|
1
|
Hu D, Wang HJ, Yu LH, Guan ZR, Jiang YP, Hu JH, Yan YX, Zhou ZH, Lou JS. The role of Ginkgo Folium on antitumor: Bioactive constituents and the potential mechanism. JOURNAL OF ETHNOPHARMACOLOGY 2024; 321:117202. [PMID: 37742878 DOI: 10.1016/j.jep.2023.117202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/16/2023] [Accepted: 09/16/2023] [Indexed: 09/26/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ginkgo biloba L. is a well-known and highly regarded resource in Chinese traditional medicine due to its effectiveness and safety. Ginkgo Folium, the leaf of Ginkgo biloba L., contains biologically active constituents with diverse pharmacological activities. Recent studies have shown promising antitumor effects of the bioactive constituents found in Ginkgo Folium against various types of cancer cells, highlighting its potential as a natural source of antitumor agents. Further research is needed to elucidate the underlying mechanisms and optimize its therapeutic potential. AIM OF THE REVIEW To provide a detailed understanding of the pharmacological activities of Ginkgo Folium and its potential therapeutic benefits for cancer patients. MATERIALS AND METHODS In this study, we conducted a thorough and systematic search of multiple online databases, including PubMed, Web of Science, Medline, using relevant keywords such as "Ginkgo Folium," "flavonoids," "terpenoids," "Ginkgo Folium extracts," and "antitumor" to cover a broad range of studies that could inform our review. Additionally, we followed a rigorous selection process to ensure that the studies included in our review met the predetermined inclusion criteria. RESULTS The active constituents of Ginkgo Folium primarily consist of flavonoids and terpenoids, with quercetin, kaempferol, isorhamnetin, ginkgolides, and bilobalide being the major compounds. These active constituents exert their antitumor effects through crucial biological events such as apoptosis, cell cycle arrest, autophagy, and inhibition of invasion and metastasis via modulating diverse signaling pathways. During the process of apoptosis, active constituents primarily exert their effects by modulating the caspase-8 mediated death receptor pathway and caspase-9 mediated mitochondrial pathway via regulating specific signaling pathways. Furthermore, by modulating multiple signaling pathways, active constituents effectively induce G1, G0/G1, G2, and G2/M phase arrest. Among these, the pathways associated with G2/M phase arrest are particularly extensive, with the cyclin-dependent kinases (CDKs) being most involved. Moreover, active constituents primarily mediate autophagy by modulating certain inflammatory factors and stressors, facilitating the fusion stage between autophagosomes and lysosomes. Additionally, through the modulation of specific chemokines and matrix metalloproteinases, active constituents effectively inhibit the processes of epithelial-mesenchymal transition (EMT) and angiogenesis, exerting a significant impact on cellular invasion and migration. Synergistic effects are observed among the active constituents, particularly quercetin and kaempferol. CONCLUSION Active components derived from Ginkgo Folium demonstrate a comprehensive antitumor effect across various levels and pathways, presenting compelling evidence for their potential in new drug development. However, in order to facilitate their broad and adaptable clinical application, further extensive experimental investigations are required to thoroughly explore their efficacy, safety, and underlying mechanisms of action.
Collapse
Affiliation(s)
- Die Hu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Hao-Jie Wang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Li-Hua Yu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Zheng-Rong Guan
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Ya-Ping Jiang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Jun-Hu Hu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Ya-Xin Yan
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Zhao-Huang Zhou
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Jian-Shu Lou
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.
