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Sun R, Li Y, Feng Y, Shao X, Li R, Li H, Sun S, Wang J. PFN1 Knockdown Aggravates Mitophagy to Retard Lung Adenocarcinoma Initiation and M2 Macrophage Polarization. Mol Biotechnol 2024:10.1007/s12033-024-01228-0. [PMID: 39120820 DOI: 10.1007/s12033-024-01228-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 06/17/2024] [Indexed: 08/10/2024]
Abstract
Tumor-associated macrophages (TAM) are considered as crucial influencing factors of lung adenocarcinoma (LUAD) carcinogenesis and metastasis. Profilin 1 (PFN1) has been proposed as a potent driver of migration and drug resistance in LUAD. The focus of this work was to figure out the functional mechanism of PFN1 in macrophage polarization in LUAD. PFN1 expression and its significance in patients' survival were detected by ENCORI and Kaplan-Meier Plotter. RT-qPCR and western blotting examined PFN1 expression in LUAD cells. CCK-8 assay and colony formation assay detected cell proliferation. Flow cytometry detected cell apoptosis. Relevant assay kit tested caspase3 concentration. Western blotting analyzed the expression of proliferation- and apoptosis-related proteins. RT-qPCR and immunofluorescence staining measured M1 and M2 macrophages markers. Mitophagy was assessed by MitoTracker Red staining, immunofluorescence staining, and western blotting. PFN1 expression was increased in LUAD tissues and cells and correlated with the poor survival rate of LUAD patients. Deficiency of PFN1 hindered the proliferation, whereas facilitated the apoptosis of LUAD cells. Additionally, PFN1 interference impaired M2 macrophage polarization. Moreover, PFN1 knockdown exacerbated the mitophagy in LUAD cells and mitophagy inhibitor mitochondrial division inhibitor 1 (Mdivi-1) notably reversed the effects of PFN1 down-regulation on the proliferation, apoptosis as well as macrophage polarization in LUAD cells. To sum up, activation of mitophagy initiated by PFN1 depletion might obstruct the occurrence and M2 macrophage polarization in LUAD.
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Affiliation(s)
- Rongrong Sun
- Department of Oncology, Xuzhou Central Hospital, 199 Jiefang South Road, XuZhou, 221000, Jiangsu, China.
| | - Yang Li
- Department of Oncology, Xuzhou Central Hospital, 199 Jiefang South Road, XuZhou, 221000, Jiangsu, China
| | - Yu Feng
- Department of Oncology, Xuzhou Central Hospital, 199 Jiefang South Road, XuZhou, 221000, Jiangsu, China
| | - Xiaoyan Shao
- Department of Oncology, Xuzhou Central Hospital, 199 Jiefang South Road, XuZhou, 221000, Jiangsu, China
| | - Rantian Li
- Department of Oncology, Xuzhou Central Hospital, 199 Jiefang South Road, XuZhou, 221000, Jiangsu, China
| | - Hao Li
- Department of Oncology, Xuzhou Central Hospital, 199 Jiefang South Road, XuZhou, 221000, Jiangsu, China
| | - Sanyuan Sun
- Department of Oncology, Xuzhou Central Hospital, 199 Jiefang South Road, XuZhou, 221000, Jiangsu, China
| | - Jiangbo Wang
- Department of Oncology, Xuzhou Central Hospital, 199 Jiefang South Road, XuZhou, 221000, Jiangsu, China.
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Qin P, Li Q, Zu Q, Dong R, Qi Y. Natural products targeting autophagy and apoptosis in NSCLC: a novel therapeutic strategy. Front Oncol 2024; 14:1379698. [PMID: 38628670 PMCID: PMC11019012 DOI: 10.3389/fonc.2024.1379698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 03/18/2024] [Indexed: 04/19/2024] Open
Abstract
Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) being the predominant type. The roles of autophagy and apoptosis in NSCLC present a dual and intricate nature. Additionally, autophagy and apoptosis interconnect through diverse crosstalk molecules. Owing to their multitargeting nature, safety, and efficacy, natural products have emerged as principal sources for NSCLC therapeutic candidates. This review begins with an exploration of the mechanisms of autophagy and apoptosis, proceeds to examine the crosstalk molecules between these processes, and outlines their implications and interactions in NSCLC. Finally, the paper reviews natural products that have been intensively studied against NSCLC targeting autophagy and apoptosis, and summarizes in detail the four most retrieved representative drugs. This paper clarifies good therapeutic effects of natural products in NSCLC by targeting autophagy and apoptosis and aims to promote greater consideration by researchers of natural products as candidates for anti-NSCLC drug discovery.
