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Gu H, Qiu H, Yang H, Deng Z, Zhang S, Du L, He F. PRRSV utilizes MALT1-regulated autophagy flux to switch virus spread and reserve. Autophagy 2024; 20:2697-2718. [PMID: 39081059 PMCID: PMC11587858 DOI: 10.1080/15548627.2024.2386195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 07/03/2024] [Accepted: 07/25/2024] [Indexed: 08/07/2024] Open
Abstract
Porcine reproductive and respiratory syndrome virus (PRRSV) is a major swine pathogen, which can survive host antiviral immunity with various mechanisms. PRRSV infection induces macroautophagy/autophagy, facilitating virus replication. MALT1, a central immune regulator, was manipulated by PRRSV to optimize viral infection at different stages of the virus cycle. In this study, the key role of MALT1 in autophagy regulation during PRRSV infection was characterized, enlightening the role of autophagy flux in favor of virus spread and persistent infection. PRRSV-induced autophagy was confirmed to facilitate virus proliferation. Furthermore, autophagic fusion was dynamically regulated during PRRSV infection. Importantly, PRRSV-induced MALT1 facilitated autophagosome-lysosome fusion and autolysosome formation, thus contributing to autophagy flux and virus proliferation. Mechanically, MALT1 regulated autophagy via mediating MTOR-ULK1 and -TFEB signaling and affecting lysosomal homeostasis. MALT1 inhibition by inhibitor Mi-2 or RNAi induced lysosomal membrane permeabilization (LMP), leading to the block of autophagic fusion. Further, MALT1 overexpression alleviated PRRSV-induced LMP via inhibiting ROS generation. In addition, blocking autophagy flux suppressed virus release significantly, indicating that MALT1-maintained complete autophagy flux during PRRSV infection favors successful virus spread and its proliferation. In contrast, autophagosome accumulation upon MALT1 inhibition promoted PRRSV reserve for future virus proliferation once the autophagy flux recovers. Taken together, for the first time, these findings elucidate that MALT1 was utilized by PRRSV to regulate host autophagy flux, to determine the fate of virus for either proliferation or reserve.Abbreviations: 3-MA: 3-methyladenine; BafA1: bafilomycin A1; BFP/mBFP: monomeric blue fluorescent protein; CQ: chloroquine; DMSO: dimethyl sulfoxide; dsRNA: double-stranded RNA; GFP: green fluorescent protein; hpi: hours post infection; IFA: indirect immunofluorescence assay; LAMP1: lysosomal associated membrane protein 1; LGALS3: galectin 3; LLOMe: L-leucyl-L-leucine-methyl ester; LMP: lysosomal membrane permeabilization; mAb: monoclonal antibody; MALT1: MALT1 paracaspase; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NFKB/NF-κB: nuclear factor kappa B; nsp: nonstructural protein; ORF: open reading frame; pAb: polyclonal antibody; PRRSV: porcine reproductive and respiratory syndrome virus; PRRSV-N: PRRSV nucleocapsid protein; Rapa: rapamycin; RFP: red fluorescent protein; ROS: reactive oxygen species; SBI: SBI-0206965; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TCID50: 50% tissue culture infective dose; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1.
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Affiliation(s)
- Han Gu
- MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, China
- Institute of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
- TianMu Laboratory, ZJU-Xinchang Joint Innovation Centre, Xinchang, Zhejiang, P.R. China
| | - He Qiu
- MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, China
- Institute of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
- TianMu Laboratory, ZJU-Xinchang Joint Innovation Centre, Xinchang, Zhejiang, P.R. China
| | - Haotian Yang
- MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, China
- Institute of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
- TianMu Laboratory, ZJU-Xinchang Joint Innovation Centre, Xinchang, Zhejiang, P.R. China
| | - Zhuofan Deng
- MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, China
- Institute of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
- TianMu Laboratory, ZJU-Xinchang Joint Innovation Centre, Xinchang, Zhejiang, P.R. China
| | - Shengkun Zhang
- MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, China
- Institute of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
- TianMu Laboratory, ZJU-Xinchang Joint Innovation Centre, Xinchang, Zhejiang, P.R. China
| | - Liuyang Du
- MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, China
- Institute of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Fang He
- MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, China
- Institute of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
- TianMu Laboratory, ZJU-Xinchang Joint Innovation Centre, Xinchang, Zhejiang, P.R. China
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Ferreira JCC, Gonçalves MST, Preto A, Sousa MJ. Anticancer Activity of Benzo[ a]phenoxazine Compounds Promoting Lysosomal Dysfunction. Cells 2024; 13:1385. [PMID: 39195273 PMCID: PMC11352945 DOI: 10.3390/cells13161385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 08/02/2024] [Accepted: 08/12/2024] [Indexed: 08/29/2024] Open
Abstract
Specific cancer therapy remains a problem to be solved. Breast and colorectal cancer are among the cancers with the highest prevalence and mortality rates. Although there are some therapeutic options, there are still few effective agents for those cancers, which constitutes a clinical problem that requires further research efforts. Lysosomes play an important role in cancer cells' survival, and targeting lysosomes has gained increased interest. In recent years, our team has been synthetizing and testing novel benzo[a]phenoxazine derivatives, as they have been shown to possess potent pharmacological activities. Here, we investigated the anticancer activity of three of the most potent derivatives from our library, C9, A36, and A42, on colorectal- and breast-cancer-derived cell lines, and compared this with the effect on non-neoplastic cell lines. We observed that the three compounds were selective for the cancer cells, namely the RKO colorectal cancer cell line and the MCF7 breast cancer cell line. In both models, the compounds reduced cell proliferation, cell survival, and cell migration, accumulated on the lysosome, and induced cell death accompanied by lysosomal membrane permeabilization (LMP), increasing the intracellular pH and ROS accumulation. Our results demonstrated that these compounds specifically target lysosomes from cancer cells, making them promising candidates as LMP inducers for cancer therapy.
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Affiliation(s)
- João Carlos Canossa Ferreira
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal; (A.P.); (M.J.S.)
- IBS-Institute of Science and Innovation for Bio-Sustainability, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal
- Centre of Chemistry (CQUM), Department of Chemistry, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal;
| | - M. Sameiro T. Gonçalves
- Centre of Chemistry (CQUM), Department of Chemistry, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal;
| | - Ana Preto
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal; (A.P.); (M.J.S.)
- IBS-Institute of Science and Innovation for Bio-Sustainability, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal
| | - Maria João Sousa
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal; (A.P.); (M.J.S.)
- IBS-Institute of Science and Innovation for Bio-Sustainability, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal
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León D, Reyes ME, Weber H, Gutiérrez Á, Tapia C, Silva R, Viscarra T, Buchegger K, Ili C, Brebi P. In Vitro Effect of Epigallocatechin Gallate on Heme Synthesis Pathway and Protoporphyrin IX Production. Int J Mol Sci 2024; 25:8683. [PMID: 39201369 PMCID: PMC11354225 DOI: 10.3390/ijms25168683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/04/2024] [Accepted: 08/07/2024] [Indexed: 09/02/2024] Open
Abstract
Photodynamic therapy (PDT) treats nonmelanoma skin cancer. PDT kills cells through reactive oxygen species (ROS), generated by interaction among cellular O2, photosensitizer and specific light. Protoporphyrin IX (PpIX) is a photosensitizer produced from methyl aminolevulinate (MAL) by heme group synthesis (HGS) pathway. In PDT-resistant cells, PDT efficacy has been improved by addition of epigallocatechin gallate (EGCG). Therefore, the aim of this work is to evaluate the effect of EGCG properties over MAL-TFD and PpIX production on A-431 cell line. EGCG's role over cell proliferation (flow cytometry and wound healing assay) and clonogenic capability (clonogenic assay) was evaluated in A-431 cell line, while the effect of EGCG over MAL-PDT was determined by cell viability assay (MTT), PpIX and ROS detection (flow cytometry), intracellular iron quantification and gene expression of HGS enzymes (RT-qPCR). Low concentrations of EGCG (<50 µM) did not have an antiproliferative effect over A-431 cells; however, EGCG inhibited clonogenic cell capability. Furthermore, EGCG (<50 µM) improved MAL-PDT cytotoxicity, increasing PpIX and ROS levels, exerting a positive influence on PpIX synthesis, decreasing intracellular iron concentration and modifying HGS enzyme gene expression such as PGB (upregulated) and FECH (downregulated). EGCG inhibits clonogenic capability and modulates PpIX synthesis, enhancing PDT efficacy in resistant cells.
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Affiliation(s)
- Daniela León
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4780000, Chile; (D.L.); (Á.G.); (C.T.); (T.V.)
- Millennium Institute of Immunology and Immunotherapy, Santiago 8320165, Chile;
- BMRC, Biomedical Reasearch Consortium-Chile, Santiago 8320165, Chile
- Departamento de Ciencias Básicas, Facultad de Medicina, Universidad de La Frontera, Temuco 4780000, Chile
| | - María Elena Reyes
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Temuco 4810101, Chile; (M.E.R.); (R.S.)
| | - Helga Weber
- Biomedicine and Traslational Research Laboratory, Centro de Excelencia en Medicina Traslacional (CEMT), Universidad de La Frontera, Temuco 4780000, Chile;
| | - Álvaro Gutiérrez
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4780000, Chile; (D.L.); (Á.G.); (C.T.); (T.V.)
- Millennium Institute of Immunology and Immunotherapy, Santiago 8320165, Chile;
- BMRC, Biomedical Reasearch Consortium-Chile, Santiago 8320165, Chile
- Doctorado en Ciencias Mención Biología Celular y Molecular Aplicada, Universidad de La Frontera, Temuco 4780000, Chile
| | - Claudio Tapia
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4780000, Chile; (D.L.); (Á.G.); (C.T.); (T.V.)
- Millennium Institute of Immunology and Immunotherapy, Santiago 8320165, Chile;
- Carrera de Biotecnología, Facultad de Ciencias Agropecuarias y Medioambiente, Universidad de La Frontera, Temuco 4780000, Chile
| | - Ramón Silva
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Temuco 4810101, Chile; (M.E.R.); (R.S.)
| | - Tamara Viscarra
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4780000, Chile; (D.L.); (Á.G.); (C.T.); (T.V.)
- Millennium Institute of Immunology and Immunotherapy, Santiago 8320165, Chile;
- BMRC, Biomedical Reasearch Consortium-Chile, Santiago 8320165, Chile
- Biomedicine and Traslational Research Laboratory, Centro de Excelencia en Medicina Traslacional (CEMT), Universidad de La Frontera, Temuco 4780000, Chile;
| | - Kurt Buchegger
- Millennium Institute of Immunology and Immunotherapy, Santiago 8320165, Chile;
- BMRC, Biomedical Reasearch Consortium-Chile, Santiago 8320165, Chile
- Departamento de Ciencias Básicas, Facultad de Medicina, Universidad de La Frontera, Temuco 4780000, Chile
| | - Carmen Ili
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4780000, Chile; (D.L.); (Á.G.); (C.T.); (T.V.)
- Millennium Institute of Immunology and Immunotherapy, Santiago 8320165, Chile;
- BMRC, Biomedical Reasearch Consortium-Chile, Santiago 8320165, Chile
| | - Priscilla Brebi
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4780000, Chile; (D.L.); (Á.G.); (C.T.); (T.V.)
- Millennium Institute of Immunology and Immunotherapy, Santiago 8320165, Chile;
- BMRC, Biomedical Reasearch Consortium-Chile, Santiago 8320165, Chile
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Chen P, Cao XW, Dong JW, Zhao J, Wang FJ. Saponin and Ribosome-Inactivating Protein Synergistically Trigger Lysosome-Dependent Apoptosis by Inhibiting Lysophagy: Potential to Become a New Antitumor Strategy. Mol Pharm 2024; 21:2993-3005. [PMID: 38722865 DOI: 10.1021/acs.molpharmaceut.4c00140] [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] [Indexed: 06/04/2024]
Abstract
The susceptibility of lysosomal membranes in tumor cells to cationic amphiphilic drugs (CADs) enables CADs to induce lysosomal membrane permeabilization (LMP) and trigger lysosome-dependent cell death (LDCD), suggesting a potential antitumor therapeutic approach. However, the existence of intrinsic lysosomal damage response mechanisms limits the display of the pharmacological activity of CADs. In this study, we report that low concentrations of QS-21, a saponin with cationic amphiphilicity extracted from Quillaja Saponaria tree, can induce LMP but has nontoxicity to tumor cells. QS-21 and MAP30, a type I ribosome-inactivating protein, synergistically induce apoptosis in tumor cells at low concentrations of both. Mechanistically, QS-21-induced LMP helps MAP30 escape from endosomes or lysosomes and subsequently enter the endoplasmic reticulum, where MAP30 downregulates the expression of autophagy-associated LC3 proteins, thereby inhibiting lysophagy. The inhibition of lysophagy results in the impaired clearance of damaged lysosomes, leading to the leakage of massive lysosomal contents such as cathepsins into the cytoplasm, ultimately triggering LDCD. In summary, our study showed that coadministration of QS-21 and MAP30 amplified the lysosomal disruption and can be a new synergistic LDCD-based antitumor therapy.
