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Xu L, Wang Y, Hu Y, Dai X, Sun C, Cheng J. ROS-responsive oridonin and dihydroartemisinin hetero-polymeric prodrug NPs for potentiating ferroptosis in gastric cancer by disrupting redox balance. Colloids Surf B Biointerfaces 2025; 252:114637. [PMID: 40132335 DOI: 10.1016/j.colsurfb.2025.114637] [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: 11/30/2024] [Revised: 03/10/2025] [Accepted: 03/12/2025] [Indexed: 03/27/2025]
Abstract
Gastric cancer presents a significant global health concern, with conventional therapies often limited in effectiveness. The abnormal redox balance in gastric cancer cells may represent a breakthrough in the treatment of gastric cancer. In this study, we report for the first time the development of reactive oxygen species (ROS)-sensitive hetero-polymeric prodrug nanoparticles (NPs) designed for the co-delivery of the Chinese herbal extract oridonin (ORI) and dihydroartemisinin (DHA) in combination therapy for gastric cancer. This strategy aims to disrupt the intracellular redox balance and ultimately induce ferroptosis in gastric cancer cells. The ROS-responsive ORI and DHA polymeric prodrug were synthesised by conjugating ORI or DHA to poly(ethylene glycol)-block-poly(L-lysine) (PEG-b-PLL) via a ROS-sensitive linker thioketal (TK). The resulting polymeric prodrugs self-assemble in water to form NPs OD-M. After internalization by gastric cancer cells, OD-M released ORI and DHA in response to high ROS conditions within cancer cells. The released ORI reacts with GSH to induce GSH depletion while DHA amplifies intracellular ROS levels, ultimately inducing ferroptosis in gastric cancer cells. Experimental results demonstrate that OD-M acts as both a GSH scavenger and ROS generator, effectively disrupting intracellular redox balance, inducing ferroptosis, and exhibiting effective anticancer efficacy in vitro and in vivo, offering a departure from traditional methods.
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Affiliation(s)
- Luzhou Xu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China.
| | - Yan Wang
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China
| | - Yanqin Hu
- The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Xinyi Dai
- The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Cheng Sun
- The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jun Cheng
- Jiangsu Hongdian Chinese Medicine Industry Research Institute, Nanjing 210042, China
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Gao S, Li J, Wang W, Wang Y, Shan Y, Tan H. Rabdosia rubescens (Hemsl.) H. Hara: A potent anti-tumor herbal remedy - Botany, phytochemistry, and clinical applications and insights. JOURNAL OF ETHNOPHARMACOLOGY 2025; 340:119200. [PMID: 39631716 DOI: 10.1016/j.jep.2024.119200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 11/28/2024] [Accepted: 12/02/2024] [Indexed: 12/07/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Traditional Chinese herbal medicine has unique advantages as anti-cancer drugs and adjuvant therapies. Rabdosia rubescens (Hemsl.) H. Hara (R. rubescens) is a traditional medicinal plant known for its anti-inflammatory, antioxidant, antibacterial, anti-angiogenic and antitumor properties. The antitumor activity of R. rubescens is widely recognized among the folk communities in Henan Province, China. AIM OF THE STUDY This study reviews the botany, ethnopharmacology, phytochemistry, anti-tumor active ingredients, mechanisms, and clinical applications of R. rubescens, aiming to provide a comprehensive understanding for its use as an anti-cancer drug and adjuvant therapy. MATERIALS AND METHODS We systematically searched the literature in PubMed, Web of Science, and CNKI using the following keywords: "Rabdosia rubescens", "Isodon rubescens", "traditional application", "anti-tumor", "phytochemistry", "anti-tumor active compounds", "oridonin" and "clinical application". The search covered publications from 1997 to 2024. Inclusion criteria included original studies or reviews focusing on the anti-tumor properties of R. rubescens or its active components. Exclusion criteria included studies related to non-R. rubescens applications. RESULTS R. rubescens is a perennial herbaceous plant in the family Lamiaceae, mainly found in central and southern China. Historically, it has been used to treat conditions such as sore throat, cough, and excess phlegm. The plant contains various compounds, including diterpenes, triterpenes, steroids, flavonoids, phenolic acids, essential oils, amino acids, alkaloids, and polysaccharides, with diterpenes, triterpenes, flavonoids, and phenolic acids being the most active. This review identifies 50 compounds with anti-tumor properties, comprising 34 diterpenes, 2 triterpenes, 7 flavonoids, and 7 phenolic acids. Notably, besides oridonin and ponicidin, the ent-kaurane diterpenoids (20S)-11β,14β,20-trihydroxy-7α,20-epoxy-ent-kaur-16-en15-one and (20S)-11β,14β-dihydroxy-20-ethoxy7α,20-epoxy-ent-kaur-16-en-15-one demonstrate significant anti-tumor activity, attributed to their carbonyl group at C-15, hydroxyl group at C-1, and OEt group at C-20. Mechanistically, R. rubescens combats tumors by blocking the tumor cell cycle, promoting apoptosis, inhibiting cell migration and angiogenesis, inducing ferroptosis, reversing drug resistance, and enhancing radiosensitivity in tumor cells. Clinically, R. rubescens is available in various forms, including tablets, drops, syrups, capsules, and lozenges, and is primarily used for tonsillitis, pharyngitis, and stomatitis. According to the 2020 edition of the Pharmacopoeia of China, R. rubescens tablets are recognized as an adjuvant therapy for cancer. Clinical studies indicate that R. rubescens syrup, tablets, and thermal therapy can enhance cancer patient survival rates and lower tumor recurrence rates. CONCLUSIONS Given its traditional and modern uses, active anti-tumor components, and mechanisms, R. rubescens is a promising resource in traditional Chinese medicine for anti-tumor therapy. To realize its full potential, future research should explore additional active anti-tumor compounds beyond oridonin and ponicidin. For these key components, studies should focus on structural modifications to identify new active molecules and essential anti-tumor structures. Clinically, it is important to investigate how R. rubescens interacts with other Chinese herbs in anti-tumor formulations to enhance treatment efficacy and guide appropriate clinical use. Furthermore, future studies should undergo ethical review and include larger-scale randomized controlled trials to validate the efficacy of R. rubescens in treating tumors, thereby promoting its role as an anti-tumor traditional Chinese medicine.
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Affiliation(s)
- Shiyong Gao
- Drug Engineering and Technology Research Center, Harbin University of Commerce, Harbin, 150076, Heilongjiang, China; Heilongjiang Provincial Key Laboratory of Tumor Prevention and Antitumor Drugs, Harbin, 150076, Heilongjiang, China
| | - Jianwen Li
- Drug Engineering and Technology Research Center, Harbin University of Commerce, Harbin, 150076, Heilongjiang, China; Heilongjiang Provincial Key Laboratory of Tumor Prevention and Antitumor Drugs, Harbin, 150076, Heilongjiang, China
| | - Weiya Wang
- Drug Engineering and Technology Research Center, Harbin University of Commerce, Harbin, 150076, Heilongjiang, China; Heilongjiang Provincial Key Laboratory of Tumor Prevention and Antitumor Drugs, Harbin, 150076, Heilongjiang, China
| | - Yue Wang
- Drug Engineering and Technology Research Center, Harbin University of Commerce, Harbin, 150076, Heilongjiang, China; Heilongjiang Provincial Key Laboratory of Tumor Prevention and Antitumor Drugs, Harbin, 150076, Heilongjiang, China
| | - Yanmin Shan
- Drug Engineering and Technology Research Center, Harbin University of Commerce, Harbin, 150076, Heilongjiang, China; Heilongjiang Provincial Key Laboratory of Tumor Prevention and Antitumor Drugs, Harbin, 150076, Heilongjiang, China
| | - Huixin Tan
- Department of Pharmacy, Fourth Affiliated Hospital of Harbin Medicine University, Harbin, 150001, Heilongjiang, China.
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Shi X, Zheng W, He B, Huang L, Zhong Q, Yang Y, Zhou T, Huang Y. UPLC-Q-TOF/MS-based urine metabolomics for the diagnosis and staging of bladder cancer. Clin Chim Acta 2025; 565:120022. [PMID: 39471892 DOI: 10.1016/j.cca.2024.120022] [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: 05/14/2024] [Revised: 10/10/2024] [Accepted: 10/25/2024] [Indexed: 11/01/2024]
Abstract
BACKGROUND Bladder cancer (BC) is a common malignant tumour of the urinary system. Currently, the gold standard for diagnosing BC is cystoscopy, but it is an invasive examination that can lead to a certain psychological burden on the patient. In this study, we aimed to identify non-invasive potential metabolic biomarkers that could improve the diagnostic accuracy of bladder cancer. METHODS Urine from 30 healthy people and 50 BC patients, including 40 non-muscle-invasive bladder cancer (NMIBC) patients and 10 muscle-invasive bladder cancer (MIBC) patients, were analyzed by liquid chromatography coupled with mass spectrometry to identify potential diagnostic metabolites. Binary Logistic regression was used to construct biomarker panels. Correlation analysis and construction of compound-reaction-enzyme-gene network were also performed to explore the possible mechanisms of BC development. RESULTS Twenty-six metabolites were identified for differentiating BC patients from healthy controls, and eight metabolites were identified for differentiating NMIBC patients form MIBC patients. The biomarker panel consisting of urate, 4-Androstene-3α, 17β-diol and 3-Indoxyl sulfate can distinguish well between BC patients and healthy controls, with an area under the ROC curve (AUC) value of 0.983. And the biomarker panel consisting of L-Octanoylcarnitine, γ-Glutamylleucine, and heptanoylcarnitine for distinguishing NMIBC patients from MIBC patients had an AUC value of 0.941. CONCLUSIONS The diagnostic capability of the biomarker panels are superior to that of any single potential biomarker. This panel significantly benefits bladder cancer diagnostics and reveals insight into bladder cancer pathogenesis.
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Affiliation(s)
- Xingyu Shi
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
| | - Wenbin Zheng
- Department of Emergency, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Binhong He
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
| | - Longhui Huang
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
| | - Qisheng Zhong
- Guangzhou Analytical Applications Center, Shimadzu (China) Co., LTD, Guangdong 510010, China
| | - Yunfan Yang
- Guangzhou Analytical Applications Center, Shimadzu (China) Co., LTD, Guangdong 510010, China
| | - Ting Zhou
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China.
| | - Yong Huang
- Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Nanning 530000, China; Department of Emergency, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
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Cui W, Cao Q, Liu L, Yin X, Wang X, Zhao Y, Wang Y, Wei B, Xu X, Tang Y. Artemisia Argyi essential oil ameliorates acetaminophen-induced hepatotoxicity via CYP2E1 and γ-glutamyl cycle reprogramming. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156106. [PMID: 39366156 DOI: 10.1016/j.phymed.2024.156106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 09/22/2024] [Accepted: 09/28/2024] [Indexed: 10/06/2024]
Abstract
BACKGROUND The hepatotoxicity induced by acetaminophen (APAP), a commonly used antipyretic, analgesic and anti-inflammatory drug in clinical practice, has received accumulated attention. Artemisia argyi essential oil (AAEO), a volatile oil component extracted from traditional Chinese medicine Artemisia argyi H.Lév. & Vaniot, has great hepatoprotective effects. However, the potential role of AAEO in APAP-induced hepatotoxicity has not been characterized. The present study aimed to investigate the effects of AAEO on hepatic metabolic changes in mice exposed to APAP. METHODS In this study, 300.00 mg/kg acetaminophen was used to establish liver injury model in C57BL/6 J mice. Hepatoprotective effect of AAEO on APAP-induced hepatotoxicity in mice was investigated by detecting liver function enzymes and histopathological examination. Secondly, UPLC-MS/MS was used to analyze the to analyze the small molecule metabolites and metabolic pathways induced by AAEO treatment; In addition, the effect of AAEO on APAP-induced oxidative stress and inflammation were evaluated by detecting the levels of glutathione peroxidase 4, malondialdehyde, reactive oxygen species and inflammatory factors. Finally, the active components of AAEO were preliminarily screened by cellular assays. The hepatoprotective effect of AAEO against APAP-induced hepatotoxicity was examined through the Western blotting, after the CYP2E1 gene was knocked down in AML12 cells by siRNA transfection. RESULTS Compared with the APAP group, AAEO could reduce the abnormal increase in the levels of liver function enzymes caused by APAP. AAEO could enhance the antioxidant capacity by down-regulating the biosynthesis pathway of unsaturated fatty acids and promoting the activity of antioxidant enzymes SOD and CAT in liver tissue induced by APAP. Our study revealed that AAEO promoted GSH synthesis and covalently combined to form APAP-GSH conjugates to reduce the accumulation of APAP in liver tissue. In addition, the chemical constituents in AAEO were analyzed by GC-MS/MS, and it was determined to identify that dihydro-beta-ionone and (-)-verbenone in AAEO might have a significant protective effect on hepatocyte survival after APAP exposure. Further studies on the hepatoprotective mechanism of AAEO indicated that it might reduce the production of toxic metabolites by regulating CYP2E1 levels. CONCLUSION AAEO exerted hepatoprotective effects on acetaminophen-induced hepatotoxicity in mice via regulating the activity of CYP2E1 and regulating the γ-glutamyl cycle pathway.