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Affiliation(s)
- Peiyi Qin
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
- Shandong College of Traditional Chinese Medicine, Yantai, Shandong, China
| | - Qingchen Li
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Qi Zu
- Shandong College of Traditional Chinese Medicine, Yantai, Shandong, China
| | - Ruxue Dong
- Shandong College of Traditional Chinese Medicine, Yantai, Shandong, China
| | - Yuanfu Qi
- Department of Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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Dey R, Samadder A, Nandi S. Selected Phytochemicals to Combat Lungs Injury: Natural Care. Comb Chem High Throughput Screen 2022; 25:2398-2412. [PMID: 35293289 DOI: 10.2174/1386207325666220315113121] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/30/2021] [Accepted: 01/13/2022] [Indexed: 01/27/2023]
Abstract
The human has two lungs responsible for respiration and drug metabolism. Severe lung infection caused by bacteria, mycobacteria, viruses, fungi, and parasites may lead to lungs injury. Smoking and tobacco consumption may also produce lungs injury. Inflammatory and pain mediators are secreted by alveolar macrophages. The inflammatory mediators, such as cytokines, interleukin (IL)-1, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α, neutrophils, and fibroblasts are accumulated in the alveoli sac, which becomes infected. It may lead to hypoxia followed by severe pulmonary congestion and the death of the patient. There is an urgent need for the treatment of artificial respiration and ventilation. However, the situation may be the worst for patients suffering from lung cancer, pulmonary tuberculosis, and acute pneumonia caused by acute respiratory distress syndrome (ARDS). Re-urgency has been happening in the case of coronavirus disease of 2019 (COVID-19) patients. Therefore, it is needed to protect the lungs with the intake of natural phytomedicines. In the present review, several selected phyto components having the potential role in lung injury therapy have been discussed. Regular intake of natural vegetables and fruits bearing these constituents may save the lungs even in the dangerous attack of SARS-CoV-2 in lung cancer, pulmonary TB, and pneumatic patients.
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Affiliation(s)
- Rishita Dey
- Department of Zoology, Cytogenetics and Molecular Biology Lab., University of Kalyani, Kalyani, Nadia, 741235, India.,Department of Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research (Affiliated to Uttarakhand Technical University), Kashipur-244713, India
| | - Asmita Samadder
- Department of Zoology, Cytogenetics and Molecular Biology Lab., University of Kalyani, Kalyani, Nadia, 741235, India
| | - Sisir Nandi
- Department of Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research (Affiliated to Uttarakhand Technical University), Kashipur-244713, India
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Eroglu Z, Erdem C, Oktem G, Bozok Cetintas V, Duzgun Z. Effect of SIRT1 activators and inhibitors on CD44+/CD133+‑enriched non‑small cell lung cancer cells. Mol Med Rep 2020; 22:575-581. [PMID: 32377734 DOI: 10.3892/mmr.2020.11113] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 03/23/2020] [Indexed: 11/06/2022] Open
Abstract
Lung cancer is one of the most commonly diagnosed cancers and it is associated with high rates of morbidity and mortality. Metastasis and relapse of the tumor depend on the survival and proliferation of lung cancer stem cells (LCSCs). The ability to identify CSCs may prevent recurrence and lead to more effective treatments. Sirtuins are a group of deacetylases that include seven variants (SIRT1‑7), with sirtuin 1 (SIRT1) being the most intensively investigated. Evidence suggests that SIRT1 is both a tumor‑suppressor gene and an oncogene. SIRT1 can deacetylate the tumor‑suppressor protein p53 to decrease its activity. SIRT1 activators increase the deacetylation of p53, whereas SIRT1 inhibitors can stimulate p53 by inhibiting deacetylation. In the present study, CD44+ and CD133+‑enriched A549 (non‑small cell lung cancer) cells collected using the CD44 and CD133 CSC surface markers by fluorescence‑activated cell sorting method were treated with SIRT1 inhibitors (tenovin‑6 and sirtinol) and SIRT1 activators (resveratrol and SRT1720), and their effects on apoptosis, as well as the mRNA and protein expression of SIRT1 and p53 were investigated. Of these agents, it was found that resveratrol increased p53 expression by 4.1‑fold, decreased SIRT1 expression by 0.2‑fold, and it was the most potent inducer of apoptosis.