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Affiliation(s)
- Piao Chen
- Department of Applied Biology, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People's Republic of China
| | - Xue-Wei Cao
- Department of Applied Biology, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People's Republic of China
- ECUST-FONOW Joint Research Center for Innovative Medicines, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People's Republic of China
- New Drug R&D Center, Zhejiang Fonow Medicine Co., Ltd., 209 West Hulian Road, Dongyang, Zhejiang 322100, People's Republic of China
| | - Jing-Wen Dong
- ECUST-FONOW Joint Research Center for Innovative Medicines, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People's Republic of China
- New Drug R&D Center, Zhejiang Fonow Medicine Co., Ltd., 209 West Hulian Road, Dongyang, Zhejiang 322100, People's Republic of China
| | - Jian Zhao
- Department of Applied Biology, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People's Republic of China
- ECUST-FONOW Joint Research Center for Innovative Medicines, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People's Republic of China
| | - Fu-Jun Wang
- ECUST-FONOW Joint Research Center for Innovative Medicines, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People's Republic of China
- New Drug R&D Center, Zhejiang Fonow Medicine Co., Ltd., 209 West Hulian Road, Dongyang, Zhejiang 322100, People's Republic of China
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, People's Republic of China
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5
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Zhao J, Sun H, Wang C, Shang D. Breast cancer therapy: from the perspective of glucose metabolism and glycosylation. Mol Biol Rep 2024; 51:546. [PMID: 38642246 DOI: 10.1007/s11033-024-09466-w] [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: 02/12/2024] [Accepted: 03/22/2024] [Indexed: 04/22/2024]
Abstract
Breast cancer is a leading cause of mortality and the most prevalent form of malignant tumor among women worldwide. Breast cancer cells exhibit an elevated glycolysis and altered glucose metabolism. Moreover, these cells display abnormal glycosylation patterns, influencing invasion, proliferation, metastasis, and drug resistance. Consequently, targeting glycolysis and mitigating abnormal glycosylation represent key therapeutic strategies for breast cancer. This review underscores the importance of protein glycosylation and glucose metabolism alterations in breast cancer. The current research efforts in developing effective interventions targeting glycolysis and glycosylation are further discussed.
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Affiliation(s)
- Jiaqi Zhao
- Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China
| | - Haiting Sun
- Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China
| | - Che Wang
- Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China.
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Science, Liaoning Normal University, Dalian, 116081, China.
| | - Dejing Shang
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Science, Liaoning Normal University, Dalian, 116081, China.
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Arumugam G, Alagar Yadav S. Synergistic inhibitory actions of resveratrol, epigallocatechin-3-gallate, and diallyl trisulfide against skin cancer cell line A431 through mitochondrial caspase dependent pathway: a combinational drug approach. Med Oncol 2024; 41:64. [PMID: 38280077 DOI: 10.1007/s12032-023-02292-3] [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: 10/03/2023] [Accepted: 12/26/2023] [Indexed: 01/29/2024]
Abstract
The harmful effect of chemotherapeutic side effects has paid a way to discover a novel with curative way for skin cancer treatment. Skin cancer prevention is more viable with the use of combination of bioactive agents than using of single bioactive compounds. Present work was demonstrated to evaluate the interaction of Resveratrol (Res), Epigallocatechin-3-gallate (EGCG), and diallyl trisulfide (DATS) with each other as a binary combination on A431 cells. Nuclear fragmentation analysis of combination of bioactive agents using DAPI analysis, detection of apoptosis, analysis of cell cycle, ROS assay, antimigration assays, and western blotting were implemented to study the combination of bioactive compounds on A431 cell line. Among the selected combination EGCG + DATS had a synergetic effect reducing cellular migration, increased intercellular reactive oxygen species generation, condensation, cell phagocytosis induced by phosphatidylserine externalization, rise in sub-G1 DNA content, and S-phase were cell cycle arrest. The combinations EGCG + DATS induced apoptotic proteins in A431 cells by upregulation of proapoptotic Bax and Bad proteins, a downmodulation of anti-apoptotic proteins Bcl2 and caspases (caspase-3, and -9) activity got triggered by intrinsic pathway. The combination of EGCG + DATS showed good anticancer potential against A431 skin cancer cell line via the mitochondrial caspase dependent pathway with very strong synergism. This finding will help to produce a novel combination/chemoprevention using dietary bioactive agents (EGCG + DATS) for the treatment of skin cancer after clinical trial.
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Affiliation(s)
- Gobika Arumugam
- Department of Biotechnology, FASCM, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
| | - Sangilimuthu Alagar Yadav
- Department of Biotechnology, FASCM, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India.
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Preventing Persistence of HPV Infection with Natural Molecules. Pathogens 2023; 12:pathogens12030416. [PMID: 36986338 PMCID: PMC10056139 DOI: 10.3390/pathogens12030416] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 02/26/2023] [Accepted: 03/03/2023] [Indexed: 03/09/2023] Open
Abstract
Human papillomavirus (HPV) infection is one the most common sexually transmitted infections worldwide. In most cases, the infection is temporary and asymptomatic; however, when persistent, it may lead to lesions that can evolve into cancer in both women and men. Nowadays, prophylactic vaccination is the primary preventive strategy for HPV infections, but vaccines do not cover all types of HPV strains. Scientific research has uncovered the beneficial role of some natural supplements in preventing persistent HPV infections or treating HPV-related lesions. We review the current insight into the roles of natural molecules in HPV infection with a special focus on epigallocatechin gallate (EGCG), folic acid, vitamin B12, and hyaluronic acid (HA). Specifically, EGCG from green tea extracts plays a critical role in suppressing HPV oncogenes and oncoproteins (E6/E7), which are responsible for HPV oncogenic activity and cancer development. Folic acid and vitamin B12 are essential vitamins for multiple functions in the body, and accumulating evidence suggests their importance in maintaining a high degree of methylation of the HPV genome, thus decreasing the likelihood of causing malignant lesions. HA, due to its re-epithelizing property, may prevent HPV virus entry in damaged mucosa and epithelia. Thereby, based on these premises, the combination of EGCG, folic acid, vitamin B12, and HA may be a very promising therapeutic approach to prevent HPV persistence.
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Zhou L, He JN, Du L, Ho BM, Ng DSC, Chan PP, Tham CC, Pang CP, Chu WK. Epigallocatechin-3-Gallate Protects Trabecular Meshwork Cells from Endoplasmic Reticulum Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7435754. [PMID: 36406768 PMCID: PMC9671731 DOI: 10.1155/2022/7435754] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 10/25/2022] [Indexed: 09/10/2023]
Abstract
Primary open-angle glaucoma (POAG) is the most common form of glaucoma, for which elevated intraocular pressure (IOP) is a major risk factor. IOP is mainly regulated by dynamic balance of aqueous humor (AH) production and outflow via the conventional trabecular meshwork/Schlemm's canal (TM/SC) pathway. Dysfunctions of TM cells due to endoplasmic reticulum (ER) stress have been demonstrated to increase the resistance of AH outflow, resulting in IOP elevation. Epigallocatechin-3-gallate (EGCG), the most abundant polyphenolic component in green tea, has been shown to alleviate ER stress in several diseases while its potential roles in alleviating ER stress in TM cells have not been determined. In this study, we investigate the mitigation of tunicamycin-induced ER stress in TM cells by EGCG. MTT assay was used to measure the cell viability of human TM (HTM) cells and primary porcine TM (PTM) cells. ER stress levels in both HTM cells and primary PTM cells were detected by quantitative real-time PCR. The primary PTM cells isolated from porcine TM tissues were characterized by immunostaining. We found that 40 μM and 80 μM EGCG pretreatment substantially promoted HTM cell survival under 3 μM tunicamycin-induced ER stress. Pretreatment of 40 μM EGCG markedly reduced the expression of ER stress markers ATF4, HSPA5, and DDIT3, evoked by 3 μM tunicamycin in HTM cells. Furthermore, 40 μM EGCG pretreatment significantly decreased the expressions of ATF4, HSPA5, and DDIT3 at the mRNA level induced by 3 μM tunicamycin and improved cell viability in primary PTM cells. Our results show that EGCG is capable of protecting TM cells from ER stress. EGCG provides a promising therapeutic option for POAG treatment.
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Affiliation(s)
- Linbin Zhou
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong
| | - Jing Na He
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong
| | - Lin Du
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong
| | - Bo Man Ho
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong
| | - Danny Siu-Chun Ng
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong
| | - Poemen P. Chan
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong
- Lam Kin Chung. Jet King-Shing Ho Glaucoma Treatment and Research Centre, The Chinese University of Hong Kong, Hong Kong
| | - Clement C. Tham
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong
- Lam Kin Chung. Jet King-Shing Ho Glaucoma Treatment and Research Centre, The Chinese University of Hong Kong, Hong Kong
| | - Chi Pui Pang
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong
- Lam Kin Chung. Jet King-Shing Ho Glaucoma Treatment and Research Centre, The Chinese University of Hong Kong, Hong Kong
| | - Wai Kit Chu
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong
- Lam Kin Chung. Jet King-Shing Ho Glaucoma Treatment and Research Centre, The Chinese University of Hong Kong, Hong Kong
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Lu G, Wang Y, Shi Y, Zhang Z, Huang C, He W, Wang C, Shen H. Autophagy in health and disease: From molecular mechanisms to therapeutic target. MedComm (Beijing) 2022; 3:e150. [PMID: 35845350 PMCID: PMC9271889 DOI: 10.1002/mco2.150] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/01/2022] [Accepted: 06/02/2022] [Indexed: 02/05/2023] Open
Abstract
Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double-membrane structure termed autophagosome and delivered to lysosome for degradation. Over the past two decades, autophagy has been extensively studied, from the molecular mechanisms, biological functions, implications in various human diseases, to development of autophagy-related therapeutics. This review will focus on the latest development of autophagy research, covering molecular mechanisms in control of autophagosome biogenesis and autophagosome-lysosome fusion, and the upstream regulatory pathways including the AMPK and MTORC1 pathways. We will also provide a systematic discussion on the implication of autophagy in various human diseases, including cancer, neurodegenerative disorders (Alzheimer disease, Parkinson disease, Huntington's disease, and Amyotrophic lateral sclerosis), metabolic diseases (obesity and diabetes), viral infection especially SARS-Cov-2 and COVID-19, cardiovascular diseases (cardiac ischemia/reperfusion and cardiomyopathy), and aging. Finally, we will also summarize the development of pharmacological agents that have therapeutic potential for clinical applications via targeting the autophagy pathway. It is believed that decades of hard work on autophagy research is eventually to bring real and tangible benefits for improvement of human health and control of human diseases.
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Affiliation(s)
- Guang Lu
- Department of Physiology, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Yu Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Yin Shi
- Department of BiochemistryZhejiang University School of MedicineHangzhouChina
| | - Zhe Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Weifeng He
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn ResearchSouthwest HospitalArmy Medical UniversityChongqingChina
| | - Chuang Wang
- Department of Pharmacology, Provincial Key Laboratory of PathophysiologyNingbo University School of MedicineNingboZhejiangChina
| | - Han‐Ming Shen
- Department of Biomedical Sciences, Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision OncologyUniversity of MacauMacauChina
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Tarasiuk J, Kostrzewa-Nowak D, Żwierełło W. Antitumour Effects of Selected Pyridinium Salts on Sensitive Leukaemia HL60 Cells and Their Multidrug Resistant Topoisomerase II-Defective HL60/MX2 Counterparts. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27165138. [PMID: 36014378 PMCID: PMC9415637 DOI: 10.3390/molecules27165138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/30/2022] [Accepted: 08/10/2022] [Indexed: 11/16/2022]
Abstract
Multidrug resistance (MDR), having a multifactorial nature, is one of the major clinical problems causing the failure of anticancer therapy. The aim of this study was to examine the antitumour effects of selected pyridinium salts, 1-methyl-3-nitropyridine chloride (MNP) and 3,3,6,6,10-pentamethyl-3,4,6,7-tetrahydro-[1,8(2H,5H)-dion]acridine chloride (MDION), on sensitive leukaemia HL60 cells and resistant topoisomerase II-defective HL60/MX2 cells. Cell growth was determined by the MTT test. Intracellular ROS level was measured with the aid of 2′,7′-DCF-DA. The cell cycle distribution was investigated by performing PI staining. DSB formation was examined using the γ-H2AX histone phosphorylation assay. The activity of caspase-3 and caspase-8 was measured with the use of the FLICA test. The assays for examining the lysosome membrane permeabilization were carried out with the aid of LysoTracker Green DND-26. Both studied compounds exerted very similar cytotoxic activities towards sensitive HL60 cells and their MDR counterparts. They modulated the cellular ROS level in a dose-dependent and time-dependent manner and significantly increased the percentage of sensitive HL60 and resistant HL60/MX2 cells with sub-diploid DNA (sub-G1 fraction). However, the induction of DSB formation was not a significant mechanism of action of these pyridinium salts in studied cells. Both examined compounds triggered caspase-3/caspase-8-dependent apoptosis of sensitive HL60 cells and their MDR counterparts. Additionally, the findings of the study indicate that lysosomes may also participate in the programmed death of HL60 as well as HL60/MX2 cells induced by MDION. The data obtained in this work showed that both examined pyridinium salts, MNP and MDION, are able to retain high antileukaemic effects against multidrug resistant topoisomerase II-defective HL60/MX2 cells.