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Affiliation(s)
- Weiqi Cui
- Henan Key Laboratory of Rehabilitation Medicine, Henan Joint International Research Laboratory of Chronic Liver Injury, Henan Workshop of Chronic Liver Injury for Outstanding Overseas Scientists, Zhengzhou Key Laboratory of Metabolic-dysfunction-associated Fatty Liver Disease, Department of Pharmacy, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Qianwen Cao
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Luyao Liu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Xuecui Yin
- Henan Key Laboratory of Rehabilitation Medicine, Henan Joint International Research Laboratory of Chronic Liver Injury, Henan Workshop of Chronic Liver Injury for Outstanding Overseas Scientists, Zhengzhou Key Laboratory of Metabolic-dysfunction-associated Fatty Liver Disease, Department of Pharmacy, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xiaohan Wang
- Henan Key Laboratory of Rehabilitation Medicine, Henan Joint International Research Laboratory of Chronic Liver Injury, Henan Workshop of Chronic Liver Injury for Outstanding Overseas Scientists, Zhengzhou Key Laboratory of Metabolic-dysfunction-associated Fatty Liver Disease, Department of Pharmacy, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yang Zhao
- Henan Key Laboratory of Rehabilitation Medicine, Henan Joint International Research Laboratory of Chronic Liver Injury, Henan Workshop of Chronic Liver Injury for Outstanding Overseas Scientists, Zhengzhou Key Laboratory of Metabolic-dysfunction-associated Fatty Liver Disease, Department of Pharmacy, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yanhong Wang
- Henan Key Laboratory of Rehabilitation Medicine, Henan Joint International Research Laboratory of Chronic Liver Injury, Henan Workshop of Chronic Liver Injury for Outstanding Overseas Scientists, Zhengzhou Key Laboratory of Metabolic-dysfunction-associated Fatty Liver Disease, Department of Pharmacy, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Bo Wei
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
| | - Xia Xu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
| | - Youcai Tang
- Henan Key Laboratory of Rehabilitation Medicine, Henan Joint International Research Laboratory of Chronic Liver Injury, Henan Workshop of Chronic Liver Injury for Outstanding Overseas Scientists, Zhengzhou Key Laboratory of Metabolic-dysfunction-associated Fatty Liver Disease, Department of Pharmacy, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
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Chi ZC. Progress in research of ferroptosis in gastrointestinal tumors. Shijie Huaren Xiaohua Zazhi 2024; 32:699-715. [DOI: 10.11569/wcjd.v32.i10.699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/04/2024] [Accepted: 09/19/2024] [Indexed: 10/28/2024] Open
Abstract
Ferroptosis is a non-apoptotic and oxidation-damaged regulated cell death caused by iron accumulation, lipid peroxidation, and subsequent plasma membrane rupture. Ferroptosis is the main cause of tissue damage caused by iron overload and lipid peroxidation. With the deepening of the research in recent years, the understanding of the occurrence and treatment of tumors has made a major breakthrough, which brings new strategies for anti-cancer treatment. This paper reviews the relationship between ferroptosis and gastrointestinal tumors, the research of ferroptosis in cancer prevention and treatment, and the role of ferroptosis in the prevention and treatment of gastrointestinal tumors.
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Affiliation(s)
- Zhao-Chun Chi
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
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Chen HT, Yuan XY, Wang ZY, Fan D, Luo XM, Yang JH, Ma YX, Liu J, Wang X, Wang ZM. Induction of apoptosis by oridonin in nonfunctioning pituitary adenoma cells. Drug Dev Res 2024; 85:e22251. [PMID: 39188035 DOI: 10.1002/ddr.22251] [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: 05/27/2024] [Revised: 08/01/2024] [Accepted: 08/09/2024] [Indexed: 08/28/2024]
Abstract
Nonfunctioning pituitary adenoma (NFPA) is one of the major subtypes of pituitary adenomas (PA) and its primary treatment is surgical resection. However, normal surgery fails to remove lesions completely and there remains in lack of frontline treatment, so the development of new drugs for NFPA is no doubt urgent. Oridonin (ORI) has been reported to have antitumor effects on a variety of tumors, but whether it could exhibit the same effect on NFPA requires to be further investigated. The effects of ORI on pituitary-derived folliculostellate cell line (PDFS) cell viability, colony formation, proliferation ability, migration, and invasion were examined by Cell Counting Kit-8, colony formation assay, 5‑Ethynyl‑2'‑deoxyuridine proliferation assay, wound-healing assay, and Transwell assay. The differentially expressed genes in the control and ORI-treated groups were screened by transcriptome sequencing analysis and analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment. Cell cycle analysis was performed to detect changes in cell cycle. Annexin V-fluorescein isothiocyanate/propidium iodide staining was performed to detect apoptosis in ORI-treated cells. Western blot assay was performed to detect Bax, Bcl-2, and cleaved Caspase-3 protein expression. ORI inhibited PDFS cell viability and significantly suppressed cell proliferation, migration, and invasion. GO and KEGG results showed that ORI was associated with signaling pathways such as cell cycle and apoptosis in PDFS cells. In addition, ORI blocked cells in G2/M phase and induced apoptosis in PDFS cells. ORI can trigger cell cycle disruption and apoptosis collaboratively in PDFS cells, making it a promising and effective agent for NFPA therapy.
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Affiliation(s)
- Hui-Tong Chen
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xing-Yi Yuan
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zhong-Yu Wang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Dong Fan
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiong-Ming Luo
- Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, School of LifeSciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
- Department of Marine Pharmacy, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jun-Hua Yang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yu-Xin Ma
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jing Liu
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xin Wang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zong-Ming Wang
- Pituitary Tumor Center, Department of Neurosurgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Cai M, Fu T, Zhu R, Hu P, Kong J, Liao S, Du Y, Zhang Y, Qu C, Dong X, Yin X, Ni J. An iron-based metal-organic framework nanoplatform for enhanced ferroptosis and oridonin delivery as a comprehensive antitumor strategy. Acta Pharm Sin B 2024; 14:4073-4086. [PMID: 39309488 PMCID: PMC11413704 DOI: 10.1016/j.apsb.2024.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/30/2024] [Accepted: 05/07/2024] [Indexed: 09/25/2024] Open
Abstract
Ferroptosis is a recently discovered pathway for regulated cell death pathway. However, its efficacy is affected by limited iron content and intracellular ion homeostasis. Here, we designed a metal-organic framework (MOF)-based nanoplatform that incorporates calcium peroxide (CaO2) and oridonin (ORI). This platform can improve the tumor microenvironment and disrupt intracellular iron homeostasis, thereby enhancing ferroptosis therapy. Fused cell membranes (FM) were used to modify nanoparticles (ORI@CaO2@Fe-TCPP, NPs) to produce FM@ORI@CaO2@Fe-TCPP (FM@NPs). The encapsulated ORI inhibited the HSPB1/PCBP1/IREB2 and FSP1/COQ10 pathways simultaneously, working in tandem with Fe3+ to induce ferroptosis. Photodynamic therapy (PDT) guided by porphyrin (TCPP) significantly enhanced ferroptosis through excessive accumulation of reactive oxygen species (ROS). This self-amplifying strategy promoted robust ferroptosis, which could work synergistically with FM-mediated immunotherapy. In vivo experiments showed that FM@NPs inhibited 91.57% of melanoma cells within six days, a rate 5.6 times higher than chemotherapy alone. FM@NPs were biodegraded and directly eliminated in the urine or faeces without substantial toxicity. Thus, this study demonstrated that combining immunotherapy with efficient ferroptosis induction through nanotechnology is a feasible and promising strategy for melanoma treatment.
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Affiliation(s)
- Mengru Cai
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Tingting Fu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Rongyue Zhu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Panxiang Hu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Jiahui Kong
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Shilang Liao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yuji Du
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yongqiang Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Changhai Qu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xiaoxv Dong
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xingbin Yin
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Jian Ni
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
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Ye S, Hu X, Sun S, Su B, Cai J, Jiang J. Oridonin promotes RSL3-induced ferroptosis in breast cancer cells by regulating the oxidative stress signaling pathway JNK/Nrf2/HO-1. Eur J Pharmacol 2024; 974:176620. [PMID: 38685305 DOI: 10.1016/j.ejphar.2024.176620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 04/20/2024] [Accepted: 04/25/2024] [Indexed: 05/02/2024]
Abstract
The incidence and mortality of breast cancer, the most common malignant tumor among women in the world, are increasing year by year, which greatly threatens women's health. Ferroptosis is an iron and lipid reactive oxygen species (ROS)-dependent process, a novel form of cell death that is distinct from apoptosis and is closely related to the progression of breast cancer. Inducing the occurrence of ferroptosis in tumor cells can effectively block its malignant progress in vivo. Oridonin (ORI), the primary active ingredient extracted from the Chinese herbal medicine Rabdosia rubescens, has been shown to cause glutathione depletion and directly inhibit glutathione peroxidase 4 induced cell death by ferroptosis, but its mechanism of action in breast cancer remains inadequately elucidated. Therefore, we further investigated whether ORI could promote RSL3-induced ferroptosis in breast cancer cells by regulating the oxidative stress pathway JNK/Nrf2/HO-1. In our study, we assessed cell survival of RSL3 and ORI treatment by MTT assay, and found that co-treatment with RSL3 and ORI inhibited cell proliferation, as evidenced by the cloning assay. To investigate the ability of ORI to promote RSL3-induced ferroptosis in breast cancer cells, we measured levels of ROS, malondialdehyde, glutathione, superoxide dismutase, and Fe2+ content. Lipid peroxidation, ROS, and mitochondrial membrane potential levels induced by co-treatment of ORI with RSL3 were reversed by ferrostatin-1, further confirming that the cell death induced by RSL3 and ORI was ferroptosis rather than other programmed cell death modes. Moreover, RSL3 and ORI co-treatment regulated the JNK/Nrf2/HO-1 axis, as demonstrated by western blotting and target activator validation. Our results showed that ORI could enhance the inhibitory effect of RSL3 on breast cancer cells viability via the induction of ferroptosis. Mechanistically, it potentiated RSL3-induced ferroptosis in breast cancer cells by activating the JNK/Nrf2/HO-1 axis. This study provides a theoretical basis for the application of ORI based on the mechanism of ferroptosis, and provides potential natural drug candidates for cancer prevention and treatment.
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Affiliation(s)
- Shiying Ye
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
| | - Xiangyan Hu
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Shaowei Sun
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Bo Su
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jiye Cai
- Department of Chemistry, Jinan University, Guangzhou 510632, China
| | - Jinhuan Jiang
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
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Ali MA, Khan N, Ali A, Akram H, Zafar N, Imran K, Khan T, Khan K, Armaghan M, Palma‐Morales M, Rodríguez‐Pérez C, Caunii A, Butnariu M, Habtemariam S, Sharifi‐Rad J. Oridonin from Rabdosia rubescens: An emerging potential in cancer therapy - A comprehensive review. Food Sci Nutr 2024; 12:3046-3067. [PMID: 38726411 PMCID: PMC11077219 DOI: 10.1002/fsn3.3986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 01/11/2024] [Accepted: 01/15/2024] [Indexed: 05/12/2024] Open
Abstract
Cancer incidences are rising each year. In 2020, approximately 20 million new cancer cases and 10 million cancer-related deaths were recorded. The World Health Organization (WHO) predicts that by 2024 the incidence of cancer will increase to 30.2 million individuals annually. Considering the invasive characteristics of its diagnostic procedures and therapeutic methods side effects, scientists are searching for different solutions, including using plant-derived bioactive compounds, that could reduce the probability of cancer occurrence and make its treatment more comfortable. In this regard, oridonin (ORI), an ent-kaurane diterpenoid, naturally found in the leaves of Rabdosia rubescens species, has been found to have antitumor, antiangiogenesis, antiasthmatic, antiinflammatory, and apoptosis induction properties. Extensive research has been performed on ORI to find various mechanisms involved in its anticancer activities. This review article provides an overview of ORI's effectiveness on murine and human cancer populations from 1976 to 2022 and provides insight into the future application of ORI in different cancer therapies.