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Affiliation(s)
- Zuhal Eroglu
- Department of Medical Biology, Faculty of Medicine, Ege University, Bornova, Izmir 35100, Turkey
| | - Ceren Erdem
- Department of Medical Biology, Faculty of Medicine, Ege University, Bornova, Izmir 35100, Turkey
| | - Gulperi Oktem
- Department of Histology and Embryology, Faculty of Medicine, Ege University, Bornova, Izmir 35100, Turkey
| | - Vildan Bozok Cetintas
- Department of Medical Biology, Faculty of Medicine, Ege University, Bornova, Izmir 35100, Turkey
| | - Zekeriya Duzgun
- Department of Medical Biology, Faculty of Medicine, Giresun University, Debboy, Giresun 28100, Turkey
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A Potential Anti-cancer Compound Separated from the Chloroform Extract of the Chinese Medicine Formula Shenqi San. Curr Med Sci 2020; 40:138-144. [PMID: 32166676 DOI: 10.1007/s11596-020-2157-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 08/27/2019] [Indexed: 12/28/2022]
Abstract
This study examined anti-cancer compounds present in the chloroform extract of the Chinese medicine formula Shenqi San (CE-SS). Silica gel column chromatography, Sephadex LH-20, octadecylsilyl (ODS) column chromatography, and high performance liquid chromatography (HPLC) were used to separate the compounds from CE-SS. The structural formulas of the separated compounds were determined using 1D 1H and 13C experiments as well as high resolution electrospray ionization mass spectroscopy (HRESIMS). The corresponding results were compared with the reported literature data. A total of six compounds were separated and their structures were identified on the basis of corresponding spectroscopic and physico-chemical properties. They were Saikogenin F (I), Prosaikogenin D (II), Prosaikogenin F (III), β-sitosterol (IV), 3β,16β,23-trihydroxy-13,28-epoxyurs-11-ene-3-O-β-D-glucopyranoside (V), and methyl ursolic acid (VI). The separated compounds were evaluated in vitro for their inhibitory ability against the proliferation of A549 cells via MTT assay. Apoptosis was investigated using Annexin V-FITC/propidium iodide (PI) by flow cytometry. Apoptosis-associated proteins were examined by Western blotting. All the compounds were observed to have inhibitory activities against the proliferation of A549 cells to different degrees. Flow cytometry showed that compound V increased the proportion of apoptotic A549 cells in a dose-dependent manner. Western blotting showed that compound V increased the expression of Bax, cleaved-caspase-3, cleaved-caspase-9 and cleaved-poly ADP-ribose polymerase (PARP), and decreased the expression of Bcl-2. These results indicated that compound V featured a significant inhibitory effect on A549 cells when compared with other compounds, and it may be considered a potential drug against cancers.
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Molecular Insights into Potential Contributions of Natural Polyphenols to Lung Cancer Treatment. Cancers (Basel) 2019; 11:cancers11101565. [PMID: 31618955 PMCID: PMC6826534 DOI: 10.3390/cancers11101565] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/13/2019] [Accepted: 10/13/2019] [Indexed: 12/12/2022] Open
Abstract
Naturally occurring polyphenols are believed to have beneficial effects in the prevention and treatment of a myriad of disorders due to their anti-inflammatory, antioxidant, antineoplastic, cytotoxic, and immunomodulatory activities documented in a large body of literature. In the era of molecular medicine and targeted therapy, there is a growing interest in characterizing the molecular mechanisms by which polyphenol compounds interact with multiple protein targets and signaling pathways that regulate key cellular processes under both normal and pathological conditions. Numerous studies suggest that natural polyphenols have chemopreventive and/or chemotherapeutic properties against different types of cancer by acting through different molecular mechanisms. The present review summarizes recent preclinical studies on the applications of bioactive polyphenols in lung cancer therapy, with an emphasis on the molecular mechanisms that underlie the therapeutic effects of major polyphenols on lung cancer. We also discuss the potential of the polyphenol-based combination therapy as an attractive therapeutic strategy against lung cancer.