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11
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Hung SW, Li Y, Chen X, Chu KO, Zhao Y, Liu Y, Guo X, Man GCW, Wang CC. Green Tea Epigallocatechin-3-Gallate Regulates Autophagy in Male and Female Reproductive Cancer. Front Pharmacol 2022; 13:906746. [PMID: 35860020 PMCID: PMC9289441 DOI: 10.3389/fphar.2022.906746] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/17/2022] [Indexed: 11/29/2022] Open
Abstract
With a rich abundance of natural polyphenols, green tea has become one of the most popular and healthiest nonalcoholic beverages being consumed worldwide. Epigallocatechin-3-gallate (EGCG) is the predominant catechin found in green tea, which has been shown to promote numerous health benefits, including metabolic regulation, antioxidant, anti-inflammatory, and anticancer. Clinical studies have also shown the inhibitory effects of EGCG on cancers of the male and female reproductive system, including ovarian, cervical, endometrial, breast, testicular, and prostate cancers. Autophagy is a natural, self-degradation process that serves important functions in both tumor suppression and tumor cell survival. Naturally derived products have the potential to be an effective and safe alternative in balancing autophagy and maintaining homeostasis during tumor development. Although EGCG has been shown to play a critical role in the suppression of multiple cancers, its role as autophagy modulator in cancers of the male and female reproductive system remains to be fully discussed. Herein, we aim to provide an overview of the current knowledge of EGCG in targeting autophagy and its related signaling mechanism in reproductive cancers. Effects of EGCG on regulating autophagy toward reproductive cancers as a single therapy or cotreatment with other chemotherapies will be reviewed and compared. Additionally, the underlying mechanisms and crosstalk of EGCG between autophagy and other cellular processes, such as reactive oxidative stress, ER stress, angiogenesis, and apoptosis, will be summarized. The present review will help to shed light on the significance of green tea as a potential therapeutic treatment for reproductive cancers through regulating autophagy.
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Affiliation(s)
- Sze Wan Hung
- Department of Obstetrics and Gynaecology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Yiran Li
- Department of Obstetrics and Gynaecology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiaoyan Chen
- Department of Obstetrics and Gynaecology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Department of Obstetrics and Gynaecology, Shenzhen Baoan Women’s and Children’s Hospital, Shenzhen University, Shenzhen, China
| | - Kai On Chu
- Department of Ophthalmology and Visual Sciences, Hong Kong Eye Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Yiwei Zhao
- Department of Obstetrics and Gynaecology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Department of Obstetrics and Gynecology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yingyu Liu
- Department of Obstetrics and Gynaecology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Department of Obstetrics and Gynaecology, Shenzhen Baoan Women’s and Children’s Hospital, Shenzhen University, Shenzhen, China
| | - Xi Guo
- Department of Obstetrics and Gynaecology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Gene Chi-Wai Man
- Department of Obstetrics and Gynaecology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Department of Orthopaedics and Traumatology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- *Correspondence: Gene Chi-Wai Man, ; Chi Chiu Wang,
| | - Chi Chiu Wang
- Department of Obstetrics and Gynaecology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences; School of Biomedical Sciences; and Chinese University of Hong Kong-Sichuan University Joint Laboratory in Reproductive Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- *Correspondence: Gene Chi-Wai Man, ; Chi Chiu Wang,
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12
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Sahadevan R, Singh S, Binoy A, Sadhukhan S. Chemico-biological aspects of (-)-epigallocatechin- 3-gallate (EGCG) to improve its stability, bioavailability and membrane permeability: Current status and future prospects. Crit Rev Food Sci Nutr 2022; 63:10382-10411. [PMID: 35491671 DOI: 10.1080/10408398.2022.2068500] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Natural products have been a bedrock for drug discovery for decades. (-)-Epigallocatechin-3-gallate (EGCG) is one of the widely studied natural polyphenolic compounds derived from green tea. It is the key component believed to be responsible for the medicinal value of green tea. Significant studies implemented in in vitro, in cellulo, and in vivo models have suggested its anti-oxidant, anti-cancer, anti-diabetic, anti-inflammatory, anti-microbial, neuroprotective activities etc. Despite having such a wide array of therapeutic potential and promising results in preclinical studies, its applicability to humans has encountered with rather limited success largely due to the poor bioavailability, poor membrane permeability, rapid metabolic clearance and lack of stability of EGCG. Therefore, novel techniques are warranted to address those limitations so that EGCG or its modified analogs can be used in the clinical setup. This review comprehensively covers different strategies such as structural modifications, nano-carriers as efficient drug delivery systems, synergistic studies with other bioactivities to improve the chemico-biological aspects (e.g., stability, bioavailability, permeability, etc.) of EGCG for its enhanced pharmacokinetics and pharmacological properties, eventually enhancing its therapeutic potentials. We think this review article will serve as a strong platform with comprehensive literature on the development of novel techniques to improve the bioavailability of EGCG so that it can be translated to the clinical applications.
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Affiliation(s)
- Revathy Sahadevan
- Department of Chemistry, Indian Institute of Technology Palakkad, Kerala, India
| | - Satyam Singh
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Madhya Pradesh, India
| | - Anupama Binoy
- Department of Chemistry, Indian Institute of Technology Palakkad, Kerala, India
| | - Sushabhan Sadhukhan
- Department of Chemistry, Indian Institute of Technology Palakkad, Kerala, India
- Department of Biological Sciences and Engineering, Indian Institute of Technology Palakkad, Kerala, India
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13
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Istifli ES, Netz PA, Sihoglu Tepe A, Husunet MT, Sarikurkcu C, Tepe B. In silico analysis of the interactions of certain flavonoids with the receptor-binding domain of 2019 novel coronavirus and cellular proteases and their pharmacokinetic properties. J Biomol Struct Dyn 2022; 40:2460-2474. [PMID: 33111622 PMCID: PMC7605517 DOI: 10.1080/07391102.2020.1840444] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 10/17/2020] [Indexed: 11/11/2022]
Abstract
Coronavirus Disease 2019 (COVID-19) has infected more than thirty five million people worldwide and caused nearly 1 million deaths as of October 2020. The microorganism causing COVID-19 was named as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2 or 2019-nCoV). The aim of this study was to investigate the interactions of twenty-three phytochemicals belonging to different flavonoid subgroups with the receptor binding domain (RBD) of the spike glycoprotein of 2019-nCoV, and cellular proteases [transmembrane serine protease 2 (TMPRSS2), cathepsin B and L (CatB/L)]. The compounds interacted more strongly with CatB and CatL than with the other proteins. Van der Waals and hydrogen bonds played an important role in the receptor-ligand interactions. As a result of RBCI (relative binding capacity index) analysis conducted to rank flavonoids in terms of their interactions with the target proteins, (-)-epicatechin gallate interacted strongly with all the proteins studied. The results obtained from molecular dynamics and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) methods also supported this data. According to Lipinski's rule of five, (-)-epicatechin gallate showed drug-likeness properties. Although this molecule is not capable of crossing the blood-brain barrier (BBB), it was concluded that (-)-epicatechin gallate can be evaluated as a candidate molecule in drug development studies against 2019-nCoV since it was not the substrate of P-gp (P-glycoprotein), did not inhibit any of the cytochrome Ps, and did not show AMES toxicity or hepatotoxicity on eukaryotic cells.
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Affiliation(s)
- Erman Salih Istifli
- Department of Biology, Faculty of Science and Literature, Cukurova University, Adana, Turkey
| | - Paulo A. Netz
- Theoretical Chemistry Group, Institute of Chemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Arzuhan Sihoglu Tepe
- Department of Biology, Faculty of Science and Literature, Gaziantep University, Gaziantep, Turkey
| | - Mehmet Tahir Husunet
- Department of Biology, Faculty of Science and Literature, Cukurova University, Adana, Turkey
| | - Cengiz Sarikurkcu
- Department of Analytical Chemistry, Faculty of Pharmacy, Afyonkarahisar Health Sciences University, Afyonkarahisar, Turkey
| | - Bektas Tepe
- Department of Molecular Biology and Genetics, Faculty of Science and Literature, Kilis 7 Aralik University, Kilis, Turkey
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14
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Liu H, Mo L, Chen H, Chen C, Wu J, Tang Z, Guo Z, Hu C, Liu Z. Carbon Dots with Intrinsic Bioactivities for Photothermal Optical Coherence Tomography, Tumor-Specific Therapy and Postoperative Wound Management. Adv Healthc Mater 2022; 11:e2101448. [PMID: 34937144 DOI: 10.1002/adhm.202101448] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 12/13/2021] [Indexed: 12/26/2022]
Abstract
Carbon dots (CDs) are considered as promising candidates with superior biocompatibilities for multimodel cancer theranostics. However, incorporation of exogenous components, such as targeting molecules and chemo/photo therapeutic drugs, is often required to improve the therapeutic efficacy. Herein, an "all-in-one" CDs that exhibit intrinsic bioactivities for bioimaging, potent tumor therapy, and postoperative management is proposed. The multifunctional CDs derived from gallic acid and tyrosine (GT-CDs) consist of a graphitized carbon core and N, O-rich functional groups, which endow them with a high near-infrared (NIR) photothermal conversion efficiency of 33.9% and tumor-specific cytotoxicity, respectively. A new imaging modality, photothermal optical coherence tomography, is introduced using GT-CDs as the contrast agent, offering the micrometer-scale resolution 3D tissue morphology of tumor. For cancer therapy, GT-CDs initiate the intracellular generation of reactive oxygen species in tumor cells but not normal cells, further induce the mitochondrial collapse and subsequent tumor cellular apoptosis. Combined with NIR photothermal treatment, synergistic antitumor therapy is achieved in vitro and in vivo. GT-CDs also promote the healing process of bacteria-contaminated skin wound, demonstrating their potential to prevent postoperative infection. The integrated theranostic strategy based on versatile GT-CDs supplies an alternative easy-to-handle pattern for disease management.
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Affiliation(s)
- Hao Liu
- Guangdong Provincial Key Laboratory of Laser Life Science College of Biophotonics South China Normal University Guangzhou 510631 China
| | - Luoqi Mo
- Guangdong Provincial Key Laboratory of Laser Life Science College of Biophotonics South China Normal University Guangzhou 510631 China
- College of Materials and Energy South China Agricultural University Guangzhou 510642 China
| | - Haolin Chen
- Department of Hematology The Seventh Affiliated Hospital Sun Yat‐sen University Shenzhen 518107 China
| | - Chao Chen
- Guangdong Provincial Key Laboratory of Laser Life Science College of Biophotonics South China Normal University Guangzhou 510631 China
| | - Jiayi Wu
- School of Physics and Telecommunication Engineering South China Normal University Guangzhou 510006 China
| | - Zhilie Tang
- School of Physics and Telecommunication Engineering South China Normal University Guangzhou 510006 China
| | - Zhouyi Guo
- Guangdong Provincial Key Laboratory of Laser Life Science College of Biophotonics South China Normal University Guangzhou 510631 China
| | - Chaofan Hu
- College of Materials and Energy South China Agricultural University Guangzhou 510642 China
| | - Zhiming Liu
- Guangdong Provincial Key Laboratory of Laser Life Science College of Biophotonics South China Normal University Guangzhou 510631 China
- Guangzhou Key Laboratory of Spectral Analysis and Functional Probes College of Biophotonics South China Normal University Guangzhou 510631 China
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15
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Alam M, Ali S, Ashraf GM, Bilgrami AL, Yadav DK, Hassan MI. Epigallocatechin 3-gallate: From green tea to cancer therapeutics. Food Chem 2022; 379:132135. [PMID: 35063850 DOI: 10.1016/j.foodchem.2022.132135] [Citation(s) in RCA: 133] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/22/2021] [Accepted: 01/09/2022] [Indexed: 12/13/2022]
Abstract
Epigallocatechin 3-gallate (EGCG) possesses various biological functions, including anti-cancer and anti-inflammatory properties. EGCG is an abundant polyphenolic component originating from green tea extract that has exhibited versatile bioactivities in combating several cancers. This review highlights the pharmacological features of EGCG and its therapeutic implications in cancer and other metabolic diseases. It modulates numerous signaling pathways, regulating cells' undesired survival and proliferation, thus imparting strong tumor chemopreventive and therapeutic effects. EGCG initiates cell death through the intrinsic pathway and causes inhibition of EGFR, STAT3, and ERK pathways in several cancers. EGCG alters and inhibits ERK1/2, NF-κB, and Akt-mediated signaling, altering the Bcl-2 family proteins ratio and activating caspases in tumor cells. This review focuses on anti-cancer, anti-oxidant, anti-inflammatory, anti-angiogenesis, and apoptotic effects of EGCG. We further highlighted the potential of EGCG in different types of cancer, emphasizing clinical trials formulations that further improve our understanding of the therapeutic management of cancer and inflammatory diseases.
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Affiliation(s)
- Manzar Alam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Sabeeha Ali
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Ghulam Md Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Anwar L Bilgrami
- Deanship of Scientific Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Dharmendra Kumar Yadav
- College of Pharmacy, Gachon University of Medicine and Science, Hambakmoeiro, Yeonsu-gu, Incheon City 21924, South Korea.
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India.