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Affiliation(s)
| | - Noohela Khan
- Department of Nutrition SciencesRashid Latif Medical CollegeLahorePakistan
| | - Ahmad Ali
- Department of Food Science and Human NutritionUVASLahorePakistan
| | - Hira Akram
- Department of Food Science and Human NutritionUVASLahorePakistan
| | - Noushaba Zafar
- Department of Food Science and Human NutritionUVASLahorePakistan
| | - Kinza Imran
- Department of Food Science and Human NutritionUVASLahorePakistan
| | - Tooba Khan
- Department of Healthcare Biotechnology, Atta‐ur‐Rahman School of Applied BiosciencesNational University of Sciences and TechnologyIslamabadPakistan
| | | | - Muhammad Armaghan
- Department of Healthcare Biotechnology, Atta‐ur‐Rahman School of Applied BiosciencesNational University of Sciences and TechnologyIslamabadPakistan
| | - Marta Palma‐Morales
- Departamento de Nutrición y Bromatología, Facultad de FarmaciaUniversidad de GranadaGranadaSpain
- Instituto de Nutrición y Tecnología de los Alimentos ‘José Mataix’Universidad de GranadaGranadaSpain
| | - Celia Rodríguez‐Pérez
- Departamento de Nutrición y Bromatología, Facultad de FarmaciaUniversidad de GranadaGranadaSpain
- Instituto de Nutrición y Tecnología de los Alimentos ‘José Mataix’Universidad de GranadaGranadaSpain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA)GranadaSpain
| | - Angela Caunii
- “Victor Babes” University of Medicine and PharmacyTimisoaraRomania
| | - Monica Butnariu
- University of Life Sciences "King Mihai I" from TimisoaraTimisoaraRomania
| | - Solomon Habtemariam
- Pharmacognosy Research & Herbal Analysis Services UKUniversity of GreenwichKentUK
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10
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Khan F, Pandey P, Verma M, Ramniwas S, Lee D, Moon S, Park MN, Upadhyay TK, Kim B. Emerging trends of phytochemicals as ferroptosis modulators in cancer therapy. Biomed Pharmacother 2024; 173:116363. [PMID: 38479184 DOI: 10.1016/j.biopha.2024.116363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/24/2024] [Accepted: 02/27/2024] [Indexed: 03/27/2024] Open
Abstract
Ferroptosis, a novel form of regulated cell death characterized by dependence on iron and lipid peroxidation, has been implicated in a wide range of clinical conditions including neurological diseases, cardiovascular disorders, acute kidney failure, and various types of cancer. Therefore, it is critical to suppress cancer progression and proliferation. Ferroptosis can be triggered in cancer cells and some normal cells by synthetic substances, such as erastin, Ras-selective lethal small molecule-3, or clinical pharmaceuticals. Natural bioactive compounds are traditional drug discovery tools, and some have been therapeutically used as dietary additives or pharmaceutical agents against various malignancies. The fact that natural products have multiple targets and minimal side effects has led to notable advances in anticancer research. Research has indicated that ferroptosis can also be induced by natural compounds during cancer treatment. In this review, we focused on the most recent developments in emerging molecular processes and the significance of ferroptosis in cancer. To provide new perspectives on the future development of ferroptosis-related anticancer medications, we also provide a summary of the implications of natural phytochemicals in triggering ferroptosis through ROS production and ferritinophagy induction in a variety of malignancies.
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Affiliation(s)
- Fahad Khan
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, India
| | - Pratibha Pandey
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, India.
| | - Meenakshi Verma
- University Centre for Research and Development, Chandigarh University, Gharuan, Mohali, Punjab 140413, India; Department of Chemistry, University Institute of Sciences, Chandigarh University, Gharuan, Mohali, Punjab 140413, India
| | - Seema Ramniwas
- University Centre for Research and Development, Chandigarh University, Gharuan, Mohali, Punjab 140413, India
| | - Dain Lee
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemun-gu, Seoul 02447, the Republic of Korea
| | - Seungjoon Moon
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemun-gu, Seoul 02447, the Republic of Korea; Chansol Hospital of Korean Medicine, 290, Buheung-ro, Bupyeong-gu, Incheon 21390, the Republic of Korea
| | - Moon Nyeo Park
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemun-gu, Seoul 02447, the Republic of Korea
| | - Tarun Kumar Upadhyay
- Department of Biotechnology, Parul Institute of Applied Sciences and Research and Development Cell, Parul University, Vadodara 391760, India
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemun-gu, Seoul 02447, the Republic of Korea.
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11
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Yang Y, Zheng X, Lv H, Tang B, Zhong Y, Luo Q, Bi Y, Yang K, Zhong H, Chen H, Lu C. The causal relationship between serum metabolites and the risk of psoriasis: a Mendelian randomization and meta-analysis study. Front Immunol 2024; 15:1343301. [PMID: 38529280 PMCID: PMC10961426 DOI: 10.3389/fimmu.2024.1343301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 02/22/2024] [Indexed: 03/27/2024] Open
Abstract
Objective To explore the influence of serum metabolites on the risk of psoriasis. Methods In the initial stage, we applied Mendelian randomization to evaluate the association between 1,400 serum metabolites and the risk of psoriasis. Causal effects were primarily assessed through the Inverse-Variance Weighted method and Wald Ratio's odds ratios, and 95% confidence intervals. False Discovery Rate was used for multiple comparison corrections. Sensitivity analyses were conducted using Cochran's Q Test, MR-PRESSO. MR-Steiger Test was employed to check for reverse causality. In the validation stage, we sought other sources of psoriasis GWAS data to verify the initial results and used meta-analysis to combine the effect sizes to obtain robust causal relationships. In addition, we also conducted metabolic pathway enrichment analysis on known metabolites that have a causal relationship with the risk of psoriasis in both stages. Results In the initial stage, we identified 112 metabolites causally associated with psoriasis, including 32 metabolite ratios and 80 metabolites (69 known and 11 unknown). In the validation stage, 24 metabolites (16 known, 1 unknown, and 7 metabolite ratios) were confirmed to have a causal relationship with psoriasis onset. Meta-analysis results showed that the overall effect of combined metabolites was consistent with the main analysis in direction and robust in the causal relationship with psoriasis onset. Of the 16 known metabolites, most were attributed to lipid metabolism, with 5 as risk factors and 8 as protective factors for psoriasis. Peptidic metabolite Gamma-glutamylvaline levels had a negative causal relationship with psoriasis, while exogenous metabolite Catechol sulfate levels and amino acid 3-methylglutaconate levels had a positive causal relationship with the disease onset. The metabolites associated with psoriasis risk in the two stages are mainly enriched in the following metabolic pathways: Glutathione metabolism, Alpha Linolenic Acid and Linoleic Acid Metabolism, Biosynthesis of unsaturated fatty acids, Arachidonic acid metabolism, Glycerophospholipid metabolism. Conclusion Circulating metabolites may have a potential causal relationship with psoriasis risk, and targeting specific metabolites may benefit psoriasis diagnosis, disease assessment, and treatment.
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Affiliation(s)
- Yujie Yang
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xuwei Zheng
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Haiying Lv
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bin Tang
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China
- Guangdong Provincial Clinical Medicine Research Center for Chinese Medicine Dermatology, Guangzhou, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yiyuan Zhong
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qianqian Luo
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yang Bi
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Kexin Yang
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Haixin Zhong
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Haiming Chen
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China
- Guangdong Provincial Clinical Medicine Research Center for Chinese Medicine Dermatology, Guangzhou, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chuanjian Lu
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China
- Guangdong Provincial Clinical Medicine Research Center for Chinese Medicine Dermatology, Guangzhou, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
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12
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Chen YL, Xiong LA, Ma LF, Fang L, Zhan ZJ. Natural product-derived ferroptosis mediators. PHYTOCHEMISTRY 2024; 219:114002. [PMID: 38286199 DOI: 10.1016/j.phytochem.2024.114002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 01/22/2024] [Accepted: 01/22/2024] [Indexed: 01/31/2024]
Abstract
It has been 11 years since ferroptosis, a new mode of programmed cell death, was first proposed. Natural products are an important source of drug discovery. In the past five years, natural product-derived ferroptosis regulators have been discovered in an endless stream. Herein, 178 natural products discovered so far to trigger or resist ferroptosis are classified into 6 structural classes based on skeleton type, and the mechanisms of action that have been reported are elaborated upon. If pharmacodynamic data are sufficient, the structure and bioactivity relationship is also presented. This review will provide medicinal chemists with some effective ferroptosis regulators, which will promote the research of natural product-based treatment of ferroptosis-related diseases in the future.
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Affiliation(s)
- Yi-Li Chen
- Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR China
| | - Lin-An Xiong
- Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR China
| | - Lie-Feng Ma
- Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR China
| | - Luo Fang
- Department of Pharmacy, Zhejiang Cancer Hospital, PR China.
| | - Zha-Jun Zhan
- Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR China.
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13
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Zhang F, Hao Y, Yang N, Liu M, Luo Y, Zhang Y, Zhou J, Liu H, Li J. Oridonin-induced ferroptosis and apoptosis: a dual approach to suppress the growth of osteosarcoma cells. BMC Cancer 2024; 24:198. [PMID: 38347435 PMCID: PMC10863210 DOI: 10.1186/s12885-024-11951-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 02/04/2024] [Indexed: 02/15/2024] Open
Abstract
BACKGROUND Osteosarcoma (OS) is one of the most common aggressive bone malignancy tumors in adolescents. With the application of new chemotherapy regimens, finding new and effective anti-OS drugs to coordinate program implementation is urgent for the patients of OS. Oridonin had been proved to mediate anti-tumor effect on OS cells, but its mechanism has not been fully elucidated. METHODS The effects of oridonin on the viability, clonal formation and migration of 143B and U2OS cells were detected by CCK-8, colony formation assays and wound-healing test. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to explore the mechanism of oridonin on OS. Western blot (WB), real-time quantitative PCR (qRT-PCR) were used to detect the expression levels of apoptosis and ferroptosis-relative proteins and genes. Annexin V-FITC apoptosis detection kit and flow cytometry examination were used to detect the level of apoptosis. Iron assay kit was used to evaluate the relative Fe2+ content. The levels of mitochondrial membrane potential and lipid peroxidation production was determined by mitochondrial membrane potential detection kit and ROS assay kit. RESULTS Oridonin could effectively inhibit the survival, clonal formation and metastasis of OS cells. The KEGG results indicated that oridonin is associated with the malignant phenotypic signaling pathways of proliferation, migration, and drug resistance in OS. Oridonin was capable of inhibiting expressions of BAX, cl-caspase3, SLC7A11, GPX4 and FTH1 proteins and mRNA, while promoting the expressions of Bcl-2 and ACSL4 in 143B and U2OS cells. Additionally, we found that oridonin could promote the accumulation of reactive oxygen species (ROS) and Fe2+ in OS cells, as well as reduce mitochondrial membrane potential, and these effects could be significantly reversed by the ferroptosis inhibitor ferrostatin-1 (Fer-1). CONCLUSION Oridonin can trigger apoptosis and ferroptosis collaboratively in OS cells, making it a promising and effective agent for OS therapy.
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Affiliation(s)
- Feifan Zhang
- Hunan University of Chinese Medicine, Changsha, China
- Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou, China
| | - Yang Hao
- Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou, China
- Henan University of Chinese Medicine, Zhengzhou, China
| | - Ning Yang
- Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou, China
| | - Man Liu
- Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou, China
| | - Yage Luo
- Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou, China
| | - Ying Zhang
- Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou, China
| | - Jian Zhou
- Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao Municipal Hospital, Qingdao, China
| | - Hongjian Liu
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Jitian Li
- Hunan University of Chinese Medicine, Changsha, China.
- Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou, China.
- Henan University of Chinese Medicine, Zhengzhou, China.
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14
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Wang Y, Yuan X, Ren M, Wang Z. Ferroptosis: A New Research Direction of Artemisinin and Its Derivatives in Anti-Cancer Treatment. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2024; 52:161-181. [PMID: 38328829 DOI: 10.1142/s0192415x24500071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Ferroptosis, an iron-dependent cell death mechanism driven by an accumulation of lipid peroxides on cellular membranes, has emerged as a promising strategy to treat various diseases, including cancer. Ferroptosis inducers not only exhibit cytotoxic effects on multiple cancer cells, including drug-resistant cancer variants, but also hold potential as adjuncts to enhance the efficacy of other anti-cancer therapies, such as immunotherapy. In addition to synthetic inducers, natural compounds, such as artemisinin, can be considered ferroptosis inducers. Artemisinin, extracted from Artemisia annua L., is a poorly water-soluble antimalarial drug. For clinical applications, researchers have synthesized various water-soluble artemisinin derivatives such as dihydroartemisinin, artesunate, and artemether. Artemisinin and artemisinin derivatives (ARTEs) upregulate intracellular free iron levels and promote the accumulation of intracellular lipid peroxides to induce cancer cell ferroptosis, alleviating cancer development and resulting in strong anti-cancer effects in vitro and in vivo. In this review, we introduce the mechanisms of ferroptosis, summarize the research on ARTEs-induced ferroptosis in cancer cells, and discuss the clinical research progress and current challenges of ARTEs in anti-cancer treatment. This review deepens the current understanding of the relationship between ARTEs and ferroptosis and provides a theoretical basis for the clinical anti-cancer application of ARTEs in the future.