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Barbosa C, Santos-Pereira C, Soares I, Martins V, Terra-Matos J, Côrte-Real M, Lúcio M, Oliveira MECDR, Gerós H. Resveratrol-Loaded Lipid Nanocarriers Are Internalized By Endocytosis in Yeast. JOURNAL OF NATURAL PRODUCTS 2019; 82:1240-1249. [PMID: 30964667 DOI: 10.1021/acs.jnatprod.8b01003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Different positive pharmacological effects have been attributed to the natural product resveratrol (RSV), including antioxidant, antiaging, and cancer chemopreventive properties. However, its low bioavailability and rapid metabolic degradation has led to the suspicion that many of the biological activities of this compound observed in vitro may not be attainable in humans. To improve its bioavailability and pharmacokinetic profile, attempts have been made to encapsulate RSV into lipid-based nanocarrier systems. Here, the dioctadecyldimethylammonium bromide (DODAB):monoolein (MO) liposomal system (1:2) loaded with RSV revealed appropriate characteristics for drug release purposes: reduced size for cellular uptake (157 ± 23 nm), stability up to 80 days, positive surface charge (ζ ≈ +40 mV), and a controlled biphasic release of RSV from the lipid nanocarriers over a period of almost 50 h at pH 5.0 and 7.4. Moreover, the encapsulation efficiency of the nanocarrier ranged from 70% to 92% and its RSV loading capacity from 9% to 14%, when [RSV] was between 100 and 200 μM. The partition coefficient ( Kp) of RSV between lipid and aqueous phase was log Kp = 3.37 ± 0.10, suggesting moderate to high lipophilicity of this natural compound and reinforcing the lipid nanocarriers' suitability for RSV incorporation. The thermodynamic parameters of RSV partitioning in the lipid nanocarriers at 37 °C (Δ H = 43.76 ± 5.68 kJ mol-1; Δ S = 0.20 ± 0.005 kJ mol-1; and Δ G = -18.46 ± 3.48 kJ mol-1) reflected the spontaneity of the process and the establishment of hydrophobic interactions. The cellular uptake mechanism of the RSV-loaded nanocarriers labeled with the lipophilic fluorescent probe 1,6-diphenyl-1,3,5-hexatriene (DPH) was studied in the eukaryotic model system Saccharomyces cerevisiae. Thirty minutes after incubation, yeast cells readily internalized nanocarriers and the spots of blue fluorescence of DPH clustered around the central vacuole in lipid droplets colocalized with the green fluorescence of the lipophilic endocytosis probe FM1-43. Subsequent studies with the endocytosis defective yeast deletion mutant ( end3Δ) and with the endocytosis inhibitor methyl-β-cyclodextrin supported the involvement of an endocytic pathway. This novel nanotechnology approach opens good perspectives for medical applications.