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16
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Halaby R. Natural Products Induce Lysosomal Membrane Permeabilization as an Anticancer Strategy. MEDICINES 2021; 8:medicines8110069. [PMID: 34822366 PMCID: PMC8624533 DOI: 10.3390/medicines8110069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 11/03/2021] [Accepted: 11/08/2021] [Indexed: 11/26/2022]
Abstract
Cancer is a global health and economic issue. The majority of anticancer therapies become ineffective due to frequent genomic turnover and chemoresistance. Furthermore, chemotherapy and radiation are non-specific, killing all rapidly dividing cells including healthy cells. In this review, we examine the ability of some natural products to induce lysosomal-mediated cell death in neoplastic cells as a way to kill them more specifically than conventional therapies. This list is by no means exhaustive. We postulate mechanisms to explain lysosomal membrane permeabilization and its role in triggering cell death in cancer cells.
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Affiliation(s)
- Reginald Halaby
- Department of Biology, Montclair State University, Montclair, NJ 07043, USA
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17
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Targeting Drug Chemo-Resistance in Cancer Using Natural Products. Biomedicines 2021; 9:biomedicines9101353. [PMID: 34680470 PMCID: PMC8533186 DOI: 10.3390/biomedicines9101353] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer is one of the leading causes of death globally. The development of drug resistance is the main contributor to cancer-related mortality. Cancer cells exploit multiple mechanisms to reduce the therapeutic effects of anticancer drugs, thereby causing chemotherapy failure. Natural products are accessible, inexpensive, and less toxic sources of chemotherapeutic agents. Additionally, they have multiple mechanisms of action to inhibit various targets involved in the development of drug resistance. In this review, we have summarized the basic research and clinical applications of natural products as possible inhibitors for drug resistance in cancer. The molecular targets and the mechanisms of action of each natural product are also explained. Diverse drug resistance biomarkers were sensitive to natural products. P-glycoprotein and breast cancer resistance protein can be targeted by a large number of natural products. On the other hand, protein kinase C and topoisomerases were less sensitive to most of the studied natural products. The studies discussed in this review will provide a solid ground for scientists to explore the possible use of natural products in combination anticancer therapies to overcome drug resistance by targeting multiple drug resistance mechanisms.
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18
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Mishra PM, Yadav A, Kaushik K, Jaiswal A, Nandi CK. Super-Resolution Microscopy Revealed the Lysosomal Expansion During Epigallocatechin Gallate-Mediated Apoptosis. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2021; 37:10818-10826. [PMID: 34470217 DOI: 10.1021/acs.langmuir.1c01742] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Direct visualization of the dynamic events in lysosomes during drug-mediated programmed cell death (apoptosis) is a great challenge. This is due to the lack of resolving power of a conventional microscope and also the unavailability of a suitable multimodal probe that simultaneously can carry the drug with high loading capacity and ensure its specific internalization into lysosomes. In this work, using super-resolution microscopy, we observed the lysosomal expansion during apoptosis that was treated with epigallocatechin gallate (EGCG) conjugated to bovine serum albumin (BSA). Albumin protein is known to internalize into lysosomes via endocytosis, thus helping in the specific delivery of EGCG to the lysosomal compartment. The conjugation of EGCG to BSA not only helped in increasing the killing efficiency of cancer cells but it also reduces the side effects and produces minimal reactive oxygen species. The decrease in local viscosity helped in lysosomal expansion during apoptosis.
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Affiliation(s)
- Pushpendra M Mishra
- School of Basic Sciences, Indian Institute of Technology Mandi, Himachal Pradesh175001, India
- Advanced Materials Research Centre, Indian Institute of Technology Mandi, Himachal Pradesh 175001, India
- BioX Centre, Indian Institute of Technology Mandi, Himachal Pradesh 175001, India
| | - Aditya Yadav
- School of Basic Sciences, Indian Institute of Technology Mandi, Himachal Pradesh175001, India
- Advanced Materials Research Centre, Indian Institute of Technology Mandi, Himachal Pradesh 175001, India
| | - Kush Kaushik
- School of Basic Sciences, Indian Institute of Technology Mandi, Himachal Pradesh175001, India
- Advanced Materials Research Centre, Indian Institute of Technology Mandi, Himachal Pradesh 175001, India
| | - Amit Jaiswal
- School of Basic Sciences, Indian Institute of Technology Mandi, Himachal Pradesh175001, India
- BioX Centre, Indian Institute of Technology Mandi, Himachal Pradesh 175001, India
| | - Chayan K Nandi
- School of Basic Sciences, Indian Institute of Technology Mandi, Himachal Pradesh175001, India
- Advanced Materials Research Centre, Indian Institute of Technology Mandi, Himachal Pradesh 175001, India
- BioX Centre, Indian Institute of Technology Mandi, Himachal Pradesh 175001, India
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19
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Autophagy inhibition contributes to epigallocatechin-3-gallate-mediated apoptosis in papillary thyroid cancer cells. Mol Cell Toxicol 2021. [DOI: 10.1007/s13273-021-00164-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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20
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Fleisher B, Lezeau J, Werkman C, Jacobs B, Ait-Oudhia S. In vitro to Clinical Translation of Combinatorial Effects of Doxorubicin and Abemaciclib in Rb-Positive Triple Negative Breast Cancer: A Systems-Based Pharmacokinetic/Pharmacodynamic Modeling Approach. BREAST CANCER-TARGETS AND THERAPY 2021; 13:87-105. [PMID: 33628047 PMCID: PMC7899308 DOI: 10.2147/bctt.s292161] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 01/19/2021] [Indexed: 11/23/2022]
Abstract
Background Doxorubicin (DOX) and its pegylated liposomal formulation (L_DOX) are the standard of care for triple-negative breast cancer (TNBC). However, resistance to DOX often occurs, motivating the search for alternative treatment approaches. The retinoblastoma protein (Rb) is a potential pharmacological target for TNBC treatment since its expression has been associated with resistance to DOX-based therapy. Methods DOX (0.01–20 μM) combination with abemaciclib (ABE, 1–6 μM) was evaluated over 72 hours on Rb-positive (MDA-MB-231) and Rb-negative (MDA-MB-468) TNBC cells. Combination indices (CI) for DOX+ABE were calculated using Compusyn software. The TNBC cell viability time-course and fold-change from the control of phosphorylated-Rb (pRb) protein expression were measured with CCK8-kit and enzyme-linked immunosorbent assay. A cell-based pharmacodynamic (PD) model was developed, where pRb protein dynamics drove cell viability response. Clinical pharmacokinetic (PK) models for DOX, L_DOX, and ABE were developed using data extracted from the literature. After scaling cancer cell growth to clinical TNBC tumor growth, the time-to-tumor progression (TTP) was predicted for human dosing regimens of DOX, ABE, and DOX+ABE. Results DOX and ABE combinations were synergistic (CI<1) in MDA-MB-231 and antagonistic (CI>1) in MDA-MB-468. The maximum inhibitory effects (Imax) for both drugs were set to one. The drug concentrations producing 50% of Imax for DOX and ABE were 0.565 and 2.31 μM (MDA-MB-231) and 0.121 and 1.61 μM (MDA-MB-468). The first-orders rate constants of abemaciclib absorption (ka) and doxorubicin release from L_DOX (kRel) were estimated at 0.31 and 0.013 h−1. Their linear clearances were 21.7 (ABE) and 32.1 L/h (DOX). The estimated TTP for intravenous DOX (75 mg/m2 every 21 days), intravenous L_DOX (50 mg/m2 every 28 days), and oral ABE (200 mg twice a day) were 125, 31.2, and 8.6 days shorter than drug-free control. The TTP for DOX+ABE and L_DOX+ABE were 312 days and 47.5 days shorter than control, both larger than single-agent DOX, suggesting improved activity with the DOX+ABE combination. Conclusion The developed translational systems-based PK/PD model provides an in vitro-to-clinic modeling platform for DOX+ABE in TNBC. Although model-based simulations suggest improved outcomes with combination over monotherapy, tumor relapse was not prevented with the combination. Hence, DOX+ABE may not be an effective treatment combination for TNBC.
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Affiliation(s)
- Brett Fleisher
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA
| | - Jovin Lezeau
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA
| | - Carolin Werkman
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA
| | - Brehanna Jacobs
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA
| | - Sihem Ait-Oudhia
- Quantitative Pharmacology and Pharmacometrics (QP2), Merck & Co, Inc, Kenilworth, New Jersey, USA
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Induction of Lysosomal Membrane Permeabilization Is a Major Event of FTY720-Mediated Non-Apoptotic Cell Death in Human Glioma Cells. Cancers (Basel) 2020; 12:cancers12113388. [PMID: 33207629 PMCID: PMC7696845 DOI: 10.3390/cancers12113388] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 10/28/2020] [Accepted: 11/13/2020] [Indexed: 12/15/2022] Open
Abstract
Simple Summary FTY720, a sphingosine-1-phosphate (S1P) analog, is a potent immunosuppressant for the treatment of multiple sclerosis. In addition to being an immune modulator, FTY720 also features antitumor activity in several cancer models, but the molecular mechanisms are unclear. Here, we extended our research to analyze the signaling pathways mediating FTY720-induced cell death. FTY720 did not induce apoptotic cell death, autophagy, paraptosis, or necroptosis in glioma cells. Interestingly, FTY720 accumulated in lysosomes, resulting in the induction of lysosomal membrane permeabilization (LMP). Inhibition of LMP by overexpression of HSP70 and cathepsin inhibitors blocked FTY720-induced cell death. These data suggest that FTY720 induces cell death induced by LMP in glioma cells. Abstract FTY720, a sphingosine-1-phosphate (S1P) receptor modulator, is a synthetic compound produced by the modification of a metabolite from I. sinclairii. Here, we found that FTY720 induced non-apoptotic cell death in human glioma cells (U251MG, U87MG, and U118MG). FTY720 (10 µM) dramatically induced cytoplasmic vacuolation in glioma cells. However, FTY720-mediated vacuolation and cell death are not associated with autophagy. Genetic or pharmacological inhibition of autophagy did not inhibit FTY720-induced cell death. Herein, we detected that FTY720-induced cytoplasmic vacuoles were stained with lysotracker red, and FTY720 induced lysosomal membrane permeabilization (LMP). Interestingly, cathepsin inhibitors (E64D and pepstatin A) and ectopic expression of heat shock protein 70 (HSP70), which is an endogenous inhibitor of LMP, markedly inhibited FTY720-induced cell death. Our results demonstrated that FTY720 induced non-apoptotic cell death via the induction of LMP in human glioma cells.
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Bertman KA, Abeywickrama CS, Pang Y. Synthesis of a far-red emitting flavonoid-based lysosome marker for live cell imaging applications. Bioorg Chem 2020; 102:104040. [PMID: 32659485 DOI: 10.1016/j.bioorg.2020.104040] [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: 01/20/2020] [Revised: 06/21/2020] [Accepted: 06/22/2020] [Indexed: 11/29/2022]
Abstract
A bright far-red emitting flavonoid derivative (FuraET) was synthesized in good yields by inserting a π extension group (i.e., furan) into the flavonoid skeleton, via using the Suzuki-Miyaura cross-coupling reaction. FuaraET exhibited optical absorption at λab ≈ 450 nm and emission λem ≈ 660 nm by recognizing as the first far-red emitting flavonoid derivative reported. FuraET exhibited a large Stokes shift (Δλ > 150 nm) high fluorescent quantum yield (φfl ≈ 0.2-0.4), and good photostability indicating excellent characteristics for an imaging probe. Live cell fluorescent confocal microscopy imaging revealed the exceptional selectivity of the FuraET towards cellular lysosomes (Mander's overlap coefficients >0.9). The observed non-alkalinizing nature and high biocompatibility (LC50 > 50 µM) suggested that FuraET can a reliable lysosome marker for live cell imaging experiments. Our further study also indicated that FuraET may likely internalized into hydrophobic regions of the cellular lysosomes in contrast to acidic lysosomal lumen.
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Affiliation(s)
| | | | - Yi Pang
- Department of Chemistry, University of Akron, Akron, OH 44325, USA; Maurice Morton Institute of Polymer Science, University of Akron, Akron, OH 44325, USA.
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The Intrinsic Virtues of EGCG, an Extremely Good Cell Guardian, on Prevention and Treatment of Diabesity Complications. Molecules 2020; 25:molecules25133061. [PMID: 32635492 PMCID: PMC7411588 DOI: 10.3390/molecules25133061] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 07/01/2020] [Accepted: 07/02/2020] [Indexed: 12/19/2022] Open
Abstract
The pandemic proportion of diabesity—a combination of obesity and diabetes—sets a worldwide health issue. Experimental and clinical studies have progressively reinforced the pioneering epidemiological observation of an inverse relationship between consumption of polyphenol-rich nutraceutical agents and mortality from cardiovascular and metabolic diseases. With chemical identification of epigallocatechin-3-gallate (EGCG) as the most abundant catechin of green tea, a number of cellular and molecular mechanisms underlying the activities of this unique catechin have been proposed. Favorable effects of EGCG have been initially attributed to its scavenging effects on free radicals, inhibition of ROS-generating mechanisms and upregulation of antioxidant enzymes. Biologic actions of EGCG are concentration-dependent and under certain conditions EGCG may exert pro-oxidant activities, including generation of free radicals. The discovery of 67-kDa laminin as potential EGCG membrane target has broaden the likelihood that EGCG may function not only because of its highly reactive nature, but also via receptor-mediated activation of multiple signaling pathways involved in cell proliferation, angiogenesis and apoptosis. Finally, by acting as epigenetic modulator of DNA methylation and chromatin remodeling, EGCG may alter gene expression and modify miRNA activities. Despite unceasing research providing detailed insights, ECGC composite activities are still not completely understood. This review summarizes the most recent evidence on molecular mechanisms by which EGCG may activate signal transduction pathways, regulate transcription factors or promote epigenetic changes that may contribute to prevent pathologic processes involved in diabesity and its cardiovascular complications.