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Affiliation(s)
- Youke Wang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, P. R. China
- Guangdong Provincial Key Laboratory of Clinical, Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510006, Guangdong, P. R. China
| | - Xiang Yuan
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, P. R. China
| | - Min Ren
- Abdominal Oncology Ward, Division of Radiation Oncology, Cancer Center West China Hospital, Sichuan University, Chengdu 610041 Sichuan, P. R. China
| | - Zhiyu Wang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China
- Guangdong Provincial Key Laboratory of Clinical, Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510006, Guangdong, P. R. China
- Integrative Research Laboratory of Breast Cancer, Discipline of Integrated Chinese and Western Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, P. R. China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, P. R. China
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15
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Zhu J, Shen P, Xu Y, Zhang X, Chen Q, Gu K, Ji S, Yang B, Zhao Y. Ferroptosis: a new mechanism of traditional Chinese medicine for cancer treatment. Front Pharmacol 2024; 15:1290120. [PMID: 38292937 PMCID: PMC10824936 DOI: 10.3389/fphar.2024.1290120] [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: 09/07/2023] [Accepted: 01/03/2024] [Indexed: 02/01/2024] Open
Abstract
Ferroptosis, distinct from apoptosis, is a novel cellular death pathway characterized by the build-up of lipid peroxidation and reactive oxygen species (ROS) derived from lipids within cells. Recent studies demonstrated the efficacy of ferroptosis inducers in targeting malignant cells, thereby establishing a promising avenue for combating cancer. Traditional Chinese medicine (TCM) has a long history of use and is widely used in cancer treatment. TCM takes a holistic approach, viewing the patient as a system and utilizing herbal formulas to address complex diseases such as cancer. Recent TCM studies have elucidated the molecular mechanisms underlying ferroptosis induction during cancer treatment. These studies have identified numerous plant metabolites and derivatives that target multiple pathways and molecular targets. TCM can induce ferroptosis in tumor cells through various regulatory mechanisms, such as amino acid, iron, and lipid metabolism pathways, which may provide novel therapeutic strategies for apoptosis-resistant cancer treatment. TCM also influence anticancer immunotherapy via ferroptosis. This review comprehensively elucidates the molecular mechanisms underlying ferroptosis, highlights the pivotal regulatory genes involved in orchestrating this process, evaluates the advancements made in TCM research pertaining to ferroptosis, and provides theoretical insights into the induction of ferroptosis in tumors using botanical drugs.
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Affiliation(s)
- Jiahao Zhu
- Department of Radiotherapy and Oncology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
- Wuxi Clinical Cancer Center, Wuxi, Jiangsu, China
| | - Peipei Shen
- Department of Radiotherapy and Oncology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
- Wuxi Clinical Cancer Center, Wuxi, Jiangsu, China
| | - Yu Xu
- Department of Radiotherapy and Oncology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
- Wuxi Clinical Cancer Center, Wuxi, Jiangsu, China
| | - Xiaojun Zhang
- Department of Radiotherapy and Oncology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
- Wuxi Clinical Cancer Center, Wuxi, Jiangsu, China
| | - Qingqing Chen
- Department of Radiotherapy and Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
| | - Ke Gu
- Department of Radiotherapy and Oncology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
- Wuxi Clinical Cancer Center, Wuxi, Jiangsu, China
| | - Shengjun Ji
- Department of Radiotherapy and Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
| | - Bo Yang
- Department of Radiotherapy and Oncology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
- Wuxi Clinical Cancer Center, Wuxi, Jiangsu, China
| | - Yutian Zhao
- Department of Radiotherapy and Oncology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
- Wuxi Clinical Cancer Center, Wuxi, Jiangsu, China
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16
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Consoli V, Fallica AN, Sorrenti V, Pittalà V, Vanella L. Novel Insights on Ferroptosis Modulation as Potential Strategy for Cancer Treatment: When Nature Kills. Antioxid Redox Signal 2024; 40:40-85. [PMID: 37132605 PMCID: PMC10824235 DOI: 10.1089/ars.2022.0179] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 04/19/2023] [Accepted: 04/20/2023] [Indexed: 05/04/2023]
Abstract
Significance: The multifactorial nature of the mechanisms implicated in cancer development still represents a major issue for the success of established antitumor therapies. The discovery of ferroptosis, a novel form of programmed cell death distinct from apoptosis, along with the identification of the molecular pathways activated during its execution, has led to the uncovering of novel molecules characterized by ferroptosis-inducing properties. Recent advances: As of today, the ferroptosis-inducing properties of compounds derived from natural sources have been investigated and interesting findings have been reported both in vitro and in vivo. Critical Issues: Despite the efforts made so far, only a limited number of synthetic compounds have been identified as ferroptosis inducers, and their utilization is still limited to basic research. In this review, we analyzed the most important biochemical pathways involved in ferroptosis execution, with particular attention to the newest literature findings on canonical and non-canonical hallmarks, together with mechanisms of action of natural compounds identified as novel ferroptosis inducers. Compounds have been classified based on their chemical structure, and modulation of ferroptosis-related biochemical pathways has been reported. Future Directions: The outcomes herein collected represent a fascinating starting point from which to take hints for future drug discovery studies aimed at identifying ferroptosis-inducing natural compounds for anticancer therapies. Antioxid. Redox Signal. 40, 40-85.
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Affiliation(s)
- Valeria Consoli
- Department of Drug and Health Sciences, University of Catania, Catania, Italy
| | | | - Valeria Sorrenti
- Department of Drug and Health Sciences, University of Catania, Catania, Italy
- Department of Drug and Health Sciences, CERNUT—Research Centre on Nutraceuticals and Health Products, University of Catania, Catania, Italy
| | - Valeria Pittalà
- Department of Drug and Health Sciences, University of Catania, Catania, Italy
- Department of Drug and Health Sciences, CERNUT—Research Centre on Nutraceuticals and Health Products, University of Catania, Catania, Italy
| | - Luca Vanella
- Department of Drug and Health Sciences, University of Catania, Catania, Italy
- Department of Drug and Health Sciences, CERNUT—Research Centre on Nutraceuticals and Health Products, University of Catania, Catania, Italy
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Zuo HL, Huang HY, Lin YCD, Liu KM, Lin TS, Wang YB, Huang HD. Effects of Natural Products on Enzymes Involved in Ferroptosis: Regulation and Implications. Molecules 2023; 28:7929. [PMID: 38067658 PMCID: PMC10708253 DOI: 10.3390/molecules28237929] [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: 09/30/2023] [Revised: 11/18/2023] [Accepted: 11/30/2023] [Indexed: 12/18/2023] Open
Abstract
Ferroptosis is a form of regulated cell death that is characterized by the accumulation of iron-dependent lipid peroxides. The regulation of ferroptosis involves both non-enzymatic reactions and enzymatic mechanisms. Natural products have demonstrated potential effects on various enzymes, including GPX4, HO-1, NQO1, NOX4, GCLC, and GCLM, which are mainly involved in glutathione metabolic pathway or oxidative stress regulation, and ACSL3 and ACSL4, which mainly participate in lipid metabolism, thereby influencing the regulation of ferroptosis. In this review, we have provided a comprehensive overview of the existing literature pertaining to the effects of natural products on enzymes involved in ferroptosis and discussed their potential implications for the prevention and treatment of ferroptosis-related diseases. We also highlight the potential challenge that the majority of research has concentrated on investigating the impact of natural products on the expression of enzymes involving ferroptosis while limited attention is given to the regulation of enzyme activity. This observation underscores the considerable potential and scope for exploring the influence of natural products on enzyme activity.
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Affiliation(s)
- Hua-Li Zuo
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Shenzhen 518172, China; (H.-Y.H.); (Y.-C.-D.L.); (T.-S.L.); (Y.-B.W.)
- Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Shenzhen 518172, China
| | - Hsi-Yuan Huang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Shenzhen 518172, China; (H.-Y.H.); (Y.-C.-D.L.); (T.-S.L.); (Y.-B.W.)
- Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Shenzhen 518172, China
| | - Yang-Chi-Dung Lin
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Shenzhen 518172, China; (H.-Y.H.); (Y.-C.-D.L.); (T.-S.L.); (Y.-B.W.)
- Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Shenzhen 518172, China
| | - Kun-Meng Liu
- Center for Medical Artificial Intelligence, Qingdao Academy of Chinese Medical Sciences, Shandong University of Traditional Chinese Medicine, Qingdao 266112, China;
| | - Ting-Syuan Lin
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Shenzhen 518172, China; (H.-Y.H.); (Y.-C.-D.L.); (T.-S.L.); (Y.-B.W.)
- Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Shenzhen 518172, China
| | - Yi-Bing Wang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Shenzhen 518172, China; (H.-Y.H.); (Y.-C.-D.L.); (T.-S.L.); (Y.-B.W.)
- Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Shenzhen 518172, China
| | - Hsien-Da Huang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Shenzhen 518172, China; (H.-Y.H.); (Y.-C.-D.L.); (T.-S.L.); (Y.-B.W.)
- Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Shenzhen 518172, China
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Xu G, Wang J, Zhang Y, Chen Z, Deng R. GGT1 Suppresses the Development of Ferroptosis and Autophagy in Mouse Retinal Ganglion Cell Through Targeting GCLC. Eye Brain 2023; 15:139-151. [PMID: 38020723 PMCID: PMC10676118 DOI: 10.2147/eb.s434280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 11/03/2023] [Indexed: 12/01/2023] Open
Abstract
Background Glaucoma is a neurodegenerative disorder characterized with optic nerve injury and the loss of retinal ganglion cells (RGCs). Ferroptosis has been proved to be associated with the degradation of RGCs. The aim of this study is to elucidate the relationship between ferroptosis and glaucoma pathogenesis, and unveil the underlying mechanism. Methods Methyl thiazolyl tetrazolium (MTT) assay was used to evaluate the proliferation of RGCs. The accumulation of cellular iron was measured by Iron assay kit, and the level of reactive oxygen species (ROS) was detected by fluorescence probe. The mitochondrial morphology and autophagosomes were analysed by using transmission electron microscopy (TEM). The contents of glutathione (GSH) and malondialdehyde (MDA) were tested by a GSH assay kit and an MDA detection kit, respectively. The expression of autophagy-related proteins was detected by Western blotting. Results A serious cell damage, aberrant iron homeostasis, and oxidative stress was shown in RGC-5 after oxygen-glucose deprivation/reoxygenation (OGD/R) treatment and gamma-Glutamyl transpeptidase 1 (GGT1) knockdown, but these effects were significantly alleviated by overexpression of GGT1 or ferroptosis inhibitors. The TEM and immunofluorescent results indicated that mitochondria impairment and autophagosome accumulation in OGD/R-treated cells was improved after GGT1 overexpression, while the phenomenon in GGT1-silenced cells was aggravated. Furthermore, we found that GGT1 can interact with glutamate cysteine ligase catalytic subunit (GCLC) to inhibit autophagy and ferroptosis in RGC-5 cells. Conclusion GGT1 represses autophagy in RGC-5 cells by targeting GCLC, which further restrains the development of ferroptosis in cells.
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Affiliation(s)
- Guihua Xu
- Eye Department, Huizhou Municipal Central Hospital, Huizhou, Guangdong, People’s Republic of China
| | - Juanjuan Wang
- Eye Department, Huizhou Municipal Central Hospital, Huizhou, Guangdong, People’s Republic of China
| | - Yiting Zhang
- Eye Department, Huizhou Municipal Central Hospital, Huizhou, Guangdong, People’s Republic of China
| | - Zilin Chen
- Eye Department, Huizhou Municipal Central Hospital, Huizhou, Guangdong, People’s Republic of China
| | - Ruidong Deng
- Eye Department, Huizhou Municipal Central Hospital, Huizhou, Guangdong, People’s Republic of China
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Di Giacomo C, Malfa GA, Tomasello B, Bianchi S, Acquaviva R. Natural Compounds and Glutathione: Beyond Mere Antioxidants. Antioxidants (Basel) 2023; 12:1445. [PMID: 37507985 PMCID: PMC10376414 DOI: 10.3390/antiox12071445] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 07/14/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
The tripeptide glutathione plays important roles in many cell processes, including differentiation, proliferation, and apoptosis; in fact, disorders in glutathione homeostasis are involved both in the etiology and in the progression of several human diseases, including cancer. Natural compounds have been found to modulate glutathione levels and function beyond their role as mere antioxidants. For example, certain compounds can upregulate the expression of glutathione-related enzymes, increase the availability of cysteine, the limiting amino acid for glutathione synthesis, or directly interact with glutathione and modulate its function. These compounds may have therapeutic potential in a variety of disease states where glutathione dysregulation is a contributing factor. On the other hand, flavonoids' potential to deplete glutathione levels could be significant for cancer treatment. Overall, while natural compounds may have potential therapeutic and/or preventive properties and may be able to increase glutathione levels, more research is needed to fully understand their mechanisms of action and their potential benefits for the prevention and treatment of several diseases. In this review, particular emphasis will be placed on phytochemical compounds belonging to the class of polyphenols, terpenoids, and glucosinolates that have an impact on glutathione-related processes, both in physiological and pathological conditions. These classes of secondary metabolites represent the most food-derived bioactive compounds that have been intensively explored and studied in the last few decades.