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Affiliation(s)
- Célia Barbosa
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology , University of Minho , Campus of Gualtar , 4710-057 Braga , Portugal
| | - Cátia Santos-Pereira
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology , University of Minho , Campus of Gualtar , 4710-057 Braga , Portugal
- Centre of Biological Engineering (CEB), Department of Biological Engineering , University of Minho , Campus de Gualtar , 4710-057 Braga , Portugal
| | - Inês Soares
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology , University of Minho , Campus of Gualtar , 4710-057 Braga , Portugal
| | - Viviana Martins
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology , University of Minho , Campus of Gualtar , 4710-057 Braga , Portugal
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB) , University of Trás-os-Montes e Alto Douro , Quinta de Prados , 5000-801 Vila Real , Portugal
| | - Joana Terra-Matos
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology , University of Minho , Campus of Gualtar , 4710-057 Braga , Portugal
| | - Manuela Côrte-Real
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology , University of Minho , Campus of Gualtar , 4710-057 Braga , Portugal
| | - Marlene Lúcio
- Centre of Physics (CFUM), Department of Physics , University of Minho , Campus of Gualtar , 4710-057 Braga , Portugal
| | - M E C D Real Oliveira
- Centre of Physics (CFUM), Department of Physics , University of Minho , Campus of Gualtar , 4710-057 Braga , Portugal
| | - Hernâni Gerós
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology , University of Minho , Campus of Gualtar , 4710-057 Braga , Portugal
- Centre of Biological Engineering (CEB), Department of Biological Engineering , University of Minho , Campus de Gualtar , 4710-057 Braga , Portugal
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB) , University of Trás-os-Montes e Alto Douro , Quinta de Prados , 5000-801 Vila Real , Portugal
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Kim TH, Park JH, Woo JS. Resveratrol induces cell death through ROS‑dependent downregulation of Notch1/PTEN/Akt signaling in ovarian cancer cells. Mol Med Rep 2019; 19:3353-3360. [PMID: 30816513 DOI: 10.3892/mmr.2019.9962] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 02/12/2019] [Indexed: 11/06/2022] Open
Abstract
Resveratrol, a natural polyphenol compound, has been reported to exert anticancer activity in various cancer cells. The present study investigated the effect and underlying mechanisms of resveratrol in the human ovarian cancer cell lines, A2780 and SKOV3. Treatment with resveratrol induced apoptotic cell death in dose‑ and time‑dependent manners, as well as a transient increase of reactive oxygen species (ROS) generation. Resveratrol‑induced cell death was attenuated by the antioxidant, N‑acetylcysteine (NAC), suggesting that ROS were involved in the observed cell death. Treatment with resveratrol resulted in a ROS‑dependent decrease of Notch1 signaling. When cells were transfected to overexpress Notch1 using EF.hlCN1.CMV.GFP, resveratrol‑induced cell death was blocked. Western blot analysis demonstrated that resveratrol also upregulated phospho‑phosphatase and tensin homolog (p‑PTEN) and downregulated phospho‑Akt (p‑Akt). Overexpression of p‑Akt by transfection with a constitutively active form (caAkt), and the p‑PTEN inhibitor SF1670 prevented resveratrol‑induced cell death. The caspase‑3 inhibitor z‑DEVD‑FMK significantly attenuated the resveratrol‑induced caspase‑3 cleavage. Taken together, the results of the present study suggest that resveratrol induces caspase‑dependent cell death through suppression of Notch1 and PTEN/Akt signaling and it is mediated by increased ROS generation in human ovarian cancer cells.
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Affiliation(s)
- Thae Hyun Kim
- Department of Physiology, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Ji Hye Park
- Department of Physiology, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Jae Suk Woo
- Department of Physiology, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
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Hermawan A, Putri H. Current report of natural product development against breast cancer stem cells. Int J Biochem Cell Biol 2018; 104:114-132. [DOI: 10.1016/j.biocel.2018.09.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 09/18/2018] [Accepted: 09/19/2018] [Indexed: 02/08/2023]
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Elshaer M, Chen Y, Wang XJ, Tang X. Resveratrol: An overview of its anti-cancer mechanisms. Life Sci 2018; 207:340-349. [DOI: 10.1016/j.lfs.2018.06.028] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 06/21/2018] [Accepted: 06/25/2018] [Indexed: 02/07/2023]
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Rasheduzzaman M, Jeong JK, Park SY. Resveratrol sensitizes lung cancer cell to TRAIL by p53 independent and suppression of Akt/NF-κB signaling. Life Sci 2018; 208:208-220. [PMID: 30031063 DOI: 10.1016/j.lfs.2018.07.035] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 07/12/2018] [Accepted: 07/18/2018] [Indexed: 12/31/2022]
Abstract