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Maruszewska A, Tarasiuk J. Quercetin Triggers Induction of Apoptotic and Lysosomal Death of Sensitive and Multidrug Resistant Leukaemia HL60 Cells. Nutr Cancer 2020; 73:484-501. [PMID: 32329631 DOI: 10.1080/01635581.2020.1752745] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Multidrug resistance (MDR) constitutes the major cause of the failure in anticancer therapy. One of the most important mechanisms leading to the occurrence of MDR is related to the modulation of cellular death pathways. The aim of this study was to determine the effect of quercetin (Q) on triggering the programed death of human promyelocytic leukemia sensitive cells HL60 as well as multidrug resistant HL60/VINC cells overexpressing P-glycoprotein and HL60/MX2 cells characterized by the presence of mutated α isoform of topoisomerase II and the absence of β isoform of this enzyme. Q exerted comparable cytotoxic activities toward sensitive HL60 cells and their MDR counterparts. It was also found that this compound modulated the cellular level of reactive oxygen species (ROS) and led to the marked decrease in cellular GSH level. Furthermore, it was demonstrated that Q used at IC50 and IC90 significantly increased the percentage of sub-G1 subpopulation of all studied leukemia cells causing oligonucleosomal DNA fragmentation. The present study also indicated that Q used at IC90 triggers predominantly programed cell death of sensitive HL60 cells and their MDR counterparts by induction of apoptosis occurring with the involvement of caspase-3 and caspase-8 as well as by lysosome membrane permeabilization-dependent mechanisms.
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Affiliation(s)
- Agnieszka Maruszewska
- Department of Biochemistry, Faculty of Biology, University of Szczecin, Szczecin, Poland.,Molecular Biology and Biotechnology Center, Faculty of Biology, University of Szczecin, Szczecin, Poland
| | - Jolanta Tarasiuk
- Department of Biochemistry, Faculty of Biology, University of Szczecin, Szczecin, Poland.,Molecular Biology and Biotechnology Center, Faculty of Biology, University of Szczecin, Szczecin, Poland
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25
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Mao X, Xiao X, Chen D, Yu B, He J. Tea and Its Components Prevent Cancer: A Review of the Redox-Related Mechanism. Int J Mol Sci 2019; 20:E5249. [PMID: 31652732 PMCID: PMC6862630 DOI: 10.3390/ijms20215249] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 10/21/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023] Open
Abstract
Cancer is a worldwide epidemic and represents a major threat to human health and survival. Reactive oxygen species (ROS) play a dual role in cancer cells, which includes both promoting and inhibiting carcinogenesis. Tea remains one of the most prevalent beverages consumed due in part to its anti- or pro-oxidative properties. The active compounds in tea, particularly tea polyphenols, can directly or indirectly scavenge ROS to reduce oncogenesis and cancerometastasis. Interestingly, the excessive levels of ROS induced by consuming tea could induce programmed cell death (PCD) or non-PCD of cancer cells. On the basis of illustrating the relationship between ROS and cancer, the current review discusses the composition and efficacy of tea including the redox-relative (including anti-oxidative and pro-oxidative activity) mechanisms and their role along with other components in preventing and treating cancer. This information will highlight the basis for the clinical utilization of tea extracts in the prevention or treatment of cancer in the future.
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Affiliation(s)
- Xiangbing Mao
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China.
- Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Chengdu 611130, China.
- Key Laboratory of Animal Disease-Resistance Nutrition and Feed, Ministry of Agriculture and Rural Affairs, Chengdu 611130, China.
- Key Laboratory of Animal Disease-Resistance Nutrition, Chengdu 611130, China.
| | - Xiangjun Xiao
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China.
| | - Daiwen Chen
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China.
- Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Chengdu 611130, China.
- Key Laboratory of Animal Disease-Resistance Nutrition and Feed, Ministry of Agriculture and Rural Affairs, Chengdu 611130, China.
- Key Laboratory of Animal Disease-Resistance Nutrition, Chengdu 611130, China.
| | - Bing Yu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China.
- Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Chengdu 611130, China.
- Key Laboratory of Animal Disease-Resistance Nutrition and Feed, Ministry of Agriculture and Rural Affairs, Chengdu 611130, China.
- Key Laboratory of Animal Disease-Resistance Nutrition, Chengdu 611130, China.
| | - Jun He
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China.
- Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Chengdu 611130, China.
- Key Laboratory of Animal Disease-Resistance Nutrition and Feed, Ministry of Agriculture and Rural Affairs, Chengdu 611130, China.
- Key Laboratory of Animal Disease-Resistance Nutrition, Chengdu 611130, China.
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Hong JM, Kim JH, Kim H, Lee WJ, Hwang YI. SB365, Pulsatilla Saponin D Induces Caspase-Independent Cell Death and Augments the Anticancer Effect of Temozolomide in Glioblastoma Multiforme Cells. Molecules 2019; 24:molecules24183230. [PMID: 31491945 PMCID: PMC6766801 DOI: 10.3390/molecules24183230] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 12/28/2022] Open
Abstract
SB365, a saponin D extracted from the roots of Pulsatilla koreana, has been reported to show cytotoxicity in several cancer cell lines. We investigated the effects of SB365 on U87-MG and T98G glioblastoma multiforme (GBM) cells, and its efficacy in combination with temozolomide for treating GBM. SB365 exerted a cytotoxic effect on GBM cells not by inducing apoptosis, as in other cancer cell lines, but by triggering caspase-independent cell death. Inhibition of autophagic flux and neutralization of the lysosomal pH occurred rapidly after application of SB365, followed by deterioration of mitochondrial membrane potential. A cathepsin B inhibitor and N-acetyl cysteine, an antioxidant, partially recovered cell death induced by SB365. SB365 in combination with temozolomide exerted an additive cytotoxic effect in vitro and in vivo. In conclusion, SB365 inhibits autophagic flux and induces caspase-independent cell death in GBM cells in a manner involving cathepsin B and mainly reactive oxygen species, and its use in combination with temozolomide shows promise for the treatment of GBM.
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Affiliation(s)
- Jun-Man Hong
- Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Korea.
| | - Jin-Hee Kim
- Department of Biomedical Laboratory Science, Cheongju University, Cheongju 28503, Korea.
| | - Hyemin Kim
- Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea.
| | - Wang Jae Lee
- Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Korea.
| | - Young-Il Hwang
- Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Korea.
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Rady I, Mohamed H, Rady M, Siddiqui IA, Mukhtar H. Cancer preventive and therapeutic effects of EGCG, the major polyphenol in green tea. ACTA ACUST UNITED AC 2019. [DOI: 10.1016/j.ejbas.2017.12.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Islam Rady
- School of Medicine and Public Health, Department of Dermatology, University of Wisconsin-Madison, WI 53706, USA
- Department of Zoology, Faculty of Science, Al-Azhar University, Cairo, Egypt
| | - Hadir Mohamed
- School of Medicine and Public Health, Department of Dermatology, University of Wisconsin-Madison, WI 53706, USA
| | - Mohamad Rady
- Department of Zoology, Faculty of Science, Al-Azhar University, Cairo, Egypt
| | - Imtiaz A. Siddiqui
- School of Medicine and Public Health, Department of Dermatology, University of Wisconsin-Madison, WI 53706, USA
| | - Hasan Mukhtar
- School of Medicine and Public Health, Department of Dermatology, University of Wisconsin-Madison, WI 53706, USA
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28
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Maruszewska A, Tarasiuk J. Antitumour effects of selected plant polyphenols, gallic acid and ellagic acid, on sensitive and multidrug-resistant leukaemia HL60 cells. Phytother Res 2019; 33:1208-1221. [PMID: 30838722 DOI: 10.1002/ptr.6317] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 01/18/2019] [Accepted: 01/24/2019] [Indexed: 12/30/2022]
Abstract
The aim of this study was to examine the antitumour effects of plant phenolic acids, gallic acid (GA) and ellagic acid (EA), on human promyelocytic leukaemia sensitive HL60 cell line and its resistant sublines exhibiting two MDR phenotypes: HL60/VINC (overexpressing P-glycoprotein) and HL60/MX2 (characterized by the presence of mutated α isoform of topoisomerase II). Both studied compounds exerted comparable cytotoxic activities towards sensitive HL60 cells and their MDR counterparts. It was also found that GA and EA modulated the cellular level of reactive oxygen species in a dose-dependent and time-dependent manner. Furthermore, it was demonstrated that GA (IC90 ) and EA (IC50 and IC90 ) significantly increased the percentage of sub-G1 subpopulation of all studied leukaemia cells causing oligonucleosomal DNA fragmentation. Both compounds used at IC90 triggered mainly the apoptotic death of these cells. However, GA had no effect on the activity of caspase-3 as well as caspase-8 in sensitive HL60 cells and their MDR counterparts. In contrast, EA provoked a significant activation of these caspases in all studied leukaemia cells. It was also found that lysosomes were not involved in triggering programmed death of sensitive HL60 and MDR cells by GA and EA.
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Affiliation(s)
- Agnieszka Maruszewska
- Department of Biochemistry, Faculty of Biology, University of Szczecin, 3c Felczaka St, Szczecin, 71-412, Poland.,Molecular Biology and Biotechnology Center, Faculty of Biology, University of Szczecin, 13 Wąska St, Szczecin, 71-415, Poland
| | - Jolanta Tarasiuk
- Department of Biochemistry, Faculty of Biology, University of Szczecin, 3c Felczaka St, Szczecin, 71-412, Poland.,Molecular Biology and Biotechnology Center, Faculty of Biology, University of Szczecin, 13 Wąska St, Szczecin, 71-415, Poland
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Nabavi SF, Sureda A, Sanches-Silva A, Pandima Devi K, Ahmed T, Shahid M, Sobarzo-Sánchez E, Dacrema M, Daglia M, Braidy N, Vacca RA, Berindan-Neagoe I, Gulei D, Barreca D, Banach M, Nabavi SM, Dehpour AR, Shirooie S. Novel therapeutic strategies for stroke: The role of autophagy. Crit Rev Clin Lab Sci 2019; 56:182-199. [PMID: 30821184 DOI: 10.1080/10408363.2019.1575333] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Autophagy is an important biological mechanism involved in the regulation of numerous fundamental cellular processes that are mainly associated with cellular growth and differentiation. Autophagic pathways are vital for maintaining cellular homeostasis by enhancing the turnover of nonfunctional proteins and organelles. Neuronal cells, like other eukaryotic cells, are dependent on autophagy for neuroprotection in response to stress, but can also induce cell death in cerebral ischemia. Recent studies have demonstrated that autophagy may induce neuroprotection following acute brain injury, including ischemic stroke. However in some special circumstances, activation of autophagy can induce cell death, playing a deleterious role in the etiology and progression of ischemic stroke. Currently, there are no therapeutic options against stroke that demonstrate efficient neuroprotective abilities. In the present work, we will review the significance of autophagy in the context of ischemic stroke by first outlining its role in ischemic neuronal death. We will also highlight the potential therapeutic applications of pharmacological modulators of autophagy, including some naturally occurring polyphenolic compounds that can target this catabolic process. Our findings provide renewed insight on the mechanism of action of autophagy in stroke together with potential neuroprotective compounds, which may partially exert their function through enhancing mitochondrial function and attenuating damaging autophagic processes.
