, alterations of the JAK/STAT pathways contribute to mammary carcinogenesis, while the PI3K/AKT/mTOR pathway controls most of the cancer's characteristics such as the cell cycle, survival, differentiation, proliferation, motility, metabolism, and genetic stability. Therefore, the purpose of the present review is, through the accumulated scientific evidence, to find the concordance between the signaling pathways involved among obesity and breast cancer, which can be modulated by using flavonoids.
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Affiliation(s)
- Oswaldo Pablo Martínez-Rodríguez
- Departamento de Ingeniería Bioquímica, Instituto Politécnico Nacional, Escuela Nacional de Ciencias Biológicas, Ciudad de México, México
| | - María Del Rocío Thompson-Bonilla
- Laboratorio de Medicina Genómica, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado ISSSTE, Ciudad de México, México
| | - María Eugenia Jaramillo-Flores
- Departamento de Ingeniería Bioquímica, Instituto Politécnico Nacional, Escuela Nacional de Ciencias Biológicas, Ciudad de México, México
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Shen X, Wang L, Zhou N, Gai S, Liu X, Zhang S. Beneficial effects of combination therapy of phloretin and metformin in streptozotocin-induced diabetic rats and improved insulin sensitivity in vitro. Food Funct 2020; 11:392-403. [PMID: 31821397 DOI: 10.1039/c9fo01326a] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Phloretin combined with metformin ameliorates glucose and lipid metabolism in STZ-induced T2D rats via AKT/GLUT4 signaling pathways.
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Affiliation(s)
- Xin Shen
- Department of Medicinal Chemistry
- School of Pharmacy
- The Air Force Medical University
- Xi'an
- China
| | - Libin Wang
- Department of Medicinal Chemistry
- School of Pharmacy
- The Air Force Medical University
- Xi'an
- China
| | - Nan Zhou
- Department of Pharmacy
- Qingdao Women and Children's Hospital
- Qingdao
- China
| | - Shouchang Gai
- Department of Pharmacy
- Hospital of 79 Group Army
- Liaoyang
- China
| | - Xueying Liu
- Department of Medicinal Chemistry
- School of Pharmacy
- The Air Force Medical University
- Xi'an
- China
| | - Shengyong Zhang
- Department of Medicinal Chemistry
- School of Pharmacy
- The Air Force Medical University
- Xi'an
- China
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Abdel-Wahab AF, Mahmoud W, Al-Harizy RM. Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy. Pharmacol Res 2019; 150:104511. [DOI: 10.1016/j.phrs.2019.104511] [Citation(s) in RCA: 136] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 10/19/2019] [Accepted: 10/23/2019] [Indexed: 12/24/2022]
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48
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Mariadoss AVA, Vinyagam R, Rajamanickam V, Sankaran V, Venkatesan S, David E. Pharmacological Aspects and Potential Use of Phloretin: A Systemic Review. Mini Rev Med Chem 2019; 19:1060-1067. [PMID: 30864525 DOI: 10.2174/1389557519666190311154425] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 07/18/2018] [Accepted: 08/08/2018] [Indexed: 12/27/2022]
Abstract
Over the past two decades, many researchers have concluded that a diet rich in polyphenolic compounds plays an important therapeutic role in reducing the risk of cancer, cardiovascular disease, inflammation, diabetes, and other degenerative diseases. Polyphenolic compounds have been reported to be involved in neutralization of reactive oxygen species and charged radicals, and have anticarcinogenic effects, hepatoprotective effects, low-glycaemic response, and other benefits. The benefits of fruits and vegetables may be partly attributable to polyphenolic compounds, which have antioxidant and free radical scavenging properties. Fruits such as apples contain a variety of phytochemicals, including (+)-catechin and (-)-epicatechin, phlorizin, phloretin quercetin, cyanidin-3-Ogalactoside, chlorogenic acid, and p-coumaric acid, all of which are strong antioxidants. Phloretin, a natural phenolic compound, is a dihydrochalcone, which is present in the apple. It exhibits a wide variety of activities such as antioxidative, anti-inflammatory, anti-microbial, anti-allergic, anticarcinogenic, anti-thrombotic, and hepatoprotective, besides being involved in the activation of apoptotic associated gene expression and signal transduction in molecular pathways. Despite a multitude of clinical studies, new efforts are needed in clinical research to determine the complete therapeutic potential of phloretin.