AIMS TRAIL is a promising anticancer agent that has the potential to sensitize a wide variety of cancer or transformed cells by inducing apoptosis. However, resistance to TRAIL is a growing concern. Current manuscript aimed to employ combination treatment to investigate resveratrol induced TRAIL sensitization in NSCLC. METHOD A549 and HCC-15 cells were used in an experimental design. Cell viability was determined by morphological image, crystal violet staining and MTT assay. Apoptosis was evaluated by LDH assay, Annexin V and DAPI staining. Autophagy and apoptosis indicator protein were examined by western blotting. TEM and puncta assay was carried out to evaluate the autophagy. MTP and ROS activity was evaluated by JC-1 and H2DCFDA staining. FINDINGS Resveratrol is a polyphenolic compound capable of activation of tumor suppressor p53 and its pro-apoptotic modulator PUMA. Herein, we showed the p53-independent apoptosis by decrease the expression of phosphorylated Akt-mediated suppression of NF-κB that is also substantiated with the downregulation of anti-apoptotic factors Bcl-2 and Bcl-xl in NSCLC, resulting in an attenuation of TRAIL resistance in combined treatment. Furthermore, apoptosis was induced in TRAIL-resistant lung cancer cells with a co-treatment of resveratrol and TRAIL assessed by the loss of MMP, ROS generations which resulting the translocation of cytochrome c from the mitochondria into the cytosol due to mitochondrial dysfunction. Moreover, autophagy flux was not affected by resveratrol-induced TRAIL-mediated apoptosis in NSCLC. SIGNIFICANCE Overall, targeting the NF-κB (p65) pathway via resveratrol attenuates TRAIL resistance and induces TRAIL-mediated apoptosis which could be the effective TRAIL-based cancer therapy regimen.
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Affiliation(s)
- Mohammad Rasheduzzaman
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk 54596, South Korea
| | - Jae-Kyo Jeong
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk 54596, South Korea
| | - Sang-Youel Park
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk 54596, South Korea.
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Zhu XD, Lei XP, Dong WB. Resveratrol as a potential therapeutic drug for respiratory system diseases. DRUG DESIGN DEVELOPMENT AND THERAPY 2017; 11:3591-3598. [PMID: 29290681 PMCID: PMC5736354 DOI: 10.2147/dddt.s148868] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Respiratory system diseases are common and major ailments that seriously endanger human health. Resveratrol, a polyphenolic phytoalexin, is considered an anti-inflammatory, antioxidant, and anticancer agent. Thanks to its wide range of biological activities, resveratrol has become a hotspot in many fields, including respiratory system diseases. Indeed, research has demonstrated that resveratrol is helpful to relieve pulmonary function in the general population. Meanwhile, growing evidence indicates that resveratrol plays a protective role in respiratory system diseases. This review aimed to summarize the main protective effects of resveratrol in respiratory system diseases, including its anti-inflammatory, antiapoptotic, antioxidant, antifibrotic, antihypertensive, and anticancer activities. We found that resveratrol plays a protective role in the respiratory system through a variety of mechanisms, and so it may become a new drug for the treatment of respiratory system diseases.
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Affiliation(s)
- Xiao-Dan Zhu
- Department of Newborn Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Xiao-Ping Lei
- Department of Newborn Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Wen-Bin Dong
- Department of Newborn Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China
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Carlson A, Alderete KS, Grant MKO, Seelig DM, Sharkey LC, Zordoky BNM. Anticancer effects of resveratrol in canine hemangiosarcoma cell lines. Vet Comp Oncol 2017; 16:253-261. [PMID: 29235249 DOI: 10.1111/vco.12375] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 11/08/2017] [Accepted: 11/09/2017] [Indexed: 12/20/2022]
Abstract
Hemangiosarcoma (HSA) is a highly malignant tumour with aggressive biological behaviour. HSAs are more common in dogs than other domestic animals. The median survival time of dogs with HSA remains short, even with chemotherapy and surgery. Therefore, there is a critical need to improve the adjuvant chemotherapeutic regimens to improve clinical outcomes in dogs with HSA. Resveratrol has been shown to possess strong anti-proliferative and/or pro-apoptotic properties in human cancer cell lines. Nevertheless, the potential anticancer effects of resveratrol have not been reported in canine HSAs. The objective of this study is to determine the growth inhibitory effects of resveratrol in HSA cells when used alone or in combination with doxorubicin, a commonly used chemotherapeutic agent. Frog and DD-1 canine HSA cell lines were treated with varying concentrations of resveratrol with and without doxorubicin. Cell viability was measured by the MTT assay. The expression of apoptotic proteins, activation of p38 mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK) and extracellular signal-regulated kinase 1/2 (ERK1/2) were assessed by western blotting. Similar to human cancer cell lines, resveratrol markedly inhibited the growth and induced apoptosis in both HSA cell lines. Mechanistically, resveratrol activated p38 MAPK, but did not affect the AMPK or the ERK1/2 pathways. Additional experiments showed that resveratrol augmented the growth-inhibitory and apoptotic effects of doxorubicin in both HSA cell lines. These findings suggest that resveratrol has pro-apoptotic effects in canine HSA cells; therefore, its use as a potential adjunct therapy in canine HSA patients warrants further investigation.