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Affiliation(s)
- Claudia Di Giacomo
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
- Research Centre on Nutraceuticals and Health Products (CERNUT), University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Giuseppe Antonio Malfa
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
- Research Centre on Nutraceuticals and Health Products (CERNUT), University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Barbara Tomasello
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
- Research Centre on Nutraceuticals and Health Products (CERNUT), University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Simone Bianchi
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
- Research Centre on Nutraceuticals and Health Products (CERNUT), University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Rosaria Acquaviva
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
- Research Centre on Nutraceuticals and Health Products (CERNUT), University of Catania, Viale A. Doria 6, 95125 Catania, Italy
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20
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Fan X, Fan YT, Zeng H, Dong XQ, Lu M, Zhang ZY. Role of ferroptosis in esophageal cancer and corresponding immunotherapy. World J Gastrointest Oncol 2023; 15:1105-1118. [PMID: 37546564 PMCID: PMC10401468 DOI: 10.4251/wjgo.v15.i7.1105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/28/2023] [Accepted: 04/24/2023] [Indexed: 07/12/2023] Open
Abstract
Esophageal cancer (EC) is one of the most common digestive system malignancies in the world. The combined modality treatment of EC is usually surgery and radiation therapy, however, its clinical efficacy for advanced patients is relatively limited. Ferroptosis, a new type of iron-dependent programmed cell death, is different from apoptosis, necrosis and autophagy. In recent years, many studies have further enlightened that ferroptosis plays an essential role in the occurrence, development and metastasis of tumors. Targeting ferroptosis stimulates a new direction for further exploration of oncologic treatment regimens. Furthermore, ferroptosis has a critical role in the immune microenvironment of tumors. This paper reviews the mechanism of ferroptosis and the ferroptosis research progress in the treatment of EC. We further elaborate the interaction between ferroptosis and immunotherapy, and the related mechanisms of ferroptosis participation in the immunotherapy of EC, so as to provide new directions and ideas for the treatment of EC.
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Affiliation(s)
- Xin Fan
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330000, Jiangxi Province, China
| | - Yan-Ting Fan
- The First Clinical Medical College, Nanchang University, Nanchang 330000, Jiangxi Province, China
| | - Hui Zeng
- Department of Stomatology, The Second Affiliated Hospital of Nanchang University, Nanchang 330000, Jiangxi Province, China
| | - Xi-Qi Dong
- The First Clinical Medical College, Nanchang University, Nanchang 330000, Jiangxi Province, China
| | - Min Lu
- Department of Emergency Medicine, Shangrao Hospital Affiliated to Nanchang University, Shangrao 334000, Jiangxi Province, China
| | - Zhi-Yuan Zhang
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330000, Jiangxi Province, China
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21
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Yu D, Wang Q, Zhang Q, Cai M, Liu S, Zhang W. Molecular mechanisms of ferroptosis and its antitumor applications in natural products. Acta Biochim Biophys Sin (Shanghai) 2023; 55:1337-1347. [PMID: 37408372 PMCID: PMC10520475 DOI: 10.3724/abbs.2023120] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 04/18/2023] [Indexed: 07/07/2023] Open
Abstract
Ferroptosis, an iron-dependent form of regulated cell death, results in lipid peroxidation of polyunsaturated fatty acids in the cell membrane, which is catalyzed by iron ions and accumulated to lethal levels. It is mechanistically distinct from other forms of cell death, such as apoptosis, pyroptosis, and necroptosis, so it may address the problem of cancer resistance to apoptosis and provide new therapeutic strategies for cancer treatment, which has been intensively studied over the past few years. Notably, considerable advances have been made in the antitumor research of natural products due to their multitargets and few side effects. According to research, natural products can also induce ferroptosis in cancer therapies. In this review we summarize the molecular mechanisms of ferroptosis, introduce the key regulatory genes of ferroptosis, and discuss the progress of natural product research in the field of ferroptosis to provide theoretical guidance for research on natural product-induced ferroptosis in tumors.
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Affiliation(s)
- Dianping Yu
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai201203China
| | - Qun Wang
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai201203China
| | - Qing Zhang
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai201203China
| | - Minchen Cai
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai201203China
| | - Sanhong Liu
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai201203China
| | - Weidong Zhang
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai201203China
- Department of PhytochemistrySchool of PharmacySecond Military Medical UniversityShanghai200433China
- The Research Center for Traditional Chinese MedicineShanghai Institute of Infectious Diseases and BiosecurityShanghai University of Traditional Chinese MedicineShanghai201203China
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Zhang W, Shi L, Zhou W, Liu X, Xi Y, Wang X, Li Y, Xu X, Tang Y. Oridonin impedes breast cancer growth by blocking cells in S phase and inhibiting the PI3K/AKT/mTOR signaling pathway. Heliyon 2023; 9:e18046. [PMID: 37519735 PMCID: PMC10372243 DOI: 10.1016/j.heliyon.2023.e18046] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 07/03/2023] [Accepted: 07/05/2023] [Indexed: 08/01/2023] Open
Abstract
Breast cancer is one of the most common cancers. Oridonin, a traditional Chinese medicine, is believed to inhibit tumor growth, but its particular effects on breast cancer remain unknown. In this study, we examined oridonin's effects on 4T1, MCF-7, and MDAMB-231 cellular activity using CCK8. Scratch assays were used to detect oridonin's effects on cellular migration. Oridonin's effects on the breast cancer cell cycle were studied using flow cytometry, and expression of cell cycle related proteins p53, CDK2, and p21 was detected using Western blot assays. Metabolomics assays were used to detect changes in small molecule metabolites and metabolic pathways in breast cancer cells after treatment with oridonin. Oridonin's effects on breast cancer growth were also studied using xenograft mice. Metabolomics assays were used to detect changes in metabolites and metabolic pathways in xenograft mouse plasma in a control group, model group, and drug administration group. Experimental results showed that oridonin could significantly inhibit breast cancer growth both in vivo and in vitro. Scratch experiments showed that oridonin could inhibit breast cancer cell migration. Oridonin was also able to arrest cells in S phase by affecting several cell cycle-related proteins, including p53, CDK2, and p21. Metabolomic analysis of 4T1 cells identified a total of 33 differential metabolites, including multiple amino acids (such as l-Glutamic acid, l-Asparagine, l-Histidine, l-Valine, and l-Isoleucine). KEGG pathway enrichment analysis showed significant changes in aminoacyl-tRNA biosynthesis, and in multiple amino acid metabolic pathways. Plasma metabolomic analyses of xenograft mice revealed 28 differentially-expressed metabolites between the different animal model groups, including multiple amino acids. KEGG pathway analysis showed significant alterations in multiple amino acid metabolic pathways in oridonin-treated mice. Additionally, changes in the expression of PI3K, AKT and mTOR proteins, as well as in branched amino acids, suggest that oridonin affects the PI3K/AKT/mTOR signaling pathway by inhibiting the biosynthesis of valine, leucine and isoleucine. Taken together, our results suggest that oridonin has strong anti-tumor activity in vitro and in vivo, and has potential as an adjuvant to breast cancer treatment regimens.
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Affiliation(s)
- Weijie Zhang
- Department of Pharmacy, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Lei Shi
- Department of Pharmacy, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Wei Zhou
- Department of Pharmacy, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xin Liu
- Department of Blood Transfusion, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yuan Xi
- Department of Pharmacy, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xinyin Wang
- Department of Pharmacy, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Ya Li
- Department of Pediatrics, The Fifth Affiliated Hospital, Zhengzhou University, 3 Kangfuqian Street, Zhengzhou, Henan 450052, China
- Henan Key Laboratory of Rehabilitation Medicine, The Fifth Affiliated Hospital, Zhengzhou University, 3 Kangfuqian Street, Zhengzhou, Henan 450052, China
- Henan Joint International Research Laboratory of Chronic Liver Injury, The Fifth Affiliated Hospital, Zhengzhou University, 3 Kangfuqian Street, Zhengzhou, Henan 450052, China
- Henan Workshop of Chronic Liver Injury for Outstanding Overseas Scientists, The Fifth Affiliated Hospital, Zhengzhou University, 3 Kangfuqian Street, Zhengzhou, Henan 450052, China
- Zhengzhou Key Laboratory of Metabolic-dysfunction-associated Fatty Liver Disease, The Fifth Affiliated Hospital, Zhengzhou University, 3 Kangfuqian Street, Zhengzhou, Henan 450052, China
| | - Xia Xu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Youcai Tang
- Department of Pediatrics, The Fifth Affiliated Hospital, Zhengzhou University, 3 Kangfuqian Street, Zhengzhou, Henan 450052, China
- Henan Key Laboratory of Rehabilitation Medicine, The Fifth Affiliated Hospital, Zhengzhou University, 3 Kangfuqian Street, Zhengzhou, Henan 450052, China
- Henan Joint International Research Laboratory of Chronic Liver Injury, The Fifth Affiliated Hospital, Zhengzhou University, 3 Kangfuqian Street, Zhengzhou, Henan 450052, China
- Henan Workshop of Chronic Liver Injury for Outstanding Overseas Scientists, The Fifth Affiliated Hospital, Zhengzhou University, 3 Kangfuqian Street, Zhengzhou, Henan 450052, China
- Zhengzhou Key Laboratory of Metabolic-dysfunction-associated Fatty Liver Disease, The Fifth Affiliated Hospital, Zhengzhou University, 3 Kangfuqian Street, Zhengzhou, Henan 450052, China
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23
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Koeberle SC, Kipp AP, Stuppner H, Koeberle A. Ferroptosis-modulating small molecules for targeting drug-resistant cancer: Challenges and opportunities in manipulating redox signaling. Med Res Rev 2023; 43:614-682. [PMID: 36658724 PMCID: PMC10947485 DOI: 10.1002/med.21933] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/07/2022] [Accepted: 01/03/2023] [Indexed: 01/21/2023]
Abstract
Ferroptosis is an iron-dependent cell death program that is characterized by excessive lipid peroxidation. Triggering ferroptosis has been proposed as a promising strategy to fight cancer and overcome drug resistance in antitumor therapy. Understanding the molecular interactions and structural features of ferroptosis-inducing compounds might therefore open the door to efficient pharmacological strategies against aggressive, metastatic, and therapy-resistant cancer. We here summarize the molecular mechanisms and structural requirements of ferroptosis-inducing small molecules that target central players in ferroptosis. Focus is placed on (i) glutathione peroxidase (GPX) 4, the only GPX isoenzyme that detoxifies complex membrane-bound lipid hydroperoxides, (ii) the cystine/glutamate antiporter system Xc - that is central for glutathione regeneration, (iii) the redox-protective transcription factor nuclear factor erythroid 2-related factor (NRF2), and (iv) GPX4 repression in combination with induced heme degradation via heme oxygenase-1. We deduce common features for efficient ferroptotic activity and highlight challenges in drug development. Moreover, we critically discuss the potential of natural products as ferroptosis-inducing lead structures and provide a comprehensive overview of structurally diverse biogenic and bioinspired small molecules that trigger ferroptosis via iron oxidation, inhibition of the thioredoxin/thioredoxin reductase system or less defined modes of action.
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Affiliation(s)
- Solveigh C. Koeberle
- Michael Popp Institute, Center for Molecular Biosciences Innsbruck (CMBI)University of InnsbruckTirolInnsbruckAustria
- Department of Molecular Nutritional Physiology, Institute of Nutritional SciencesFriedrich Schiller University JenaThüringenJenaGermany
| | - Anna P. Kipp
- Department of Molecular Nutritional Physiology, Institute of Nutritional SciencesFriedrich Schiller University JenaThüringenJenaGermany
| | - Hermann Stuppner
- Unit of Pharmacognosy, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck (CMBI)University of InnsbruckTirolInnsbruckAustria
| | - Andreas Koeberle
- Michael Popp Institute, Center for Molecular Biosciences Innsbruck (CMBI)University of InnsbruckTirolInnsbruckAustria
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24
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Zhao CQ, Wang C, Liu MM, Cao M, Peng J, Kong DQ, Ren XT, Liu R, Hai CX, Zhang XD. Single-cell transcriptomes reveal heterogeneity of chlorine-induced mice acute lung injury and the inhibitory effect of pentoxifylline on ferroptosis. Sci Rep 2023; 13:6833. [PMID: 37100790 PMCID: PMC10131515 DOI: 10.1038/s41598-023-32093-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Accepted: 03/22/2023] [Indexed: 04/28/2023] Open
Abstract
To investigate the effect of pentoxifylline (PTX) on Chlorine (Cl2)-induced acute lung injury (ALI) by single-cell RNA sequencing (scRNA-seq). Female BALB/c mice were exposed to Cl2 at 400 ppm for 15 min. H&E staining was used to observe the degree of lung injury. scRNA-seq was conducted to analysis of normal and Cl2-exposed mice lung tissues. Immunofluorescence was used to observe genes of interest. Thirty-two mice were randomly divided into four groups: Control, Cl2, Cl2+Fer-1, Cl2+PTX. TEM, WB and ELISA were used to detect ferroptosis-related indicators. The 5, 8, 10, 12, 16, 20 clusters were epithelial cells and 4, 15, 18, 19, 21 clusters were endothelial cells. Pseudo-time analysis revealed the differentiation trajectory of epithelial cells and key regulatory genes (Gclc, Bpifa1, Dnah5 and Dnah9) during the process of injury. Cell-cell communication analysis identified several important receptor-ligand complexes (Nrp1-Vegfa, Nrp2-Vegfa, Flt1-Vegfa and Flt4-Vegfa). Ferroptosis were found up-regulated in epithelial and endothelial cells by GSVA analysis. Highly expressed genes to which closely related ferroptosis were found by SCENIC analysis. PTX could significantly decrease the levels of MDA and abnormal high expression of solute carrier family 7 member 11 (SLC7A11, the key transporter of cystine) as well as increase the expression of GSH/GSSG and glutathione peroxidase 4 (GPX4) (p < 0.05). This study revealed novel molecular features of Cl2-induced ALI. PTX may be a potential specific drug by inhibiting the process of ferroptosis in epithelial and endothelial cells.