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Affiliation(s)
- Arokia V A Mariadoss
- Department of Biotechnology, Thiruvalluvar University, Serkadu, Vellore- 632115 Tamil Nadu, India
| | - Ramachandran Vinyagam
- Department of Biotechnology, Thiruvalluvar University, Serkadu, Vellore- 632115 Tamil Nadu, India
| | - Vinothkumar Rajamanickam
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Vijayalakshmi Sankaran
- Department of Biotechnology, Thiruvalluvar University, Serkadu, Vellore- 632115 Tamil Nadu, India
| | - Sathish Venkatesan
- Department of Biotechnology, Thiruvalluvar University, Serkadu, Vellore- 632115 Tamil Nadu, India
| | - Ernest David
- Department of Biotechnology, Thiruvalluvar University, Serkadu, Vellore- 632115 Tamil Nadu, India
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Martino E, Vuoso DC, D'Angelo S, Mele L, D'Onofrio N, Porcelli M, Cacciapuoti G. Annurca apple polyphenol extract selectively kills MDA-MB-231 cells through ROS generation, sustained JNK activation and cell growth and survival inhibition. Sci Rep 2019; 9:13045. [PMID: 31506575 PMCID: PMC6736874 DOI: 10.1038/s41598-019-49631-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 07/23/2019] [Indexed: 01/15/2023] Open
Abstract
Polyphenols represent the most studied class of nutraceuticals that can be therapeutics for a large spectrum of diseases, including cancer. In this study, we investigated for the first time the antitumor activities of polyphenol extract from Annurca apple (APE) in MDA-MB-231 triple negative breast cancer cells, and we explored the underlying mechanisms. APE selectively inhibited MDA-MB-231 cell viability and caused G2/M phase arrest associated with p27 and phospho-cdc25C upregulation and with p21 downregulation. APE promoted reactive oxygen species (ROS) generation in MDA-MB-231 cells while it acted as antioxidant in non-tumorigenic MCF10A cells. We demonstrated that ROS generation represented the primary step of APE antitumor activity as pretreatment with antioxidant N-acetylcysteine (NAC) prevented APE-induced G2/M phase arrest, apoptosis, and autophagy. APE downregulated Dusp-1 and induced a significant increase in JNK/c-Jun phosphorylation that were both prevented by NAC. Moreover, downregulation of JNK by its specific inhibitor SP600125 significantly diminished the anticancer activity of APE indicating that ROS generation and sustained JNK activation represented the main underlying mechanism of APE-induced cell death. APE also inhibited AKT activation and downregulated several oncoproteins, such as NF-kB, c-myc, and β-catenin. In light of these results, APE may be an attractive candidate for drug development against triple negative breast cancer.
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Affiliation(s)
- Elisa Martino
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", via Luigi De Crecchio 7, 80138, Naples, Italy
| | - Daniela Cristina Vuoso
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", via Luigi De Crecchio 7, 80138, Naples, Italy
| | - Stefania D'Angelo
- Department of Motor Sciences and Wellness, "Parthenope" University, via Medina 40, 80133, Naples, Italy
| | - Luigi Mele
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", via Luciano Armanni 5, 80138, Naples, Italy
| | - Nunzia D'Onofrio
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", via Luigi De Crecchio 7, 80138, Naples, Italy
| | - Marina Porcelli
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", via Luigi De Crecchio 7, 80138, Naples, Italy
| | - Giovanna Cacciapuoti
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", via Luigi De Crecchio 7, 80138, Naples, Italy.
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Takeno A, Kanazawa I, Tanaka KI, Notsu M, Sugimoto T. Phloretin Suppresses Bone Morphogenetic Protein-2-Induced Osteoblastogenesis and Mineralization via Inhibition of Phosphatidylinositol 3-kinases/Akt Pathway. Int J Mol Sci 2019; 20:ijms20102481. [PMID: 31137461 PMCID: PMC6566987 DOI: 10.3390/ijms20102481] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 05/15/2019] [Accepted: 05/16/2019] [Indexed: 12/15/2022] Open
Abstract
Phloretin has pleiotropic effects, including glucose transporter (GLUT) inhibition. We previously showed that phloretin promoted adipogenesis of bone marrow stromal cell (BMSC) line ST2 independently of GLUT1 inhibition. This study investigated the effect of phloretin on osteoblastogenesis of ST2 cells and osteoblastic MC3T3-E1 cells. Treatment with 10 to 100 µM phloretin suppressed mineralization and expression of osteoblast differentiation markers, such as alkaline phosphatase (ALP), osteocalcin (OCN), type 1 collagen, runt-related transcription factor 2 (Runx2), and osterix (Osx), while increased adipogenic markers, peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), fatty acid-binding protein 4, and adiponectin. Phloretin also inhibited mineralization and decreased osteoblast differentiation markers of MC3T3-E1 cells. Phloretin suppressed phosphorylation of Akt in ST2 cells. In addition, treatment with a phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor, LY294002, suppressed the mineralization and the expression of osteoblast differentiation markers other than ALP. GLUT1 silencing by siRNA did not affect mineralization, although it decreased the expression of OCN and increased the expression of ALP, Runx2, and Osx. The effects of GLUT1 silencing on osteoblast differentiation markers and mineralization were inconsistent with those of phloretin. Taken together, these findings suggest that phloretin suppressed osteoblastogenesis of ST2 and MC3T3-E1 cells by inhibiting the PI3K/Akt pathway, suggesting that the effects of phloretin may not be associated with glucose uptake inhibition.
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Affiliation(s)
- Ayumu Takeno
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1, Enya-cho, Izumo, Shimane 693-8501, Japan.
| | - Ippei Kanazawa
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1, Enya-cho, Izumo, Shimane 693-8501, Japan.
| | - Ken-Ichiro Tanaka
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1, Enya-cho, Izumo, Shimane 693-8501, Japan.
| | - Masakazu Notsu
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1, Enya-cho, Izumo, Shimane 693-8501, Japan.
| | - Toshitsugu Sugimoto
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1, Enya-cho, Izumo, Shimane 693-8501, Japan.
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