| |
Collapse
|
|
2
|
Owczarek M, Herczyńska L, Sitarek P, Kowalczyk T, Synowiec E, Śliwiński T, Krucińska I. Chitosan Nanoparticles-Preparation, Characterization and Their Combination with Ginkgo biloba Extract in Preliminary In Vitro Studies. Molecules 2023; 28:4950. [PMID: 37446611 DOI: 10.3390/molecules28134950] [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: 04/11/2023] [Revised: 06/16/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Nanoparticles (NPs), due to their size, have a key position in nanotechnology as a spectrum of solutions in medicine. NPs improve the ability of active substances to penetrate various routes: transdermal, but also digestive (active endocytosis), respiratory and injection. Chitosan, an N-deacetylated derivative of chitin, is a natural biodegradable cationic polymer with antioxidant, anti-inflammatory and antimicrobial properties. Cross-linked chitosan is an excellent matrix for the production of nanoparticles containing active substances, e.g., the Ginkgo biloba extract (GBE). Chitosan nanoparticles with the Ginkgo biloba extract (GBE) were obtained by ion gelation using TPP as a cross-linking agent. The obtained product was characterized in terms of morphology and size based on SEM and Zeta Sizer analyses as well as an effective encapsulation of GBE in nanoparticles-FTIR-ATR and UV-Vis analyses. The kinetics of release of the active substance in water and physiological saline were checked. Biological studies were carried out on normal and cancer cell lines to check the cytotoxic effect of GBE, chitosan nanoparticles and a combination of the chitosan nanoparticles with GBE. The obtained nanoparticles contained and released GBE encapsulated in research media. Pure NPs, GBE and a combination of NPs and the extract showed cytotoxicity against tumor cells, with no cytotoxicity against the physiological cell line.
Collapse
Affiliation(s)
- Monika Owczarek
- Łukasiewicz Research Network-Lodz Institute of Technology, Skłodowskiej-Curie 19/27, 90-570 Lodz, Poland
- Institute of Materials Science of Textiles and Polymer Composites, Faculty of Material Technologies and Textile Design, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland
| | - Lucyna Herczyńska
- Institute of Materials Science of Textiles and Polymer Composites, Faculty of Material Technologies and Textile Design, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland
| | - Przemysław Sitarek
- Department of Medical Biology, Medical University of Lodz, ul. Muszyńskiego 1, 90-151 Lodz, Poland
| | - Tomasz Kowalczyk
- Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
| | - Ewelina Synowiec
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
| | - Tomasz Śliwiński
- Department of Medical Biochemistry, Medical University of Lodz, 90-001 Lodz, Poland
| | - Izabella Krucińska
- Institute of Materials Science of Textiles and Polymer Composites, Faculty of Material Technologies and Textile Design, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland
| |
Collapse
|
|
3
|
Jiang W, Zhong S, Chen Z, Qian J, Huang X, Zhang H, Wen L, Zhang Y, Yao G. 2D-CuPd nanozyme overcome tamoxifen resistance in breast cancer by regulating the PI3K/AKT/mTOR pathway. Biomaterials 2023; 294:121986. [PMID: 36623325 DOI: 10.1016/j.biomaterials.2022.121986] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 11/28/2022] [Accepted: 12/23/2022] [Indexed: 01/01/2023]
Abstract
Tamoxifen is the most commonly used treatment for estrogen-receptor (ER) positive breast cancer patients, but its efficacy is severely hampered by resistance. PI3K/AKT/mTOR pathway inhibition was proven to augment the benefit of endocrine therapy and exhibited potential for reversing tamoxifen-induced resistance. However, the vast majority of PI3K inhibitors currently approved for clinical use are unsatisfactory in terms of safety and efficacy. We developed two-dimensional CuPd (2D-CuPd) nanosheets with oxidase and peroxidase nanozyme activities to offer a novel solution to inhibit the activity of the PI3K/AKT/mTOR pathway. 2D-CuPd exhibit superior dual nanozyme activities converting hydrogen peroxide accumulated in drug-resistant cells into more lethal hydroxyl radicals while compensating for the insufficient superoxide anion produced by tamoxifen. The potential clinical utility was further demonstrated in an orthotopically implanted tamoxifen-resistant PDX breast cancer model. Our results reveal a novel nanozyme ROS-mediated protein mechanism for the regulation of the PI3K subunit, illustrate the cellular pathways through which increased p85β protein expression contributes to tamoxifen resistance, and reveal p85β protein as a potential therapeutic target for overcoming tamoxifen resistance. 2D-CuPd is the first reported nanomaterial capable of degrading PI3K subunits, and its high performance combined with further materials engineering may lead to the development of nanozyme-based tumor catalytic therapy.