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Affiliation(s)
- Chen-Qian Zhao
- Department of Medical Experiment Center, Shaanxi University of Chinese Medicine, Xi'an, 712046, Xianyang, China
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Air Force Medical University, Xi'an, 710032, China
| | - Chong Wang
- Department of Medical Experiment Center, Shaanxi University of Chinese Medicine, Xi'an, 712046, Xianyang, China
| | - Meng-Meng Liu
- Department of Health Service, Logistics University of Chinese People's Armed Police Force, Tianjin, 300309, China
| | - Meng Cao
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Air Force Medical University, Xi'an, 710032, China
| | - Jie Peng
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Air Force Medical University, Xi'an, 710032, China
| | - De-Qin Kong
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Air Force Medical University, Xi'an, 710032, China
| | - Xiao-Ting Ren
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Air Force Medical University, Xi'an, 710032, China
| | - Rui Liu
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Air Force Medical University, Xi'an, 710032, China
| | - Chun-Xu Hai
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Air Force Medical University, Xi'an, 710032, China.
| | - Xiao-di Zhang
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Air Force Medical University, Xi'an, 710032, China.
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25
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Wang W, Zhang N. Oridonin inhibits Hela cell proliferation via downregulation of glutathione metabolism: a new insight from metabolomics. J Pharm Pharmacol 2023:7087210. [DOI: 10.1093/jpp/rgad025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 03/09/2023] [Indexed: 03/29/2023]
Abstract
AbstractObjectivesThis study aims to elucidate Oridonin' s inhibitory mechanism to cervical cancer using metabolomics methods and pharmacological assays.MethodsNetwork pharmacology and KEGG pathway analysis are used to identify overlapped targets and involved metabolic pathways. UPLC-MS/MS metabolomics analysis is used to determine altered metabolites after Oridonin treatment. Other bioassays are also employed to uncover the changes in critical molecules that are highly related to altered metabolites.Key findingsSeventy-five overlapped targets are identified between Oridonin and cervical cancer. Twenty-one metabolites involved in tricarboxylic acid cycle glutathione metabolism, branched-chain amino acid metabolism and so on changes significantly after Oridonin treatment. Oridonin treatment significantly reduces the content of cysteine and inhibit the catalytic activity of glutamine–cysteine ligase subunit, a rate-limiting enzyme for the synthesis of glutathione. As a result, the content of glutathione is also reduced. The antioxidant enzyme glutathione peroxidase 4 which uses glutathione as a cofactor, is inactivated, resulting in a burst release of reactive oxygen species. The ATP content is also significantly reduced in Hela cells after Oridonin treatment.ConclusionsThis study finds that Oridonin treatment induces Hela cell apoptosis possibly via inhibition of the glutathione metabolism.
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Zhang R, Kang R, Tang D. Ferroptosis in gastrointestinal cancer: From mechanisms to implications. Cancer Lett 2023; 561:216147. [PMID: 36965540 DOI: 10.1016/j.canlet.2023.216147] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/16/2023] [Accepted: 03/22/2023] [Indexed: 03/27/2023]
Abstract
Ferroptosis is a form of regulated cell death that is initiated by excessive lipid peroxidation that results in plasma membrane damage and the release of damage-associated molecular patterns. In recent years, ferroptosis has gained significant attention in cancer research due to its unique mechanism compared to other forms of regulated cell death, especially caspase-dependent apoptotic cell death. Gastrointestinal (GI) cancer encompasses malignancies that arise in the digestive tract, including the stomach, intestines, pancreas, colon, liver, rectum, anus, and biliary system. These cancers are a global health concern, with high incidence and mortality rates. Despite advances in medical treatments, drug resistance caused by defects in apoptotic pathways remains a persistent challenge in the management of GI cancer. Hence, exploring the role of ferroptosis in GI cancers may lead to more efficacious treatment strategies. In this review, we provide a comprehensive overview of the core mechanism of ferroptosis and discuss its function, regulation, and implications in the context of GI cancers.
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Affiliation(s)
- Ruoxi Zhang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
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27
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Bu XM, Zhao WD, Zhang MY, Wu DQ, Wu JY, Xu X, Chen D. Matrix-assisted laser desorption/ionization high-resolution mass spectrometry for high-throughput analysis of androgenic steroid adulteration in traditional Chinese medicine based on d/d-Girard's reagent P labeling. Talanta 2023. [DOI: 10.1016/j.talanta.2022.124006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Zhang X, Xing M, Ma Y, Zhang Z, Qiu C, Wang X, Zhao Z, Ji Z, Zhang JY. Oridonin Induces Apoptosis in Esophageal Squamous Cell Carcinoma by Inhibiting Cytoskeletal Protein LASP1 and PDLIM1. Molecules 2023; 28:805. [PMID: 36677861 PMCID: PMC9862004 DOI: 10.3390/molecules28020805] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 01/07/2023] [Accepted: 01/09/2023] [Indexed: 01/15/2023] Open
Abstract
Esophageal squamous cell carcinoma is a severe malignancy for its high mortality and poor prognosis. Mainstay chemotherapies cause serious side effects for their ways of inducing cell death. Oridonin is the main bioactive constituent from natural plants that has anticancer ability and weak side effects. The proteomics method is efficient to understand the anticancer mechanism. However, proteins identified by proteomics aimed at understanding oridonin's anticancer mechanism is seldom overlapped by different groups. This study used proteomics based on two-dimensional electrophoresis sodium dodecyl sulfate-polyacrylamide gel electrophoresis (2-DE SDS-PAGE) integrated with mass spectrometry and Gene Set Enrichment Analysis (GSEA) to understand the anticancer mechanism of oridonin on esophageal squamous cell carcinoma (ESCC). The results showed that oridonin induced ESCC cell death via apoptosis by decreasing the protein expression of LASP1 and PDLIM1.
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Affiliation(s)
- Xiaojun Zhang
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Mengtao Xing
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Yangcheng Ma
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Zhuangli Zhang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Cuipeng Qiu
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Xiao Wang
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Zhihong Zhao
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Zhenyu Ji
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Jian-Ying Zhang
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
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Wang W, Tian X, Yan L, Guan X, Dong B, Zhao M, Liu D, Wu J, Hao C. Identification of the γ-glutamyl cycle as a novel therapeutic target and 5-oxoproline as a new biomarker for diagnosing pancreatic cancer. Ann Med 2023; 55:2242247. [PMID: 37544888 PMCID: PMC10405758 DOI: 10.1080/07853890.2023.2242247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 06/23/2023] [Accepted: 07/24/2023] [Indexed: 08/08/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant solid tumours, and abnormal metabolic reprogramming in the tumour microenvironment is regarded as an important contributor to its pathogenesis. OBJECTIVES As there is an urgency to identify new targets based on the metabolic features that are highly refractory to PDAC treatment, this study aimed to identify suitable therapeutic targets for PDAC. METHODS In this study, gene set enrichment and Kyoto Encyclopedia of Genes and Genomes analyses were performed on 163 PDAC tissue samples and 165 normal pancreatic tissue samples from The Cancer Genome Atlas and Genotype-Tissue Expression databases to identify alterations in critical metabolites that may contribute to PDAC pathogenesis. Furthermore, ultra-performance liquid chromatography-tandem mass spectrometry was performed to identify significant metabolic pathways between 24 pairs of tumour and adjacent non-tumour tissues and between serum samples from PDAC patients and healthy donors. RESULTS Fifty-one tissue metabolites and 26 serum metabolites were altered in PDAC. Among them, those in the γ-glutamyl cycle were the most substantially changed, and 5-oxoproline was the biomarker of PDAC with the most significantly decreased levels. CONCLUSIONS The γ-glutamyl cycle and 5-oxoproline might be potential biomarkers and therapeutic targets to improve the diagnosis, therapy, and prognosis of PDAC.
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Affiliation(s)
- Weijia Wang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery/Sarcoma Center, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
- Department of International Medical Services (IMS), Beijing Tiantan Hospital of Capital Medical University, Beijing, People’s Republic of China
| | - Xiuyun Tian
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery/Sarcoma Center, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Liang Yan
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery/Sarcoma Center, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Xiaoya Guan
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery/Sarcoma Center, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Bin Dong
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Central Laboratory, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Min Zhao
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Daoning Liu
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery/Sarcoma Center, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Jianhui Wu
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery/Sarcoma Center, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Chunyi Hao
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery/Sarcoma Center, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
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Yin L, Liu P, Jin Y, Ning Z, Yang Y, Gao H. Ferroptosis-related small-molecule compounds in cancer therapy: Strategies and applications. Eur J Med Chem 2022; 244:114861. [DOI: 10.1016/j.ejmech.2022.114861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/07/2022] [Accepted: 10/17/2022] [Indexed: 01/17/2023]
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Ferulic Acid Mitigates Growth and Invasion of Esophageal Squamous Cell Carcinoma through Inducing Ferroptotic Cell Death. DISEASE MARKERS 2022; 2022:4607966. [PMID: 36267458 PMCID: PMC9578864 DOI: 10.1155/2022/4607966] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 09/02/2022] [Accepted: 09/06/2022] [Indexed: 11/17/2022]
Abstract
Objective Ferroptosis is an iron- and ROS-dependent form of cell death initiated by lipid peroxidation. The rapidly developing study of ferroptosis has facilitated its application in cancer therapeutics. The current study is aimed at investigating the functional property of ferulic acid (FA, a phenolic acid substance) on inducing ferroptosis in antiesophageal squamous cell carcinoma (ESCC). Methods ESCC cells were administrated with gradient doses of FA or with ferroptosis inhibitor deferoxamine. Cellular growth was measured with CCK-8 and colony formation experiments. LDH, caspase-3, MDA, SOD, GSH, and iron were assayed with corresponding kits. Apoptotic level was evaluated through Annexin V-FITC apoptosis staining, with migration and invasion utilizing Transwell assays. Through quantitative RT-PCR, angiogenesis-relevant genes VEGFA and PDGFB were detected. ROS generation was measured via DCFH-DA probe. Immunoblotting was conducted for monitoring ACSL4, SLC7A11, HO-1, and GPX4. Results FA administration observably mitigated cellular viability and colony formation capacity and motivated LDH release, caspase-3 activity, and apoptosis in EC-1 and TE-4 cells. In addition, migration and invasion together with angiogenesis of ESCC cells were restraint by FA. FA exposure led to the increase of MDA content, ROS production, and iron load as well as the reduction of SOD activity and GSH content. Also, FA augmented the activities of ACSL4 and HO-1, with lessening SLC7A11 and GPX4. Nonetheless, deferoxamine restrained the effect of FA on ESCC ferroptosis. Conclusion Altogether, FA may act as a ferroptosis inducer and thus attenuates cell growth and invasion of ESCC, which boosts the clinical application of FA in ESCC therapeutics.
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Maimaitizunong R, Wang K, Li H. Ferroptosis and its emerging role in esophageal cancer. Front Mol Biosci 2022; 9:1027912. [PMID: 36237575 PMCID: PMC9551460 DOI: 10.3389/fmolb.2022.1027912] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 09/14/2022] [Indexed: 11/29/2022] Open
Abstract
The occurrence and development of tumors involve a series of life activities of cells, among which cell death has always been a crucial part in the research of tumor mechanisms and treatment methods. Ferroptosis is a non-apoptotic form of cell death, which is characterized by lipid peroxidation accumulation and further cell membrane rupture caused by excessive production of intracellular oxygen free radicals dependent on iron ions. Esophageal cancer is one of the common digestive tract tumors. Patients in the early stage are mainly treated with surgery, and the curative effect is awe-inspiring. However, surgery is far from enough for terminal patients, and it is the best choice to combine radiotherapy and chemotherapy before the operation or during the perioperative period. Although the treatment plan for patients with advanced esophageal cancer is constantly being optimized, we are disappointed at the still meager 5-year survival rate of patients and the poor quality of life. A series of complex problems, such as increased chemotherapy drug resistance and decreased radiotherapy sensitivity of esophageal cancer cells, are waiting for us to tackle. Perhaps ferroptosis can provide practical and feasible solutions and bring new hope to patients with advanced esophageal cancer. The occurrence of ferroptosis is related to the dysregulation of iron metabolism, lipid metabolism, and glutamate metabolism. Therefore, these dysregulated metabolic participant proteins and signaling pathways are essential entry points for using cellular ferroptosis to resist the occurrence and development of cancer cells. This review first introduced the main regulatory mechanisms of ferroptosis. It then summarized the current research status of ferroptosis in esophageal cancer, expecting to provide ideas for the research related to ferroptosis in esophageal cancer.