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Affiliation(s)
- Seyed Fazel Nabavi
- a Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences , Tehran , Iran
| | - Antoni Sureda
- b Research Group on Community Nutrition and Oxidative Stress (NUCOX) and CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), University of Balearic Islands , Palma de Mallorca , Spain
| | - Ana Sanches-Silva
- c National Institute for Agricultural and Veterinary Research (INIAV) , Vila do Conde , Portugal.,d Center for Study in Animal Science (CECA), ICETA, University of Oporto , Oporto , Portugal
| | - Kasi Pandima Devi
- e Department of Biotechnology , Alagappa University , Karaikudi , Tamil Nadu, India
| | - Touqeer Ahmed
- f Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology , Islamabad , Pakistan
| | - Momina Shahid
- f Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology , Islamabad , Pakistan
| | - Eduardo Sobarzo-Sánchez
- g Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Santiago de Compostela , Santiago de Compostela , Spain.,h Instituto de Investigación e Innovación en Salud, Facultad de Ciencias de la Salud , Universidad Central de Chile , Chile
| | - Marco Dacrema
- i Department of Drug Sciences , Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia , Pavia , Italy
| | - Maria Daglia
- i Department of Drug Sciences , Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia , Pavia , Italy
| | - Nady Braidy
- j Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales , New South Wales , Australia
| | - Rosa Anna Vacca
- k Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies National Council of Research , Bari , Italy
| | - Ioana Berindan-Neagoe
- l MEDFUTURE - Research Center for Advanced Medicine, "Iuliu-Hatieganu" University of Medicine and Pharmacy , Cluj-Napoca , Romania.,m Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy , Cluj-Napoca , Romania.,n Department of Functional Genomics and Experimental Pathology , The Oncology Institute "Prof. Dr. Ion Chiricuta" , Cluj-Napoca , Romania
| | - Diana Gulei
- l MEDFUTURE - Research Center for Advanced Medicine, "Iuliu-Hatieganu" University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Davide Barreca
- o Department of Chemical, Biological, Pharmaceutical and Environmental Sciences , University of Messina , Messina , Italy
| | - Maciej Banach
- p Department of Hypertension , WAM University Hospital in Lodz, Medical University of Lodz , Lodz , Poland.,q Polish Mother's Memorial Hospital Research Institute (PMMHRI) , Lodz , Poland.,r Cardiovascular Research Centre, University of Zielona Gora , Zielona Gora , Poland
| | - Seyed Mohammad Nabavi
- a Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences , Tehran , Iran
| | - Ahmad Reza Dehpour
- s Department of Pharmacology, Faculty of Medicine , Tehran University of Medical Sciences , Tehran , Iran.,t Experimental Medicine Research Center, Tehran University of Medical Sciences , Tehran , Iran
| | - Samira Shirooie
- u Department of Pharmacology, School of Pharmacy , Kermanshah University of Medical Sciences , Kermanshah , Iran
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Prasanth MI, Sivamaruthi BS, Chaiyasut C, Tencomnao T. A Review of the Role of Green Tea ( Camellia sinensis) in Antiphotoaging, Stress Resistance, Neuroprotection, and Autophagy. Nutrients 2019; 11:nu11020474. [PMID: 30813433 PMCID: PMC6412948 DOI: 10.3390/nu11020474] [Citation(s) in RCA: 201] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 02/14/2019] [Accepted: 02/19/2019] [Indexed: 12/26/2022] Open
Abstract
Tea is one of the most widely consumed beverages worldwide, and is available in various forms. Green tea is richer in antioxidants compared to other forms of tea. Tea is composed of polyphenols, caffeine, minerals, and trace amounts of vitamins, amino acids, and carbohydrates. The composition of the tea varies depending on the fermentation process employed to produce it. The phytochemicals present in green tea are known to stimulate the central nervous system and maintain overall health in humans. Skin aging is a complex process mediated by intrinsic factors such as senescence, along with extrinsic damage induced by external factors such as chronic exposure to ultraviolet (UV) irradiation—A process known as photoaging—Which can lead to erythema, edema, sunburn, hyperplasia, premature aging, and the development of non-melanoma and melanoma skin cancers. UV can cause skin damage either directly, through absorption of energy by biomolecules, or indirectly, by increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Green tea phytochemicals are a potent source of exogenous antioxidant candidates that could nullify excess endogenous ROS and RNS inside the body, and thereby diminish the impact of photoaging. Several in vivo and in vitro studies suggest that green tea supplementation increases the collagen and elastin fiber content, and suppresses collagen degrading enzyme MMP-3 production in the skin, conferring an anti-wrinkle effect. The precise mechanism behind the anti-photoaging effect of green tea has not been explored yet. Studies using the worm model have suggested that green tea mediated lifespan extension depends on the DAF-16 pathway. Apart from this, green tea has been reported to have stress resistance and neuroprotective properties. Its ROS scavenging activity makes it a potent stress mediator, as it can also regulate the stress induced by metal ions. It is known that tea polyphenols can induce the expression of different antioxidant enzymes and hinder the DNA oxidative damage. Growing evidence suggests that green tea can also be used as a potential agent to mediate neurodegenerative diseases, including Alzheimer’s disease. EGCG, an abundant catechin in tea, was found to suppress the neurotoxicity induced by Aβ as it activates glycogen synthase kinase-3β (GSK-3β), along with inhibiting c-Abl/FE65—the cytoplasmic nonreceptor tyrosine kinase which is involved in the development of the nervous system and in nuclear translocation. Additionally, green tea polyphenols induce autophagy, thereby revitalizing the overall health of the organism consuming it. Green tea was able to activate autophagy in HL-60 xenographs by increasing the activity of PI3 kinase and BECLIN-1. This manuscript describes the reported anti-photoaging, stress resistance, and neuroprotective and autophagy properties of one of the most widely known functional foods—green tea.
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Affiliation(s)
- Mani Iyer Prasanth
- Age-Related Inflammation and Degeneration Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
| | - Bhagavathi Sundaram Sivamaruthi
- Innovation Center for Holistic Health, Nutraceuticals and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand.
| | - Chaiyavat Chaiyasut
- Innovation Center for Holistic Health, Nutraceuticals and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand.
| | - Tewin Tencomnao
- Age-Related Inflammation and Degeneration Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
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Abeywickrama CS, Bertman KA, Pang Y. A bright red-emitting flavonoid for Al3+ detection in live cells without quenching ICT fluorescence. Chem Commun (Camb) 2019; 55:7041-7044. [DOI: 10.1039/c9cc02322d] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
A bright red-emitting flavonoid derivative was synthesized, which exhibited a large Stokes shift (Δλ > 150 nm) and high fluorescence quantum yields (ϕfl = 0.10–0.35).
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Affiliation(s)
| | | | - Yi Pang
- Department of Chemistry
- University of Akron
- Akron
- USA
- Maurice Morton Institute of Polymer Science
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32
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Wang YQ, Lu JL, Liang YR, Li QS. Suppressive Effects of EGCG on Cervical Cancer. Molecules 2018; 23:E2334. [PMID: 30213130 PMCID: PMC6225117 DOI: 10.3390/molecules23092334] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 09/05/2018] [Accepted: 09/11/2018] [Indexed: 02/07/2023] Open
Abstract
Cervical cancer is the fourth most common gynecological cancer worldwide. Although prophylactic vaccination presents the most effective method for cervical cancer prevention, chemotherapy is still the primary invasive intervention. It is urgent to exploit low-toxic natural anticancer drugs on account of high cytotoxicity and side-effects of conventional agents. As a natural product, (-)-epigallocatechingallate (EGCG) has abilities in anti-proliferation, anti-metastasis and pro-apoptosis of cervical cancer cells. Moreover, EGCG also has pharmaceutical synergistic effects with conventional agents such as cisplatin (CDDP) and bleomycin (BLM). The underlying mechanisms of EGCG suppressive effects on cervical cancer are reviewed in this article. Further research directions and ambiguous results are also discussed.
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Affiliation(s)
- Ying-Qi Wang
- Tea Research Institute, Zhejiang University, # 866 Yuhangtang Road, Hangzhou 310058, China.
| | - Jian-Liang Lu
- Tea Research Institute, Zhejiang University, # 866 Yuhangtang Road, Hangzhou 310058, China.
| | - Yue-Rong Liang
- Tea Research Institute, Zhejiang University, # 866 Yuhangtang Road, Hangzhou 310058, China.
| | - Qing-Sheng Li
- Tea Research Institute, Zhejiang University, # 866 Yuhangtang Road, Hangzhou 310058, China.
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33
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Bertman KA, Abeywickrama CS, Baumann HJ, Alexander N, McDonald L, Shriver LP, Konopka M, Pang Y. A fluorescent flavonoid for lysosome detection in live cells under "wash free" conditions. J Mater Chem B 2018; 6:5050-5058. [PMID: 32254534 DOI: 10.1039/c8tb00325d] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Lysosomes are vital organelles in living cells, which have acidic environments (pH 4.0-5.0) where macrobiomolecules and malfunctioning organelles are broken down into monomers by hydrolase activity. The majority of the currently reported fluorescent probes for detecting lysosomes suffer from small Stokes shifts (Δλ < 20 nm) and higher cytotoxicity due to an "alkalinizing effect". An interesting flavonoid-based lysosome probe is synthesized by introducing a morpholine moiety onto the flavonoid skeleton. This new probe has shown excellent selectivity to detect lysosomes in MO3.13 oligodendrocytes and normal human lung fibroblast cell lines. Probes 1a and 1b have shown excellent fluorescence quantum yield (φfl up to 0.43 in non-aqueous solvents) and large Stokes shifts (120-150 nm). These new fluorescent probes also exhibit a large quantum yield difference from an aqueous to organic environment, making them potentially useful as "wash-free" stains for visualizing lysosomes. Cell viability evaluation of these probes shows excellent biocompatibility with the median lethal concentration being LC50 ≈ 50 μM.
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Knudsen ES, Hutcheson J, Vail P, Witkiewicz AK. Biological specificity of CDK4/6 inhibitors: dose response relationship, in vivo signaling, and composite response signature. Oncotarget 2018; 8:43678-43691. [PMID: 28620137 PMCID: PMC5546433 DOI: 10.18632/oncotarget.18435] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 05/31/2017] [Indexed: 12/27/2022] Open
Abstract
Recently developed potent and selective CDK4/6 inhibitors fall into two classes based on structure and toxicity profiles in clinical studies. One class, exemplified by palbociclib and ribociclib, exhibits neutropenia as a dose-limiting toxicity and requires discontinuous dosing. In contrast, the structurally distinct CDK4/6 inhibitor abemaciclib is dosed continuously, and has diarrhea and fatigue as dose-limiting toxicities. In preclinical models, palbociclib has been extensively studied and induces cell cycle inhibition in an RB-dependent manner. Thus far, abemaciclib has been less extensively evaluated. We found that abemaciclib cell cycle inhibitory activity is RB-dependent at clinically achievable concentrations. Abemaciclib elicited potent suppression of RB/E2F regulated genes associated with prognosis in ER-positive breast cancer. However, unlike palbociclib, at 250nM-1 µM doses abemaciclib induced cell death in RB-deficient cell lines. This response was associated with a rapidly-induced multi-vacuolar phenotype indicative of lysosomal membrane permeabilization that could be ameliorated with chloroquine. This event was not a reflection of inhibition of other CDK family members, but could be recapitulated with CBX4945 that inhibits casein and DYRK/HIPK kinases. To determine if these "off-target" features of abemaciclib were observed in vivo, mice harboring matched RB-positive and negative xenografts were treated with palbociclib and abemaciclib. In vivo, all of the apparent activity of abemaciclib was RB-dependent and strongly elicited suppression of cell cycle regulatory genes in a fashion markedly similar to palbociclib. Using gene expression data from cell lines and tumors treated with abemaciclib and palbociclib a composite signature of response to CDK4/6 inhibition was developed that included many genes that are individually required for tumor cell proliferation or viability. These data indicate that while abemaciclib and palbociclib can exert distinct biological and molecular effects, there are common gene expression features that could be broadly utilized in measuring the response to CDK4/6 inhibition.
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Affiliation(s)
- Erik S Knudsen
- University of Arizona Cancer Center, Tucson, AZ, USA.,Department of Medicine, University of Arizona, Tucson, AZ, USA
| | | | - Paris Vail
- University of Arizona Cancer Center, Tucson, AZ, USA.,Department of Medicine, University of Arizona, Tucson, AZ, USA
| | - Agnieszka K Witkiewicz
- University of Arizona Cancer Center, Tucson, AZ, USA.,Department of Pathology, University of Arizona, Tucson, AZ, USA
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Gallagher LE, Radhi OA, Abdullah MO, McCluskey AG, Boyd M, Chan EYW. Lysosomotropism depends on glucose: a chloroquine resistance mechanism. Cell Death Dis 2017; 8:e3014. [PMID: 28837152 PMCID: PMC5596595 DOI: 10.1038/cddis.2017.416] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 07/13/2017] [Accepted: 07/19/2017] [Indexed: 12/14/2022]
Abstract
There has been long-standing interest in targeting pro-survival autophagy as a combinational cancer therapeutic strategy. Clinical trials are in progress testing chloroquine (CQ) or its derivatives in combination with chemo- or radiotherapy for solid and haematological cancers. Although CQ has shown efficacy in preclinical models, its mechanism of action remains equivocal. Here, we tested how effectively CQ sensitises metastatic breast cancer cells to further stress conditions such as ionising irradiation, doxorubicin, PI3K-Akt inhibition and serum withdrawal. Contrary to the conventional model, the cytotoxic effects of CQ were found to be autophagy-independent, as genetic targeting of ATG7 or the ULK1/2 complex could not sensitise cells, like CQ, to serum depletion. Interestingly, although CQ combined with serum starvation was robustly cytotoxic, further glucose starvation under these conditions led to a full rescue of cell viability. Inhibition of hexokinase using 2-deoxyglucose (2DG) similarly led to CQ resistance. As this form of cell death did not resemble classical caspase-dependent apoptosis, we hypothesised that CQ-mediated cytotoxicity was primarily via a lysosome-dependent mechanism. Indeed, CQ treatment led to marked lysosomal swelling and recruitment of Galectin3 to sites of membrane damage. Strikingly, glucose starvation or 2DG prevented CQ from inducing lysosomal damage and subsequent cell death. Importantly, we found that the related compound, amodiaquine, was more potent than CQ for cell killing and not susceptible to interference from glucose starvation. Taken together, our data indicate that CQ effectively targets the lysosome to sensitise towards cell death but is prone to a glucose-dependent resistance mechanism, thus providing rationale for the related compound amodiaquine (currently used in humans) as a better therapeutic option for cancer.