Collapse
Affiliation(s)
- Wenwei Jiang
- Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, P. R. China
| | - Suqin Zhong
- School of Medicine, School of Biomedical Sciences and Engineering, South China University of Technology, 510006, Guangzhou, P. R. China
| | - Ziying Chen
- School of Medicine, School of Biomedical Sciences and Engineering, South China University of Technology, 510006, Guangzhou, P. R. China
| | - Jieying Qian
- School of Medicine, School of Biomedical Sciences and Engineering, South China University of Technology, 510006, Guangzhou, P. R. China
| | - Xiaowan Huang
- School of Medicine, School of Biomedical Sciences and Engineering, South China University of Technology, 510006, Guangzhou, P. R. China
| | - Hao Zhang
- School of Medicine, School of Biomedical Sciences and Engineering, South China University of Technology, 510006, Guangzhou, P. R. China
| | - Longping Wen
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510080, Guangzhou, P. R. China.
| | - Yunjiao Zhang
- School of Medicine, School of Biomedical Sciences and Engineering, South China University of Technology, 510006, Guangzhou, P. R. China; National Engineering Research Center for Tissue Restoration and Reconstruction and Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, 510006, Guangzhou, P. R. China.
| | - Guangyu Yao
- Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, P. R. China.
| |
Collapse
|
|
4
|
Zhang S, Sun Y, Yao F, Li H, Yang Y, Li X, Bai Z, Hu Y, Wang P, Xu X. Ginkgo Biflavones Cause p53 Wild-Type Dependent Cell Death in a Transcription-Independent Manner of p53. JOURNAL OF NATURAL PRODUCTS 2023; 86:346-356. [PMID: 36700552 DOI: 10.1021/acs.jnatprod.2c00959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Ginkgo biloba, as a medicinal plant in both traditional and western medicine, emerged as a potential therapeutic agent for the management of a variety of diseases, but ginkgo biflavones (bilobetin, isoginkgetin, and ginkgetin) application in cancer therapy and underlying mechanisms of action remained elusive. In the present study, we identified ginkgo biflavones as potential p53 activators that could enhance p53 protein expression level by inhibiting MDM2 protein expression. At the same time, they induced cell death independent of p53 transcriptional activity. Moreover, ginkgetin was a standout among ginkgo biflavones that reduced the survival of HCT-116 cells by induction of apoptosis and G2/M phase arrest. Furthermore, ginkgo biflavones induced ROS generation significantly, which resulted in ferroptosis. Finally, we provide evidence that ginkgetin strengthened the antitumor effect of fluorouracil (5-FU) in the HCT-116 colon cancer xenograft model. To sum up, ginkgo biflavones represent a new class of p53 activator that depends on the p53 wild-type status and warrants further exploration as potential anticancer agents.