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Affiliation(s)
- Rezeye Maimaitizunong
- Department of Biochemistry and Molecular Biology, Basic Medicine School, Xinjiang Medical University, Urumqi, China
| | - Kai Wang
- Department of Medical Engineering and Technology, Xinjiang Medical University, Urumqi, China
| | - Hui Li
- Central Laboratory of Xinjiang Medical University, Urumqi, China
- *Correspondence: Hui Li,
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Exploring the Mechanism of Realgar against Esophageal Cancer Based on Ferroptosis Induced by ROS-ASK1-p38 MAPK Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:3698772. [PMID: 36133791 PMCID: PMC9484897 DOI: 10.1155/2022/3698772] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 08/09/2022] [Indexed: 11/18/2022]
Abstract
Background. Realgar (REA), a Chinese herbal decoction, has been used to treat various tumors and has produced positive outcomes; however, there is a lack of convincing evidence for the treatment of esophageal cancer. The present study aimed to investigate the effects of REA on esophageal cancer (EC) and explore its mechanism. Methods. EC cells Eca109 and KYSE150 were selected for this study, and different groups of treated cells were set up. We studied the inhibition rate and half inhibition concentration (IC50) by CCK-8 method, the clone formation assay was used to detect the clone formation ability, the scratch assay is used to determine the cell migration ability, the Transwell assay was used to detect the cell invasion ability, the protein expressions of E-cadherin, Slug, N-cadherin, ASK1, p38 MAPK, p-p38 MAPK, and GPX4 were determined using Western blot, the mRNA expressions of ASK1 and p38 MAPK were assessed using qRT-PCR, transmission electron microscopy was used to observe the cellular ultrastructure, Prussian blue staining was used to observe the intracellular iron particle distribution, and biochemical analysis of cellular MDA, SOD, GSH, and GPXS activities, flow cytometric analysis of cellular ROS levels, immunofluorescence staining to detect cellular GPX4 expression, and JC-1 method to detect mitochondrial membrane potential were used. Results. REA inhibited the proliferation of Eca109 and KYSE150 cells in a time- and concentration-dependent manner, and REA significantly inhibited the migration and invasion of Eca109 and KYSE150 cells and activated the cellular ferroptosis and ROS-ASK1-p38 MAPK signaling pathways (
). Inhibition of activation of the ROS-ASK1-p38 MAPK signaling pathway promoted the inhibition of proliferation, migration, and invasion of Eca109 and KYSE150 cells and the induction of ferroptosis by REA. Conclusion. REA induced ferroptosis and inhibited the migration of EC cells by activating the ROS-ASK1-p38 MAPK signaling pathway.
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Li JJ, Xia XP, Wu LM, Zhu Z, Shi YN, Zhang XC, Xia YS, Lu GR. Cancer suppression by ferroptosis and its role in digestive system tumors. Shijie Huaren Xiaohua Zazhi 2022; 30:718-728. [DOI: 10.11569/wcjd.v30.i16.718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Jia-Jia Li
- Department of Gastroenterology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Xuan-Ping Xia
- Department of Gastroenterology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Li-Min Wu
- Department of Gastroenterology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Zheng Zhu
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Yu-Ning Shi
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Xu-Chao Zhang
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Yu-Shan Xia
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Guang-Rong Lu
- Department of Gastroenterology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
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Wang Z, Wu S, Zhu C, Shen J. The role of ferroptosis in esophageal cancer. Cancer Cell Int 2022; 22:266. [PMID: 35999642 PMCID: PMC9396912 DOI: 10.1186/s12935-022-02685-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 08/16/2022] [Indexed: 11/30/2022] Open
Abstract
Esophageal cancer is one of the most common cancers with high mortality rate around the world. Although the treatment strategy of this disease has made great progress, the prognosis of advanced patients is not ideal. Ferroptosis, a novel regulatory cell death model, that is different from traditional apoptosis and characterized by increased Fenton reaction mediated by intracellular free iron and lipid peroxidation of cell membrane. Ferroptosis has been proved to be closely linked to a variety of diseases, especially cancer. This review aims to summarize the core mechanism of ferroptosis in esophageal cancer, the regulation of ferroptosis signaling pathway and its current application. At the same time, we emphasize the potential and prospect of ferroptosis in the treatment of esophageal cancer. Collectively, targeting ferroptosis pathway may provide new insights into the diagnosis, treatment and prognosis of esophageal cancer.
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Affiliation(s)
- Zimin Wang
- Department of Thoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.,Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, China
| | - Sikai Wu
- Department of Thoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.,Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, China
| | - Chengchu Zhu
- Department of Thoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China. .,Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, China.
| | - Jianfei Shen
- Department of Thoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China. .,Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, China.
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Zhang L, Hobeika CS, Khabibullin D, Yu D, Filippakis H, Alchoueiry M, Tang Y, Lam HC, Tsvetkov P, Georgiou G, Lamb C, Stone E, Puigserver P, Priolo C, Henske EP. Hypersensitivity to ferroptosis in chromophobe RCC is mediated by a glutathione metabolic dependency and cystine import via solute carrier family 7 member 11. Proc Natl Acad Sci U S A 2022; 119:e2122840119. [PMID: 35867762 PMCID: PMC9651629 DOI: 10.1073/pnas.2122840119] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 04/14/2022] [Indexed: 01/11/2023] Open
Abstract
Chromophobe (Ch) renal cell carcinoma (RCC) arises from the intercalated cell in the distal nephron. There are no proven treatments for metastatic ChRCC. A distinguishing characteristic of ChRCC is strikingly high levels of reduced (GSH) and oxidized (GSSG) glutathione. Here, we demonstrate that ChRCC-derived cells exhibit higher sensitivity to ferroptotic inducers compared with clear-cell RCC. ChRCC-derived cells are critically dependent on cystine via the cystine/glutamate antiporter xCT to maintain high levels of glutathione, making them sensitive to inhibitors of cystine uptake and cyst(e)inase. Gamma-glutamyl transferase 1 (GGT1), a key enzyme in glutathione homeostasis, is markedly suppressed in ChRCC relative to normal kidney. Importantly, GGT1 overexpression inhibits the proliferation of ChRCC cells in vitro and in vivo, suppresses cystine uptake, and decreases levels of GSH and GSSG. Collectively, these data identify ferroptosis as a metabolic vulnerability in ChRCC, providing a potential avenue for targeted therapy for these distinctive tumors.
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Affiliation(s)
- Long Zhang
- Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Charbel S. Hobeika
- Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Damir Khabibullin
- Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Deyang Yu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115
- Broad Institute of MIT and Harvard, Cambridge, MA 02139
| | - Harilaos Filippakis
- Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Michel Alchoueiry
- Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Yan Tang
- Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Hilaire C. Lam
- Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | | | - George Georgiou
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712
- Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712
| | - Candice Lamb
- Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712
| | - Everett Stone
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712
| | - Pere Puigserver
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115
- Broad Institute of MIT and Harvard, Cambridge, MA 02139
| | - Carmen Priolo
- Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Elizabeth P. Henske
- Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
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Guo W, Cao P, Wang X, Hu M, Feng Y. Medicinal Plants for the Treatment of Gastrointestinal Cancers From the Metabolomics Perspective. Front Pharmacol 2022; 13:909755. [PMID: 35833022 PMCID: PMC9271783 DOI: 10.3389/fphar.2022.909755] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/23/2022] [Indexed: 12/27/2022] Open
Abstract
Gastrointestinal cancer (GIC), primarily including colorectal cancer, gastric cancer, liver cancer, pancreatic cancer, and esophageal cancer, is one of the most common causes of cancer-related deaths with increasing prevalence and poor prognosis. Medicinal plants have been shown to be a great resource for the treatment of GIC. Due to their complex manifestations of multi-component and multi-target, the underlying mechanisms how they function against GIC remain to be completely deciphered. Cell metabolism is of primary importance in the initialization and development of GIC, which is reported to be a potential target. As an essential supplement to the newest “omics” sciences, metabolomics focuses on the systematic study of the small exogenous and endogenous metabolites involved in extensive biochemical metabolic pathways of living system. In good agreement with the systemic perspective of medicinal plants, metabolomics offers a new insight into the efficacy assessment and action mechanism investigation of medicinal plants as adjuvant therapeutics for GIC therapy. In this review, the metabolomics investigations on metabolism-targeting therapies for GIC in the recent 10 years were systematically reviewed from five aspects of carbohydrate, lipid, amino acid, and nucleotide metabolisms, as well as other altered metabolisms (microbial metabolism, inflammation, and oxidation), with particular attention to the potential of active compounds, extracts, and formulae from medicinal plants. Meanwhile, the current perspectives and future challenges of metabolism-targeting therapies of medicinal plants for GIC were also discussed. In conclusion, the understanding of the action mechanisms of medicinal plants in GIC from the metabolomics perspective will contribute to the clinical application of potential candidates from the resourceful medicinal plants as novel and efficient adjuvant therapeutics for GIC therapy.
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Affiliation(s)
- Wei Guo
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Peng Cao
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Xuanbin Wang
- Laboratory of Chinese Herbal Pharmacology, Department of Pharmacy, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Min Hu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
- *Correspondence: Min Hu, ; Yibin Feng,
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- *Correspondence: Min Hu, ; Yibin Feng,
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Cui W, Zhang J, Wu D, Zhang J, Zhou H, Rong Y, Liu F, Wei B, Xu X. Ponicidin suppresses pancreatic cancer growth by inducing ferroptosis: Insight gained by mass spectrometry-based metabolomics. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 98:153943. [PMID: 35104766 DOI: 10.1016/j.phymed.2022.153943] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 01/06/2022] [Accepted: 01/12/2022] [Indexed: 05/16/2023]
Abstract
BACKGROUND Pancreatic cancer is one of the most common malignant tumors of the digestive tract. Ponicidin, a tetracyclic diterpenoid active ingredient extracted from the traditional phytomedicine Rubescens, has high safety and great inhibitory effect on the proliferation of a variety of cancer cells, especially malignant tumor cells of the digestive tract. However, the inhibitory effect and mechanism of ponicidin on pancreatic cancer cells is still unclear. Our study aimed to use metabonomics technology to analyze and explore the suppressive effect of ponidicin against pancreatic cancer cells. METHODS MTT and flow cytometry were conducted to study the potential effect of ponicidin on SW1990 cells. Secondly, UPLC-MS/MS was used to analyze the small molecule metabolites and relevant differential metabolic pathways induced by ponicidin treatment. Furthermore, through the determination of glutathione peroxidase 4 (GPX4) activity and molecular docking simulation experiments, the effects of intracellular GPX4 activity and GSH/GSSG ratio after ponicidin were evaluated. Finally, the determination of the content of iron ions and malondialdehyde in cells, and the experiment of the effect of ferroptosis inhibitors on cell viability, the effect of ponicidin on the induction of ferroptosis in SW1990 cells was also detected. RESULTS The IC50 of ponicidin on SW1990 cells was 20 μM, which could significantly induce cell apoptosis and arrest the cells in G2/M phase. Metabolomics results showed that the contents of endogenous small molecules such as gamma-glutamylcysteine, 5-oxoproline, glutamic acid, reduced glutathione (GSH), oxidized glutathione (GSSG) and arachidonic acid have changed significantly. Main differential compounds were involved in the gamma-glutamyl cycle and polyunsaturated fatty acid metabolism of pancreatic cancer cell lines. Additionally, ponicidin could covalently bind to GSH in SW1990 cells to form a conjugate Pon-GSH, which further reduced the content of free GSH and GPX4 activity in cells. Notably, ponicidin dose-dependently increased levels of iron ions, malondialdehyde and reactive oxygen species in SW1990 cells, and the ferroptosis inhibitors could significantly block the effects of ponicidin on the proliferation of SW1990 cells. CONCLUSION Ponicidin could suppress the pancreatic cancer cell proliferation via inducing ferroptosis by inhibiting the gamma-glutamyl cycle and regulating the polyunsaturated fatty acid metabolism in SW1990 cells.
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Affiliation(s)
- Weiqi Cui
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, P. R. China
| | - Junwei Zhang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, P. R. China
| | - Deqiao Wu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, P. R. China
| | - Jingxian Zhang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, P. R. China
| | - Hui Zhou
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, P. R. China
| | - Ying Rong
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, P. R. China
| | - Fanglin Liu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, P. R. China
| | - Bo Wei
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, P. R. China.
| | - Xia Xu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, P. R. China.
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Correia MJ, Pimpão AB, Fernandes DGF, Morello J, Sequeira CO, Calado J, Antunes AMM, Almeida MS, Branco P, Monteiro EC, Vicente JB, Serpa J, Pereira SA. Cysteine as a Multifaceted Player in Kidney, the Cysteine-Related Thiolome and Its Implications for Precision Medicine. Molecules 2022; 27:1416. [PMID: 35209204 PMCID: PMC8874463 DOI: 10.3390/molecules27041416] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/15/2022] [Accepted: 02/17/2022] [Indexed: 11/16/2022] Open
Abstract
In this review encouraged by original data, we first provided in vivo evidence that the kidney, comparative to the liver or brain, is an organ particularly rich in cysteine. In the kidney, the total availability of cysteine was higher in cortex tissue than in the medulla and distributed in free reduced, free oxidized and protein-bound fractions (in descending order). Next, we provided a comprehensive integrated review on the evidence that supports the reliance on cysteine of the kidney beyond cysteine antioxidant properties, highlighting the relevance of cysteine and its renal metabolism in the control of cysteine excess in the body as a pivotal source of metabolites to kidney biomass and bioenergetics and a promoter of adaptive responses to stressors. This view might translate into novel perspectives on the mechanisms of kidney function and blood pressure regulation and on clinical implications of the cysteine-related thiolome as a tool in precision medicine.