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Affiliation(s)
- Laura E Gallagher
- Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland G4 0RE, UK
| | - Ohood A Radhi
- Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland G4 0RE, UK
| | - Mahmud O Abdullah
- Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland G4 0RE, UK
| | - Anthony G McCluskey
- Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland G4 0RE, UK
| | - Marie Boyd
- Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland G4 0RE, UK
| | - Edmond Y W Chan
- Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland G4 0RE, UK
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Yan XF, Zhao P, Ma DY, Jiang YL, Luo JJ, Liu L, Wang XL. Salvianolic acid B protects hepatocytes from H 2O 2 injury by stabilizing the lysosomal membrane. World J Gastroenterol 2017; 23:5333-5344. [PMID: 28839433 PMCID: PMC5550782 DOI: 10.3748/wjg.v23.i29.5333] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 03/27/2017] [Accepted: 05/09/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the capability of salvianolic acid B (Sal B) to protect hepatocytes from hydrogen peroxide (H2O2)/carbon tetrachloride (CCl4)-induced lysosomal membrane permeabilization. METHODS Cell Counting Kit-8 assay was used to measure cell viability. Apoptosis and death were assayed through flow cytometry. BrdU incorporation was used to detect cell proliferation. Serum alanine aminotransferase activity and liver malondialdehyde (MDA) content were measured. Liver histopathological changes were evaluated using hematoxylin-eosin staining. Lysosomal membrane permeability was detected with LysoTracker Green-labeled probes and acridine orange staining. The levels of protein carbonyl content (PCC), cathepsins (Cat)B/D, and lysosome-associated membrane protein 1 (LAMP1) were evaluated through western blotting. Cytosol CatB activity analysis was performed with chemiluminescence detection. The mRNA level of LAMP1 was evaluated through quantitative real-time polymerase chain reaction. RESULTS Results indicated that H2O2 induced cell injury/death. Sal B attenuated H2O2-induced cell apoptosis and death, restored the inhibition of proliferation, decreased the amount of PCC, and stabilized the lysosome membrane by increasing the LAMP1 protein level and antagonizing CatB/D leakage into the cytosol. CCl4 also triggered hepatocyte death. Furthermore, Sal B effectively rescued hepatocytes by increasing LAMP1 expression and by reducing lysosomal enzyme translocation to the cytosol. CONCLUSION Sal B protected mouse embryonic hepatocytes from H2O2/CCl4-induced injury/death by stabilizing the lysosomal membrane.
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37
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Galloylation of polyphenols alters their biological activity. Food Chem Toxicol 2017; 105:223-240. [DOI: 10.1016/j.fct.2017.04.021] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 03/23/2017] [Accepted: 04/15/2017] [Indexed: 01/08/2023]
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Gan RY, Li HB, Sui ZQ, Corke H. Absorption, metabolism, anti-cancer effect and molecular targets of epigallocatechin gallate (EGCG): An updated review. Crit Rev Food Sci Nutr 2017. [DOI: 10.1080/10408398.2016.1231168 pmid: 27645804] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2022]
Affiliation(s)
- Ren-You Gan
- Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China
- School of Biological Sciences, The University of Hong Kong, Hong Kong
| | - Hua-Bin Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Zhong-Quan Sui
- Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China
| | - Harold Corke
- Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China
- School of Biological Sciences, The University of Hong Kong, Hong Kong
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Gan RY, Li HB, Sui ZQ, Corke H. Absorption, metabolism, anti-cancer effect and molecular targets of epigallocatechin gallate (EGCG): An updated review. Crit Rev Food Sci Nutr 2017; 58:924-941. [PMID: 27645804 DOI: 10.1080/10408398.2016.1231168] [Citation(s) in RCA: 285] [Impact Index Per Article: 35.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Green tea is one of the most popular beverages in the world, especially in Asian countries. Consumption of green tea has been demonstrated to possess many health benefits, which mainly attributed to the main bioactive compound epigallocatechin gallate (EGCG), a flavone-3-ol polyphenol, in green tea. EGCG is mainly absorbed in the intestine, and gut microbiota play a critical role in its metabolism prior to absorption. EGCG exhibits versatile bioactivities, with its anti-cancer effect most attracting due to the cancer preventive effect of green tea consumption, and a great number of studies intensively investigated its anti-cancer effect. In this review, we therefore, first stated the absorption and metabolism process of EGCG, and then summarized its anti-cancer effect in vitro and in vivo, including its manifold anti-cancer actions and mechanisms, especially its anti-cancer stem cell effect, and next highlighted its various molecular targets involved in cancer inhibition. Finally, the anti-cancer effect of EGCG analogs and nanoparticles, as well as the potential cancer promoting effect of EGCG were also discussed. Understanding of the absorption, metabolism, anti-cancer effect and molecular targets of EGCG can be of importance to better utilize it as a chemopreventive and chemotherapeutic agent.
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Affiliation(s)
- Ren-You Gan
- a Department of Food Science and Engineering, School of Agriculture and Biology , Shanghai Jiao Tong University , Shanghai , China.,b School of Biological Sciences , The University of Hong Kong , Hong Kong
| | - Hua-Bin Li
- c Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition , School of Public Health, Sun Yat-Sen University , Guangzhou , China
| | - Zhong-Quan Sui
- a Department of Food Science and Engineering, School of Agriculture and Biology , Shanghai Jiao Tong University , Shanghai , China
| | - Harold Corke
- a Department of Food Science and Engineering, School of Agriculture and Biology , Shanghai Jiao Tong University , Shanghai , China.,b School of Biological Sciences , The University of Hong Kong , Hong Kong
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Xie J, Yun JP, Yang YN, Hua F, Zhang XW, Lin H, Lv XX, Li K, Zhang PC, Hu ZW. A novel ECG analog 4-(S)-(2,4,6-trimethylthiobenzyl)-epigallocatechin gallate selectively induces apoptosis of B16-F10 melanoma via activation of autophagy and ROS. Sci Rep 2017; 7:42194. [PMID: 28186123 PMCID: PMC5301500 DOI: 10.1038/srep42194] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 01/06/2017] [Indexed: 12/13/2022] Open
Abstract
Autophagy-induced cancer cell death has become a novel strategy for the development of cancer therapeutic drugs. Numerous studies have indicated that green tea polyphenols induce both autophagy and apoptosis in a variety of cancer cells. Here, we synthesized a series of green tea polyphenol analogues, among which JP8 was shown to potently activate autophagy. JP8 treatment had a stronger effect on apoptosis in B16-F10 melanoma cells than that in normal AML-12 hepatocytes. JP8 selectively resulted in reactive oxygen species (ROS) accumulation in B16-F10 cells, and this effect was associated with corresponding increases in key components of the ER stress-mediated apoptosis pathway. Pharmacological inhibition of ROS by N-acetyl-L-cysteine (NAC) attenuated JP8-induced autophagy and apoptosis, indicating an upstream role of ROS in JP8-induced autophagy. An in vivo study showed that JP8 had significant antitumor effects in a B16-F10 xenograft mouse model. Our results indicate that JP8 is a novel anticancer candidate with both autophagy and ROS induction activities.
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Affiliation(s)
- Jing Xie
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.,Department of Pharmacy, China-Japan Friendship Hospital, Beijing 100050, People's Republic of China
| | - Ju-Ping Yun
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Ya-Nan Yang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Fang Hua
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Xiao-Wei Zhang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Heng Lin
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Xiao-Xi Lv
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Ke Li
- Laboratory of Antiviral Research, Institute of Medicinal Biotechnology; Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Pei-Cheng Zhang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
| | - Zhuo-Wei Hu
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China
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41
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Guamán-Ortiz LM, Orellana MIR, Ratovitski EA. Natural Compounds As Modulators of Non-apoptotic Cell Death in Cancer Cells. Curr Genomics 2017; 18:132-155. [PMID: 28367073 PMCID: PMC5345338 DOI: 10.2174/1389202917666160803150639] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 11/24/2015] [Accepted: 11/28/2015] [Indexed: 02/07/2023] Open
Abstract
Cell death is an innate capability of cells to be removed from microenvironment, if and when they are damaged by multiple stresses. Cell death is often regulated by multiple molecular pathways and mechanism, including apoptosis, autophagy, and necroptosis. The molecular network underlying these processes is often intertwined and one pathway can dynamically shift to another one acquiring certain protein components, in particular upon treatment with various drugs. The strategy to treat human cancer ultimately relies on the ability of anticancer therapeutics to induce tumor-specific cell death, while leaving normal adjacent cells undamaged. However, tumor cells often develop the resistance to the drug-induced cell death, thus representing a great challenge for the anticancer approaches. Numerous compounds originated from the natural sources and biopharmaceutical industries are applied today in clinics showing advantageous results. However, some exhibit serious toxic side effects. Thus, novel effective therapeutic approaches in treating cancers are continued to be developed. Natural compounds with anticancer activity have gained a great interest among researchers and clinicians alike since they have shown more favorable safety and efficacy then the synthetic marketed drugs. Numerous studies in vitro and in vivo have found that several natural compounds display promising anticancer potentials. This review underlines certain information regarding the role of natural compounds from plants, microorganisms and sea life forms, which are able to induce non-apoptotic cell death in tumor cells, namely autophagy and necroptosis.
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Affiliation(s)
- Luis Miguel Guamán-Ortiz
- 1 Departamento de Ciencias de la Salud, Universidad Técnica Particular de Loja, Loja, Ecuador ; 2 Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maria Isabel Ramirez Orellana
- 1 Departamento de Ciencias de la Salud, Universidad Técnica Particular de Loja, Loja, Ecuador ; 2 Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Edward A Ratovitski
- 1 Departamento de Ciencias de la Salud, Universidad Técnica Particular de Loja, Loja, Ecuador ; 2 Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Zenkov NK, Chechushkov AV, Kozhin PM, Kandalintseva NV, Martinovich GG, Menshchikova EB. Plant Phenols and Autophagy. BIOCHEMISTRY (MOSCOW) 2017; 81:297-314. [PMID: 27293088 DOI: 10.1134/s0006297916040015] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Many plant phenols (stilbenes, curcumins, catechins, flavonoids, etc.) are effective antioxidants and protect cells during oxidative stress. Extensive clinical studies on the potential of phenolic compounds for treatment of cardiovascular, neurodegenerative, oncological, and inflammatory diseases are now being conducted. In addition to direct antioxidant effect, plant phenols may provide a protective effect via activation of the Keap1/Nrf2/ARE redox-sensitive signaling system and regulation of autophagy. In this review, mechanisms of effects of the most common plant phenols on autophagy are presented.
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Affiliation(s)
- N K Zenkov
- Research Institute of Experimental and Clinical Medicine, Novosibirsk, 630117, Russia.
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Epigallocatechin-3-gallate Sensitizes Human 786-O Renal Cell Carcinoma Cells to TRAIL-Induced Apoptosis. Cell Biochem Biophys 2016; 72:157-64. [PMID: 25539708 DOI: 10.1007/s12013-014-0428-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent. Epigallocatechin-3-gallate (EGCG) is a polyphenolic constituent of green tea. In this study, potentiating effect of EGCG on TRAIL-induced apoptosis human renal carcinoma cell line 786-O which is relatively resistant to TRAIL was examined, and the possible mechanism was investigated. Here, we show that co-treatment with EGCG and TRAIL induced significantly more profound apoptosis in 786-O cells. Treatment of 786-O cells with EGCG and TRAIL downregulated c-FLIP, Mcl-1, and Bcl-2 proteins in a caspase-dependent pathway. Moreover, we found that pretreatment with NAC markedly inhibited the expression levels of c-FLIP, Mcl-1, and Bcl-2 downregulated by the combinatory treatment, suggesting that the regulating effect of EGCG on these above apoptosis-relevant molecules was partially mediated by generation of ROS. Taken together, the present study demonstrates that EGCG sensitizes human 786-O renal cell carcinoma cells to TRAIL-induced apoptosis by downregulation of c-FLIP, Mcl-1, and Bcl-2.
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Gómez-Sintes R, Ledesma MD, Boya P. Lysosomal cell death mechanisms in aging. Ageing Res Rev 2016; 32:150-168. [PMID: 26947122 DOI: 10.1016/j.arr.2016.02.009] [Citation(s) in RCA: 140] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Revised: 02/22/2016] [Accepted: 02/29/2016] [Indexed: 12/14/2022]
Abstract
Lysosomes are degradative organelles essential for cell homeostasis that regulate a variety of processes, from calcium signaling and nutrient responses to autophagic degradation of intracellular components. Lysosomal cell death is mediated by the lethal effects of cathepsins, which are released into the cytoplasm following lysosomal damage. This process of lysosomal membrane permeabilization and cathepsin release is observed in several physiopathological conditions and plays a role in tissue remodeling, the immune response to intracellular pathogens and neurodegenerative diseases. Many evidences indicate that aging strongly influences lysosomal activity by altering the physical and chemical properties of these organelles, rendering them more sensitive to stress. In this review we focus on how aging alters lysosomal function and increases cell sensitivity to lysosomal membrane permeabilization and lysosomal cell death, both in physiological conditions and age-related pathologies.
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Affiliation(s)
- Raquel Gómez-Sintes
- Department of Cellular and Molecular Biology, Centro de Investigaciones Biologicas, CIB-CSIC, C/Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - María Dolores Ledesma
- Department of Molecular Neurobiology, Centro Biologia Molecular Severo Ochoa, CSIC-UAM, C/Nicolás Cabrera 1, 28049 Madrid, Spain
| | - Patricia Boya
- Department of Cellular and Molecular Biology, Centro de Investigaciones Biologicas, CIB-CSIC, C/Ramiro de Maeztu 9, 28040 Madrid, Spain.