Collapse
Affiliation(s)
- Siyu Zhang
- Institute of Burns, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan 430060, P. R. China
- Center for Innovation Marine Drug Screening & Evaluation, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266071, P. R. China
- Marine Drug Screening and Evaluation Platform (QNLM), School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, P. R. China
| | - Yujie Sun
- Center for Innovation Marine Drug Screening & Evaluation, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266071, P. R. China
- Marine Drug Screening and Evaluation Platform (QNLM), School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, P. R. China
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, Shandong, P. R. China
| | - Fengli Yao
- Center for Innovation Marine Drug Screening & Evaluation, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266071, P. R. China
- Marine Drug Screening and Evaluation Platform (QNLM), School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, P. R. China
- College of Food Science and Engineering, Ocean University of China, Qingdao 266071, P. R. China
| | - Hongju Li
- Center for Innovation Marine Drug Screening & Evaluation, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266071, P. R. China
- Marine Drug Screening and Evaluation Platform (QNLM), School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, P. R. China
- College of Food Science and Engineering, Ocean University of China, Qingdao 266071, P. R. China
| | - Yacong Yang
- Center for Innovation Marine Drug Screening & Evaluation, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266071, P. R. China
- Marine Drug Screening and Evaluation Platform (QNLM), School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, P. R. China
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, Shandong, P. R. China
| | - Xionghao Li
- Center for Innovation Marine Drug Screening & Evaluation, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266071, P. R. China
- Marine Drug Screening and Evaluation Platform (QNLM), School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, P. R. China
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, Shandong, P. R. China
| | - Zhongyue Bai
- Center for Innovation Marine Drug Screening & Evaluation, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266071, P. R. China
- Marine Drug Screening and Evaluation Platform (QNLM), School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, P. R. China
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, Shandong, P. R. China
| | - Yu Hu
- Center for Innovation Marine Drug Screening & Evaluation, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266071, P. R. China
- Marine Drug Screening and Evaluation Platform (QNLM), School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, P. R. China
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, Shandong, P. R. China
| | - Peng Wang
- Center for Innovation Marine Drug Screening & Evaluation, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266071, P. R. China
- Marine Drug Screening and Evaluation Platform (QNLM), School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, P. R. China
- College of Food Science and Engineering, Ocean University of China, Qingdao 266071, P. R. China
| | - Ximing Xu
- Center for Innovation Marine Drug Screening & Evaluation, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266071, P. R. China
- Marine Drug Screening and Evaluation Platform (QNLM), School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, P. R. China
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, Shandong, P. R. China
| |
Collapse
|
|
5
|
Liu K, Fu X, Wang Z, Yang L, Yang J, Deng H. Integrating network pharmacology prediction and experimental investigation to verify ginkgetin anti-invasion and metastasis of human lung adenocarcinoma cells via the Akt/GSK-3β/Snail and Wnt/β-catenin pathway. Front Pharmacol 2023; 14:1135601. [PMID: 36937843 PMCID: PMC10018034 DOI: 10.3389/fphar.2023.1135601] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Accepted: 02/22/2023] [Indexed: 03/06/2023] Open
Abstract
Introduction: Lung cancer, one of the most frequent malignancies, has a high death rate and an increased number of new cases globally. Ginkgo biloba has been used for many years in the treatment of lung cancer. Ginkgetin is the key active ingredient extracted from Ginkgo biloba. However, the mechanism by which ginkgetin inhibits the invasive metastasis of lung cancer is unclear. Methods: We used a network pharmacology approach to obtain the molecular mechanism by which ginkgetin inhibits lung cancer metastasis. Then we analyzed potential target proteins between ginkgetin and lung cancer. Finally, we validated with molecular docking and experimental validation. Results: By analyzing the intersecting genes of lung cancer and ginkgetin, there were 79 intersecting genes, which were mainly involved in the positive regulation of cell migration, with the cancer pathway being one of the most enriched pathways. The results of in vitro experiments showed that GK had a large inhibitory effect on cell invasion and metastasis of A549 and H1299. In vivo animals GK had a great inhibitory effect on metastasis of LLC. Conclusion: This study identified the potential related GK molecular targets and signaling pathways in treating human lung cancer using network pharmacological approaches. Experiments confirmed that GK inhibits the Akt/GSK-3β/Snail and Wnt/β-catenin cascade initiation in A549, H1299 and LLC cells, preventing metastasis. This study's results align with the hypotheses derived from the network pharmacology analysis.