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Affiliation(s)
- A Carlson
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota
| | - K S Alderete
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - M K O Grant
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - D M Seelig
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota
| | - L C Sharkey
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota
| | - B N M Zordoky
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
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Li S, Jiang Z, Xu W, Xie Y, Zhao L, Tang X, Wang F, Xin F. FIP-sch2, a new fungal immunomodulatory protein from Stachybotrys chlorohalonata, suppresses proliferation and migration in lung cancer cells. Appl Microbiol Biotechnol 2017; 101:3227-3235. [PMID: 28078399 DOI: 10.1007/s00253-016-8030-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 11/21/2016] [Accepted: 11/23/2016] [Indexed: 01/09/2023]
Abstract
Fungal immunomodulatory protein (FIP)-sch2, an immunomodulatory protein identified in the ascomycete Stachybotrys chlorohalonata by a sequence similarity search, is a novel member of the FIP family. FIP-sch2 shares high sequence identity, structure, and evolutionary conservation with previously reported FIPs. It was satisfactorily expressed in Escherichia coli with a glutathione S-transferase (GST) tag and purified by GST-affinity magnetic beads. To characterize the direct antitumor effects, human lung adenocarcinoma A549 cells were treated with different concentrations of recombinant FIP (rFIP)-sch2 in vitro, and the results showed that rFIP-sch2 could reduce cell viability dose-dependently with a half-maximal inhibitory concentration (IC50) of 9.48 μg/mL. Furthermore, rFIP-sch2 at 8 μg/mL could significantly induce apoptosis and interrupt migration in A549 cells. Notably, the antitumor effect of rFIP-sch2 was equivalent to that of rLZ-8 but was obviously increased compared to rFIP-fve. In addition, the exploration of the antitumor mechanism suggested that rFIP-sch2 induced lung cancer cell death by activating apoptosis and inhibiting migration. Our results indicated that rFIP-sch2 was a promising candidate for use in future cancer therapy.
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Affiliation(s)
- Shuying Li
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Zhonghao Jiang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Wenyi Xu
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Yingying Xie
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Leiming Zhao
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Xuanming Tang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Fengzhong Wang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
| | - Fengjiao Xin
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
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15
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Minami A, Ogino M, Nakano N, Ichimura M, Nakanishi A, Murai T, Kitagishi Y, Matsuda S. Roles of oncogenes and tumor-suppressor genes in osteoclastogenesis (Review). Int J Mol Med 2017; 39:261-267. [DOI: 10.3892/ijmm.2017.2847] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 12/28/2016] [Indexed: 11/06/2022] Open
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16
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Li S, Zhao L, Xu W, Jiang Z, Kang J, Wang F, Xin F. Identification and Characterisation of a Novel Protein FIP-sch3 from Stachybotrys chartarum. PLoS One 2016; 11:e0168436. [PMID: 27997578 PMCID: PMC5173029 DOI: 10.1371/journal.pone.0168436] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 12/01/2016] [Indexed: 11/19/2022] Open
Abstract
In this study, a novel FIP named FIP-sch3 has been identified and characterised. FIP-sch3 was identified in the ascomycete Stachybotrys chartarum, making it the second FIP to be identified outside the order of Basidiomycota. Recombinant FIP-sch3 (rFIP-shc3) was produced in Escherichia coli and purified using GST-affinity magnetic beads. The bioactive characteristics of FIP-sch3 were compared to those of well-known FIPs LZ-8 from Ganoderma lucidum and FIP-fve from Flammulina velutipes, which were produced and purified using the same method. The purified rFIP-sch3 exhibited a broad spectrum of anti-tumour activity in several types of tumour cells but had no cytotoxicity in normal human embryonic kidney 293 cells. Assays that were implemented to study these properties indicated that rFIP-sch3 significantly suppressed cell proliferation, induced apoptosis and inhibited cell migration in human lung adenocarcinoma A549 cells. The anti-tumour effects of rFIP-sch3 in A549 cells were comparable to those of rLZ-8, but they were significantly greater than those of rFIP-fve. Molecular assays that were built on real-time PCR further revealed potential mechanisms related to apoptosis and migration and that underlie phenotypic effects. These results indicate that FIP-shc3 has a unique anti-tumour bioactive profile, as do other FIPs, which provide a foundation for further studies on anti-tumour mechanisms. Importantly, this study also had convenient access to FIP-sch3 with potential human therapeutic applications.