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Kitagawa N, Morikawa T, Motai C, Ninomiya K, Okugawa S, Nishida A, Yoshikawa M, Muraoka O. The Antiproliferative Effect of Chakasaponins I and II, Floratheasaponin A, and Epigallocatechin 3-O-Gallate Isolated from Camellia sinensis on Human Digestive Tract Carcinoma Cell Lines. Int J Mol Sci 2016; 17:ijms17121979. [PMID: 27898032 PMCID: PMC5187779 DOI: 10.3390/ijms17121979] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 11/11/2016] [Accepted: 11/17/2016] [Indexed: 12/16/2022] Open
Abstract
Acylated oleanane-type triterpene saponins, namely chakasaponins I (1) and II (2), floratheasaponin A (3), and their analogs, together with catechins—including (–)-epigallocatechin 3-O-gallate (4), flavonoids, and caffeine—have been isolated as characteristic functional constituents from the extracts of “tea flower”, the flower buds of Camellia sinensis (Theaceae), which have common components with that of the leaf part. These isolates exhibited antiproliferative activities against human digestive tract carcinoma HSC-2, HSC-4, MKN-45, and Caco-2 cells. The antiproliferative activities of the saponins (1–3, IC50 = 4.4–14.1, 6.2–18.2, 4.5–17.3, and 19.3–40.6 µM, respectively) were more potent than those of catechins, flavonoids, and caffeine. To characterize the mechanisms of action of principal saponin constituents 1–3, a flow cytometric analysis using annexin-V/7-aminoactinomycin D (7-AAD) double staining in HSC-2 cells was performed. The percentage of apoptotic cells increased in a concentration-dependent manner. DNA fragmentation and caspase-3/7 activation were also detected after 48 h. These results suggested that antiproliferative activities of 1–3 induce apoptotic cell death via activation of caspase-3/7.
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Affiliation(s)
- Niichiro Kitagawa
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
- Koshiro Company Ltd., 2-5-8 Doshomachi, Chuo-ku, Osaka 541-0045, Japan.
| | - Toshio Morikawa
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
- Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
| | - Chiaki Motai
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
- Koshiro Company Ltd., 2-5-8 Doshomachi, Chuo-ku, Osaka 541-0045, Japan.
| | - Kiyofumi Ninomiya
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
- Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
| | - Shuhei Okugawa
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
- Koshiro Company Ltd., 2-5-8 Doshomachi, Chuo-ku, Osaka 541-0045, Japan.
| | - Ayaka Nishida
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
| | - Masayuki Yoshikawa
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
| | - Osamu Muraoka
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
- Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
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46
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Cornwall S, Cull G, Joske D, Ghassemifar R. Green tea polyphenol "epigallocatechin-3-gallate", differentially induces apoptosis in CLL B-and T-Cells but not in healthy B-and T-Cells in a dose dependant manner. Leuk Res 2016; 51:56-61. [PMID: 27855324 DOI: 10.1016/j.leukres.2016.10.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 10/24/2016] [Accepted: 10/31/2016] [Indexed: 01/18/2023]
Abstract
B-cell chronic lymphocytic leukaemia (CLL) is characterized by an accumulation of CD5-positive monoclonal B-cells due in large part to a failure of apoptosis. The ability to study CLL B-cells in vitro has always been a challenge and hampered by the low viability of the CLL B-cells in cell culture systems. In this study, we present a multicellular cell culture system to maintain CLL B-cells viable in culture for 60h in the presence of a stromal cell feeder layer in combination with a whole white blood cell preparation. Using this optimized system, we tested and showed that the addition of epigallocatechin-3-gallate (EGCG) at concentrations ranging from 25 to 100μg/ml induced apoptosis in CLL B-cells whilst not affecting healthy control B-cells. Moreover, the results showed that in contrast to healthy controls, T-cells from CLL patients underwent apoptosis in the presence of EGCG. This study demonstrated that the combination of a cell feeder layer with a whole white blood cell preparation maintained B-cell viability in vitro over an extended period of time. In addition, the study showed that EGCG differentially induces apoptosis in CLL B-and T-Cells but not in healthy B-and T-Cells in a dose dependent manner.
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Affiliation(s)
- Scott Cornwall
- Department of Haematology, PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Nedlands, Western Australia, Australia
| | - Gavin Cull
- Department of Haematology, PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Nedlands, Western Australia, Australia; Haematology Department, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia; School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Western Australia, Australia
| | - David Joske
- Department of Haematology, PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Nedlands, Western Australia, Australia; Haematology Department, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia; School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia, Australia
| | - Reza Ghassemifar
- Department of Haematology, PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Nedlands, Western Australia, Australia; School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Western Australia, Australia.
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Zhang Y, Xu YY, Sun WJ, Zhang MH, Zheng YF, Shen HM, Yang J, Zhu XQ. FBS or BSA Inhibits EGCG Induced Cell Death through Covalent Binding and the Reduction of Intracellular ROS Production. BIOMED RESEARCH INTERNATIONAL 2016; 2016:5013409. [PMID: 27830147 PMCID: PMC5088332 DOI: 10.1155/2016/5013409] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 08/05/2016] [Accepted: 08/24/2016] [Indexed: 02/04/2023]
Abstract
Previously we have shown that (-)-epigallocatechin gallate (EGCG) can induce nonapoptotic cell death in human hepatoma HepG2 cells only under serum-free condition. However, the underlying mechanism for serum in determining the cell fate remains to be answered. The effects of fetal bovine serum (FBS) and its major component bovine serum albumin (BSA) on EGCG-induced cell death were investigated in this study. It was found that BSA, just like FBS, can protect cells from EGCG-induced cell death in a dose-dependent manner. Detailed analysis revealed that both FBS and BSA inhibited generation of ROS to protect against toxicity of EGCG. Furthermore, EGCG was shown to bind to certain cellular proteins including caspase-3, PARP, and α-tubulin, but not LC3 nor β-actin, which formed EGCG-protein complexes that were inseparable by SDS-gel. On the other hand, addition of FBS or BSA to culture medium can block the binding of EGCG to these proteins. In silico docking analysis results suggested that BSA had a stronger affinity to EGCG than the other proteins. Taken together, these data indicated that the protective effect of FBS and BSA against EGCG-induced cell death could be due to (1) the decreased generation of ROS and (2) the competitive binding of BSA to EGCG.
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Affiliation(s)
- Yin Zhang
- Department of Toxicology, Zhejiang University School of Public Health, Hangzhou, Zhejiang 310058, China
| | - Yu-Ying Xu
- Department of Toxicology, Zhejiang University School of Public Health, Hangzhou, Zhejiang 310058, China
| | - Wen-Jie Sun
- Department of Toxicology, Zhejiang University School of Public Health, Hangzhou, Zhejiang 310058, China
| | - Mo-Han Zhang
- Department of Toxicology, Zhejiang University School of Public Health, Hangzhou, Zhejiang 310058, China
| | - Yi-Fan Zheng
- Department of Toxicology, Zhejiang University School of Public Health, Hangzhou, Zhejiang 310058, China
| | - Han-Ming Shen
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
| | - Jun Yang
- Department of Toxicology, School of Public Health, Hangzhou Normal University, 16 Xue Lin Street, Hangzhou, Zhejiang 310036, China
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, National Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Xin-Qiang Zhu
- Department of Toxicology, Zhejiang University School of Public Health, Hangzhou, Zhejiang 310058, China
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Streptococcus oralis Induces Lysosomal Impairment of Macrophages via Bacterial Hydrogen Peroxide. Infect Immun 2016; 84:2042-2050. [PMID: 27113357 DOI: 10.1128/iai.00134-16] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 04/19/2016] [Indexed: 12/19/2022] Open
Abstract
Streptococcus oralis, an oral commensal, belongs to the mitis group of streptococci and occasionally causes opportunistic infections, such as bacterial endocarditis and bacteremia. Recently, we found that the hydrogen peroxide (H2O2) produced by S. oralis is sufficient to kill human monocytes and epithelial cells, implying that streptococcal H2O2 is a cytotoxin. In the present study, we investigated whether streptococcal H2O2 impacts lysosomes, organelles of the intracellular digestive system, in relation to cell death. S. oralis infection induced the death of RAW 264 macrophages in an H2O2-dependent manner, which was exemplified by the fact that exogenous H2O2 also induced cell death. Infection with either a mutant lacking spxB, which encodes pyruvate oxidase responsible for H2O2 production, or Streptococcus mutans, which does not produce H2O2, showed less cytotoxicity. Visualization of lysosomes with LysoTracker revealed lysosome deacidification after infection with S. oralis or exposure to H2O2, which was corroborated by acridine orange staining. Similarly, fluorescent labeling of lysosome-associated membrane protein-1 gradually disappeared during infection with S. oralis or exposure to H2O2 The deacidification and the following induction of cell death were inhibited by chelating iron in lysosomes. Moreover, fluorescent staining of cathepsin B indicated lysosomal destruction. However, treatment of infected cells with a specific inhibitor of cathepsin B had negligible effects on cell death; instead, it suppressed the detachment of dead cells from the culture plates. These results suggest that streptococcal H2O2 induces cell death with lysosomal destruction and then the released lysosomal cathepsins contribute to the detachment of the dead cells.
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Chen JH, Lee MS, Wang CP, Hsu CC, Lin HH. Autophagic effects of Hibiscus sabdariffa leaf polyphenols and epicatechin gallate (ECG) against oxidized LDL-induced injury of human endothelial cells. Eur J Nutr 2016; 56:1963-1981. [PMID: 27318926 DOI: 10.1007/s00394-016-1239-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 05/25/2016] [Indexed: 02/07/2023]
Abstract
PURPOSE Oxidized low-density lipoprotein (ox-LDL) contributes to the pathogenesis of atherosclerosis by promoting vascular endothelial cell injury. Hibiscus sabdariffa leaf polyphenols (HLP), rich in flavonoids, have been shown to possess antioxidant and antiatherosclerotic activities. In this study, we examined the protective role of HLP and its main compound (-)-epicatechin gallate (ECG) in human umbilical vein endothelial cells (HUVECs) exposed to ox-LDL in vitro. METHODS In a model of ox-LDL-impaired HUVECs, assessments of cell viability, cytotoxicity, cell proliferation, apoptosis, and autophagy were detected. To highlight the mechanisms of the antiapoptotic effects of HLP and ECG, the expressions of molecular proteins were measured by Western blotting, real-time PCR, and so on. RESULTS HLP or ECG improved the survival of HUVECs from ox-LDL-induced viability loss. In addition, HLP or ECG showed potential in reducing ox-LDL-dependent apoptosis. Next, the ox-LDL-induced formation of acidic vesicular organelles and upregulation of the autophagy-related genes were increased by HLP or ECG. The HLP-triggered autophagic flux was further confirmed by increasing the LC3-II level under the pretreatment of an autophagy inhibitor chloroquine. Molecular data indicated the autophagic effect of HLP or ECG might be mediated via class III PI3K/Beclin-1 and PTEN/class I PI3K/Akt cascade signaling, as demonstrated by the usage of a class III PI3K inhibitor 3-methyladenine (3-MA) and a PTEN inhibitor SF1670. CONCLUSIONS Our data imply that ECG-enriched HLP upregulates the autophagic pathway, which in turn led to reduce ox-LDL-induced HUVECs injury and apoptosis and provide a new mechanism for its antiatherosclerotic activity.
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Affiliation(s)
- Jing-Hsien Chen
- Department of Nutrition, Chung Shan Medical University, Taichung City, Taiwan
| | - Ming-Shih Lee
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Road, Taichung City, 40201, Taiwan.,Clinical Laboratory, Chung Shan Medical University Hospital, Taichung City, Taiwan
| | - Chi-Ping Wang
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Road, Taichung City, 40201, Taiwan.,Clinical Laboratory, Chung Shan Medical University Hospital, Taichung City, Taiwan
| | - Cheng-Chin Hsu
- Department of Nutrition, Chung Shan Medical University, Taichung City, Taiwan
| | - Hui-Hsuan Lin
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Road, Taichung City, 40201, Taiwan. .,Clinical Laboratory, Chung Shan Medical University Hospital, Taichung City, Taiwan.
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58-F, a flavanone from Ophiopogon japonicus, prevents hepatocyte death by decreasing lysosomal membrane permeability. Sci Rep 2016; 6:27875. [PMID: 27306715 PMCID: PMC4910050 DOI: 10.1038/srep27875] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 05/26/2016] [Indexed: 12/13/2022] Open
Abstract
Lysosome membrane permeabilization (LMP) has been implicated in cell death. In the present study, we investigated the relationship between cell death and H2O2-/CCl4-induced LMP in hepatocytes in vitro and following acute liver injury in vivo. The key finding was that H2O2 triggered LMP by oxidative stress, as evidenced by a suppression of LAMP1 expression, a reduction in LysoTracker Green and AO staining, and the leakage of proton and cathepsin B/D from the lysosome to the cytoplasm, resulting in cell death. CCl4 also triggered hepatocyte death by decreasing lysosome LAMP1 expression and by inducing the accumulation of products of peroxidative lipids and oxidized proteins. Furthermore, a novel compound 5,8-dimethoxy-6-methyl-7-hydroxy-3-3(2-hydroxy-4-methoxybenzyl) chroman-4-one (58-F) was extracted from Ophiopogon japonicus and served as a potential therapeutic drug. In vivo and in vitro results showed that 58-F effectively rescued hepatocytes by decreasing LMP and by inducing lysosomal enzyme translocation to the cytosol.
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