Collapse
Affiliation(s)
| | | | | | | | - Jia Yang
- *Correspondence: Jia Yang, ; Haibin Deng,
| | | |
Collapse
|
|
6
|
Role of Plant-Derived Active Constituents in Cancer Treatment and Their Mechanisms of Action. Cells 2022; 11:cells11081326. [PMID: 35456005 PMCID: PMC9031068 DOI: 10.3390/cells11081326] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 03/31/2022] [Accepted: 04/11/2022] [Indexed: 02/07/2023] Open
Abstract
Despite significant technological advancements in conventional therapies, cancer remains one of the main causes of death worldwide. Although substantial progress has been made in the control and treatment of cancer, several limitations still exist, and there is scope for further advancements. Several adverse effects are associated with modern chemotherapy that hinder cancer treatment and lead to other critical disorders. Since ancient times, plant-based medicines have been employed in clinical practice and have yielded good results with few side effects. The modern research system and advanced screening techniques for plants’ bioactive constituents have enabled phytochemical discovery for the prevention and treatment of challenging diseases such as cancer. Phytochemicals such as vincristine, vinblastine, paclitaxel, curcumin, colchicine, and lycopene have shown promising anticancer effects. Discovery of more plant-derived bioactive compounds should be encouraged via the exploitation of advanced and innovative research techniques, to prevent and treat advanced-stage cancers without causing significant adverse effects. This review highlights numerous plant-derived bioactive molecules that have shown potential as anticancer agents and their probable mechanisms of action and provides an overview of in vitro, in vivo and clinical trial studies on anticancer phytochemicals.
Collapse
|
|
7
|
Adnan M, Siddiqui AJ, Hamadou WS, Snoussi M, Badraoui R, Ashraf SA, Jamal A, Awadelkareem AM, Sachidanandan M, Hadi S, Khan MA, Patel M. Deciphering the Molecular Mechanism Responsible for Efficiently Inhibiting Metastasis of Human Non-Small Cell Lung and Colorectal Cancer Cells Targeting the Matrix Metalloproteinases by Selaginella repanda. PLANTS (BASEL, SWITZERLAND) 2021; 10:979. [PMID: 34068885 PMCID: PMC8156211 DOI: 10.3390/plants10050979] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 05/07/2021] [Accepted: 05/08/2021] [Indexed: 12/23/2022]
Abstract
Selaginella species are known to have antimicrobial, antioxidant, anti-inflammatory, anti-diabetic as well as anticancer effects. However, no study has examined the cytotoxic and anti-metastatic efficacy of Selaginella repanda (S. repanda) to date. Therefore, this study aimed to evaluate the potential anti-metastatic properties of ethanol crude extract of S. repanda in human non-small-cell lung (A-549) and colorectal cancer (HCT-116) cells with possible mechanisms. Effect of S. repanda crude extract on the growth, adhesion, migration and invasion of the A-549 and HCT-116 were investigated. We demonstrated that S. repanda crude extract inhibited cell growth of metastatic cells in a dose and time dependent manner. Incubation of A-549 and HCT-116 cells with 100-500 µg/mL of S. repanda crude extract significantly inhibited cell adhesion to gelatin coated surface. In the migration and invasion assay, S. repanda crude extract also significantly inhibited cellular migration and invasion in both A-549 and HCT-116 cells. Moreover, reverse transcription-polymerase chain reaction, and real-time PCR (RT-PCR) analysis revealed that the activity and mRNA level of matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-2 (MMP-2) and membrane type 1-matrix metalloproteinase (MT1-MMP) were inhibited. While the activity of tissue inhibitor matrix metalloproteinase 1 (TIMP-1); an inhibitor of MMPs was stimulated by S. repanda crude extract in a concentration-dependent manner. Therefore, the present study not only indicated the inhibition of motility and invasion of malignant cells by S. repanda, but also revealed that such effects were likely associated with the decrease in MMP-2/-9 expression of both A-549 and HCT-116 cells. This further suggests that S. repanda could be used as a potential source of anti-metastasis agent in pharmaceutical development for cancer therapy.