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Affiliation(s)
- Shuying Li
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Leiming Zhao
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Wenyi Xu
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Zhonghao Jiang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Jun Kang
- School of Life Sciences, Tianjin University, Tianjin, China
| | - Fengzhong Wang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, China
- * E-mail: (FW); (FX)
| | - Fengjiao Xin
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, China
- * E-mail: (FW); (FX)
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17
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Wang Z, Gu Z, Shen Y, Wang Y, Li J, Lv H, Huo K. The Natural Product Resveratrol Inhibits Yeast Cell Separation by Extensively Modulating the Transcriptional Landscape and Reprogramming the Intracellular Metabolome. PLoS One 2016; 11:e0150156. [PMID: 26950930 PMCID: PMC4780762 DOI: 10.1371/journal.pone.0150156] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 02/10/2016] [Indexed: 12/28/2022] Open
Abstract
An increasing number of studies have shown that the promising compound resveratrol treats multiple diseases, such as cancer and aging; however, the resveratrol mode-of-action (MoA) remains largely unknown. Here, by virtue of multiple omics approaches, we adopted fission yeast as a model system with the goal of dissecting the common MoA of the anti-proliferative activity of resveratrol. We found that the anti-proliferative activity of resveratrol is mainly due to its unique role of inhibiting the separation of sister cells, similar phenotype with the C2H2 zinc finger transcription factor Ace2 knock-out strain. Microarray analysis shown that resveratrol has extensive impact on the fission yeast transcription levels. Among the changed gene's list, 40% of up-regulated genes are Core Environmental Stress Responses genes, and 57% of the down-regulated genes are periodically expressed. Moreover, resveratrol leverages the metabolome, which unbalances the intracellular pool sizes of several classes of amino acids, nucleosides, sugars and lipids, thus reflecting the remodulated metabolic networks. The complexity of the resveratrol MoA displayed in previous reports and our work demonstrates that multiple omics approaches must be applied together to obtain a complete picture of resveratrol's anti-proliferative function.
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Affiliation(s)
- Zhe Wang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, 2005 Song-Hu Road, Shanghai, 200438, China
- Division of Infectious Diseases, Weill Medical College of Cornell University, 413 E 69th St, New York, NY, 10021, United States of America
- * E-mail: (KH); (ZW); (HL)
| | - Zhongkai Gu
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, 2005 Song-Hu Road, Shanghai, 200438, China
- Institutes of Biomedical Sciences, Fudan University, 130 Dong-An Road, Shanghai, 200032, China
| | - Yan Shen
- Institutes of Biomedical Sciences, Fudan University, 130 Dong-An Road, Shanghai, 200032, China
| | - Yang Wang
- Institutes of Biomedical Sciences, Fudan University, 130 Dong-An Road, Shanghai, 200032, China
| | - Jing Li
- Department of Biological Sciences and Biotechnology, State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua University, Beijing, 100084, China
| | - Hong Lv
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, 2005 Song-Hu Road, Shanghai, 200438, China
- * E-mail: (KH); (ZW); (HL)
| | - Keke Huo
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, 2005 Song-Hu Road, Shanghai, 200438, China
- * E-mail: (KH); (ZW); (HL)
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