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Affiliation(s)
- Maria João Correia
- CEDOC, NOVA Medical School, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal; (M.J.C.); (A.B.P.); (J.M.); (C.O.S.); (M.S.A.); (P.B.); (E.C.M.); (J.S.)
| | - António B. Pimpão
- CEDOC, NOVA Medical School, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal; (M.J.C.); (A.B.P.); (J.M.); (C.O.S.); (M.S.A.); (P.B.); (E.C.M.); (J.S.)
| | - Dalila G. F. Fernandes
- Instituto de Tecnologia Química e Biológica António Xavier (ITQB NOVA), 2780-157 Oeiras, Portugal; (D.G.F.F.); (J.B.V.)
| | - Judit Morello
- CEDOC, NOVA Medical School, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal; (M.J.C.); (A.B.P.); (J.M.); (C.O.S.); (M.S.A.); (P.B.); (E.C.M.); (J.S.)
| | - Catarina O. Sequeira
- CEDOC, NOVA Medical School, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal; (M.J.C.); (A.B.P.); (J.M.); (C.O.S.); (M.S.A.); (P.B.); (E.C.M.); (J.S.)
| | - Joaquim Calado
- Centre for Toxicogenomics and Human Health (ToxOmics), Genetics, Oncology and Human Toxicology, Nova Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal;
- Nephrology Department, Centro Hospitalar Universitário de Lisboa Central, 1069-166 Lisboa, Portugal
| | - Alexandra M. M. Antunes
- Centro de Química Estrutural, Institute of Molecular Sciences, Instituto Superior Técnico, 1049-001 Lisboa, Portugal;
| | - Manuel S. Almeida
- CEDOC, NOVA Medical School, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal; (M.J.C.); (A.B.P.); (J.M.); (C.O.S.); (M.S.A.); (P.B.); (E.C.M.); (J.S.)
- Hospital de Santa Cruz, Centro Hospitalar de Lisboa Ocidental, 2790-134 Carnaxide, Portugal
| | - Patrícia Branco
- CEDOC, NOVA Medical School, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal; (M.J.C.); (A.B.P.); (J.M.); (C.O.S.); (M.S.A.); (P.B.); (E.C.M.); (J.S.)
- Hospital de Santa Cruz, Centro Hospitalar de Lisboa Ocidental, 2790-134 Carnaxide, Portugal
| | - Emília C. Monteiro
- CEDOC, NOVA Medical School, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal; (M.J.C.); (A.B.P.); (J.M.); (C.O.S.); (M.S.A.); (P.B.); (E.C.M.); (J.S.)
| | - João B. Vicente
- Instituto de Tecnologia Química e Biológica António Xavier (ITQB NOVA), 2780-157 Oeiras, Portugal; (D.G.F.F.); (J.B.V.)
| | - Jacinta Serpa
- CEDOC, NOVA Medical School, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal; (M.J.C.); (A.B.P.); (J.M.); (C.O.S.); (M.S.A.); (P.B.); (E.C.M.); (J.S.)
- Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), 1099-023 Lisboa, Portugal
| | - Sofia A. Pereira
- CEDOC, NOVA Medical School, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal; (M.J.C.); (A.B.P.); (J.M.); (C.O.S.); (M.S.A.); (P.B.); (E.C.M.); (J.S.)
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Han N, Li LG, Peng XC, Ma QL, Yang ZY, Wang XY, Li J, Li QR, Yu TT, Xu HZ, Xu X, Chen X, Wang MF, Li TF. Ferroptosis triggered by dihydroartemisinin facilitates chlorin e6 induced photodynamic therapy by inhibiting GPX4 and enhancing ROS. Eur J Pharmacol 2022; 919:174797. [PMID: 35122867 DOI: 10.1016/j.ejphar.2022.174797] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/31/2022] [Accepted: 02/01/2022] [Indexed: 01/10/2023]
Abstract
Photodynamic therapy (PDT) is noninvasive, low toxicity, and photo-selective, but may be resisted by malignant cells. A previous study found chlorin e6 (Ce6) mediated PDT showed drug resistance in lung cancer cells (LLC), which may be associated with PDT-induced DNA damage response (DDR). DDR may up-regulate glutathione peroxidase 4 (GPX4), which in turn degrade ROS induced by PDT. However, dihydroartemisinin (DHA) was found to down-regulate GPX4. Accordingly, the DHA was hypothesized to improve the resistance to PDT. The present work explores the mechanism of Ce6 mediated drug resistance and reveals whether DHA can enhance the efficacy of PDT by suppressing GPX4. The in vitro experiments found Ce6 treatment did not inhibit the viability of LLC within 6 hr without inducing significant apoptosis, suggesting LLC were resistant to PDT. Further investigation demonstrated PDT could damage DNA and up-regulate GPX4, thus degrading the generated ROS. DHA effectively inhibited the viability of LLC and induced apoptosis. Importantly, DHA displayed a prominent inhibitory effect on the GPX4 expression and thereby triggered ferroptosis. Combining DHA with Ce6 for treatment of LLC resulted in the suppressed GPX4 and elevated ROS. Finally, the findings showed DHA combined with Ce6 exhibited superb anti-lung cancer efficacy. In summary, Ce6 PDT damages DNA, up-regulates GPX4 to degrade ROS, thereby inducing drug resistance. Down-regulation of GPX4 by DHA-triggered ferroptosis significantly enhances the efficacy of PDT. This study provides an outstanding theoretical basis for the regulation of the intratumoral redox system and improving PDT efficacy against lung cancer by herbal monomer DHA.
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Affiliation(s)
- Ning Han
- School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Department of Respiratory, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Department of Pathology, Sinopharm DongFeng General Hospital, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China
| | - Liu-Gen Li
- School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Department of Respiratory, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China
| | - Xing-Chun Peng
- School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Department of Pathology, Sinopharm DongFeng General Hospital, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China
| | - Qian-Li Ma
- School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China
| | - Zi-Yi Yang
- School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China
| | - Xi-Yong Wang
- School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China
| | - Jian Li
- School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China
| | - Qi-Rui Li
- School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China
| | - Ting-Ting Yu
- School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Department of Respiratory, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China
| | - Hua-Zhen Xu
- Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Donghu Avenue No.185, Wuhan, 430072, China
| | - Xiang Xu
- School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China
| | - Xiao Chen
- Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Donghu Avenue No.185, Wuhan, 430072, China
| | - Mei-Fang Wang
- Department of Respiratory, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China.
| | - Tong-Fei Li
- School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Department of Respiratory, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Department of Pathology, Sinopharm DongFeng General Hospital, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China.
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Abstract
Cysteine is a conditionally essential amino acid required for the synthesis of proteins and many important intracellular metabolites. Cysteine depletion can trigger iron-dependent nonapoptotic cell death-ferroptosis. Despite this, cysteine itself is normally maintained at relatively low levels within the cell, and many mechanisms that could act to buffer cysteine depletion do not appear to be especially effective or active, at least in cancer cells. How do we reconcile these seemingly paradoxical features? Here, we describe the regulation of cysteine and its contribution to ferroptosis and speculate about how the levels of this amino acid are controlled to govern nonapoptotic cell death.
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Affiliation(s)
| | - Scott J. Dixon
- Department of Biology, Stanford University, Stanford, CA 94305, USA
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The Regulatory Effects and the Signaling Pathways of Natural Bioactive Compounds on Ferroptosis. Foods 2021; 10:foods10122952. [PMID: 34945503 PMCID: PMC8700948 DOI: 10.3390/foods10122952] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/19/2021] [Accepted: 11/22/2021] [Indexed: 12/15/2022] Open
Abstract
Natural bioactive compounds abundantly presented in foods and medicinal plants have recently received a remarkable attention because of their various biological activities and minimal toxicity. In recent years, many natural compounds appear to offer significant effects in the regulation of ferroptosis. Ferroptosis is the forefront of international scientific research which has been exponential growth since the term was coined. This type of regulated cell death is driven by iron-dependent phospholipid peroxidation. Recent studies have shown that numerous organ injuries and pathophysiological processes of many diseases are driven by ferroptosis, such as cancer, arteriosclerosis, neurodegenerative disease, diabetes, ischemia-reperfusion injury and acute renal failure. It is reported that the initiation and inhibition of ferroptosis plays a pivotal role in lipid peroxidation, organ damage, neurodegeneration and cancer growth and progression. Recently, many natural phytochemicals extracted from edible plants have been demonstrated to be novel ferroptosis regulators and have the potential to treat ferroptosis-related diseases. This review provides an updated overview on the role of natural bioactive compounds and the potential signaling pathways in the regulation of ferroptosis.
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Abstract
Terpenoids are the largest class of natural products, most of which are derived from plants. Amongst their numerous biological properties, their anti-tumor effects are of interest for they are extremely diverse which include anti-proliferative, apoptotic, anti-angiogenic, and anti-metastatic activities. Recently, several in vitro and in vivo studies have been dedicated to understanding the 'terpenoid induced autophagy' phenomenon in cancer cells. Light has already been shed on the intricacy of apoptosis and autophagy relationship. This latter crosstalk is driven by the delicate balance between activating or silencing of certain proteins whereby the outcome is expressed via interrelated signaling pathways. In this review, we focus on nine of the most studied terpenoids and on their cell death and autophagic activity. These terpenoids are grouped in three classes: sesquiterpenoid (artemisinin, parthenolide), diterpenoids (oridonin, triptolide), and triterpenoids (alisol, betulinic acid, oleanolic acid, platycodin D, and ursolic acid). We have selected these nine terpenoids among others as they belong to the different major classes of terpenoids and our extensive search of the literature indicated that they were the most studied in terms of autophagy in cancer. These terpenoids alone demonstrate the complexity by which these secondary metabolites induce autophagy via complex signaling pathways such as MAPK/ERK/JNK, PI3K/AKT/mTOR, AMPK, NF-kB, and reactive oxygen species. Moreover, induction of autophagy can be either destructive or protective in tumor cells. Nevertheless, should this phenomenon be well understood, we ought to be able to exploit it to create novel therapies and design more effective regimens in the management and treatment of cancer.
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Gao X, Tang M, Tian S, Li J, Liu W. A ferroptosis-related gene signature predicts overall survival in patients with lung adenocarcinoma. Future Oncol 2021; 17:1533-1544. [PMID: 33432837 DOI: 10.2217/fon-2020-1113] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Aims: To elucidate the association between ferroptosis-related genes and prognosis in patients with lung adenocarcinoma (LUAD). Materials & methods: A ferroptosis-related gene signature was made by lasso regression analysis through the LUAD datasets of the Cancer Genome Atlas. The prognostic value of the multigene signature was externally validated in the GSE72094 dataset from the Gene Expression Omnibus database. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis were used to explore underlying mechanisms. Results & conclusion: We established a novel ferroptosis-related gene signature for overall survival in LUAD that was predictive in both the training and validation cohorts. Immune-related pathways were significantly enriched, and immune status differed between the high- and low-risk groups. Targeting ferroptosis is a potential therapeutic option in LUAD. These results still need to be confirmed by more studies.
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Affiliation(s)
- Xinliang Gao
- Department of Thoracic Surgery, The First Hospital of Jilin University, 71 Xinmin Streat, Changchun, Jilin 130021, PR China
| | - Mingbo Tang
- Department of Thoracic Surgery, The First Hospital of Jilin University, 71 Xinmin Streat, Changchun, Jilin 130021, PR China
| | - Suyan Tian
- Division of Clinical Research, The First Hospital of Jilin University, 71 Xinmin Streat, Changchun, Jilin 130021, PR China
| | - Jialin Li
- Department of Thoracic Surgery, The First Hospital of Jilin University, 71 Xinmin Streat, Changchun, Jilin 130021, PR China
| | - Wei Liu
- Department of Thoracic Surgery, The First Hospital of Jilin University, 71 Xinmin Streat, Changchun, Jilin 130021, PR China
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Gaikwad S, Srivastava SK. Role of Phytochemicals in Perturbation of Redox Homeostasis in Cancer. Antioxidants (Basel) 2021; 10:83. [PMID: 33435480 PMCID: PMC7827008 DOI: 10.3390/antiox10010083] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/05/2021] [Accepted: 01/05/2021] [Indexed: 12/12/2022] Open
Abstract
Over the past few decades, research on reactive oxygen species (ROS) has revealed their critical role in the initiation and progression of cancer by virtue of various transcription factors. At certain threshold values, ROS act as signaling molecules leading to activation of oncogenic pathways. However, if perturbated beyond the threshold values, ROS act in an anti-tumor manner leading to cellular death. ROS mediate cellular death through various programmed cell death (PCD) approaches such as apoptosis, autophagy, ferroptosis, etc. Thus, external stimulation of ROS beyond a threshold is considered a promising therapeutic strategy. Phytochemicals have been widely regarded as favorable therapeutic options in many diseased conditions. Over the past few decades, mechanistic studies on phytochemicals have revealed their effect on ROS homeostasis in cancer. Considering their favorable side effect profile, phytochemicals remain attractive treatment options in cancer. Herein, we review some of the most recent studies performed using phytochemicals and, we further delve into the mechanism of action enacted by individual phytochemicals for PCD in cancer.
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Affiliation(s)
| | - Sanjay K. Srivastava
- Department of Immunotherapeutics and Biotechnology, Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA;
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