Collapse
Affiliation(s)
- Mohd Adnan
- Department of Biology, College of Science, University of Hail, Hail P.O. Box 2440, Saudi Arabia; (M.A.); (A.J.S.); (W.S.H.); (M.S.); (R.B.); (A.J.)
| | - Arif Jamal Siddiqui
- Department of Biology, College of Science, University of Hail, Hail P.O. Box 2440, Saudi Arabia; (M.A.); (A.J.S.); (W.S.H.); (M.S.); (R.B.); (A.J.)
| | - Walid Sabri Hamadou
- Department of Biology, College of Science, University of Hail, Hail P.O. Box 2440, Saudi Arabia; (M.A.); (A.J.S.); (W.S.H.); (M.S.); (R.B.); (A.J.)
| | - Mejdi Snoussi
- Department of Biology, College of Science, University of Hail, Hail P.O. Box 2440, Saudi Arabia; (M.A.); (A.J.S.); (W.S.H.); (M.S.); (R.B.); (A.J.)
| | - Riadh Badraoui
- Department of Biology, College of Science, University of Hail, Hail P.O. Box 2440, Saudi Arabia; (M.A.); (A.J.S.); (W.S.H.); (M.S.); (R.B.); (A.J.)
- Section of Histology-Cytology, Medicine Faculty of Tunis, University of Tunis El Manar, La Rabta-Tunis 1007, Tunisia
| | - Syed Amir Ashraf
- Department of Clinical Nutrition, College of Applied Medial Sciences, University of Hail, Hail P.O. Box 2440, Saudi Arabia; (S.A.A.); (A.M.A.)
| | - Arshad Jamal
- Department of Biology, College of Science, University of Hail, Hail P.O. Box 2440, Saudi Arabia; (M.A.); (A.J.S.); (W.S.H.); (M.S.); (R.B.); (A.J.)
| | - Amir Mahgoub Awadelkareem
- Department of Clinical Nutrition, College of Applied Medial Sciences, University of Hail, Hail P.O. Box 2440, Saudi Arabia; (S.A.A.); (A.M.A.)
| | - Manojkumar Sachidanandan
- Department of Oral Radiology, College of Dentistry, University of Hail, Hail P.O. Box 2440, Saudi Arabia;
| | - Sibte Hadi
- School of Forensic and Applied Sciences, University of Central Lancashire, Preston PR1 2HE, UK;
| | - Mushtaq Ahmad Khan
- Department of Microbiology and Immunology, College of Medicine and Health Sciences, UAE University, Al Ain 17666, United Arab Emirates
| | - Mitesh Patel
- Bapalal Vaidya Botanical Research Centre, Department of Biosciences, Veer Narmad South Gujarat University, Surat 394230, India
| |
Collapse
|
|
8
|
Adnan M, Rasul A, Hussain G, Shah MA, Zahoor MK, Anwar H, Sarfraz I, Riaz A, Manzoor M, Adem Ş, Selamoglu Z. Ginkgetin: A natural biflavone with versatile pharmacological activities. Food Chem Toxicol 2020; 145:111642. [PMID: 32783998 DOI: 10.1016/j.fct.2020.111642] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/12/2020] [Accepted: 07/18/2020] [Indexed: 12/13/2022]
Abstract
Natural products, being richly endowed with curative powers, have become spotlight for biomedical and pharmaceutical research to develop novel therapeutics during recent years. Ginkgetin (GK), a natural non-toxic biflavone, has been shown to exhibit anti-cancer, anti-inflammatory, anti-microbial, anti-adipogenic, and neuroprotective activities. GK combats cancer progression by arresting cell cycle, inducing apoptosis, stimulating autophagy, and targeting many deregulated signaling pathways such as JAK/STAT and MAPKs. GKhalts inflammation mediators like interleukins, iNOS, COX-2, PGE2, NF-κB, and acts as an inhibitor of PLA2. GK shows strong neuroprotection against oxidative stress-promoted cell death, inhibits cerebral micro-hemorrhage, decreases neurologic deficits, and halts apoptosis of neurons. GK also acts as anti-fungal, anti-viral, anti-bacterial, leishmanicidal and anti-plasmodial agent. GK shows substantial preventive or therapeutic effects in in vivo models of many diseases including atherosclerosis, cancer, neurodegenerative, hepatic, influenza, and inflammatory diseases. Based on various computational, in vitro and in vivo evidences, this article demonstrates the potential of ginkgetin for development of therapeutics against various diseases. Although GK has been systematically studied from pharmacological point of view, a vast field of pharmacokinetics, pre-clinical and clinical studies is still open for the researchers to fully validate its potential for the treatment of various diseases.
Collapse
Affiliation(s)
- Muhammad Adnan
- Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad, Pakistan
| | - Azhar Rasul
- Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad, Pakistan.
| | - Ghulam Hussain
- Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad, Pakistan
| | - Muhammad Ajmal Shah
- Department of Pharmacognosy, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan.
| | - Muhammad Kashif Zahoor
- Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad, Pakistan
| | - Haseeb Anwar
- Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad, Pakistan
| | - Iqra Sarfraz
- Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad, Pakistan
| | - Ammara Riaz
- Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad, Pakistan
| | - Maleeha Manzoor
- Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad, Pakistan
| | - Şevki Adem
- Department of Chemistry, Faculty of Sciences, Çankırı Karatekin University, Uluyazı Campus Çankırı, Turkey
| | - Zeliha Selamoglu
- Department of Medical Biology, Faculty of Medicine, Nigde Ömer Halisdemir University, Nigde Campus, 51240, Turkey
| |
Collapse
|
|
9
|
Ferrari C, Shivhare D, Hansen BO, Pasha A, Esteban E, Provart NJ, Kragler F, Fernie A, Tohge T, Mutwil M. Expression Atlas of Selaginella moellendorffii Provides Insights into the Evolution of Vasculature, Secondary Metabolism, and Roots. THE PLANT CELL 2020; 32:853-870. [PMID: 31988262 PMCID: PMC7145505 DOI: 10.1105/tpc.19.00780] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 01/08/2020] [Accepted: 01/14/2020] [Indexed: 05/20/2023]
Abstract
Selaginella moellendorffii is a representative of the lycophyte lineage that is studied to understand the evolution of land plant traits such as the vasculature, leaves, stems, roots, and secondary metabolism. However, only a few studies have investigated the expression and transcriptional coordination of Selaginella genes, precluding us from understanding the evolution of the transcriptional programs behind these traits. We present a gene expression atlas comprising all major organs, tissue types, and the diurnal gene expression profiles for S. moellendorffii We show that the transcriptional gene module responsible for the biosynthesis of lignocellulose evolved in the ancestor of vascular plants and pinpoint the duplication and subfunctionalization events that generated multiple gene modules involved in the biosynthesis of various cell wall types. We demonstrate how secondary metabolism is transcriptionally coordinated and integrated with other cellular pathways. Finally, we identify root-specific genes and show that the evolution of roots did not coincide with an increased appearance of gene families, suggesting that the development of new organs does not coincide with increased fixation of new gene functions. Our updated database at conekt.plant.tools represents a valuable resource for studying the evolution of genes, gene families, transcriptomes, and functional gene modules in the Archaeplastida kingdom.
Collapse
Affiliation(s)
- Camilla Ferrari
- Max Planck Institute of Molecular Plant Physiology, 14476 Potsdam, Germany
| | - Devendra Shivhare
- School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
| | - Bjoern Oest Hansen
- Max Planck Institute of Molecular Plant Physiology, 14476 Potsdam, Germany
| | - Asher Pasha
- Department of Cell and Systems Biology/Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Ontario M5S 3B2, Canada
| | - Eddi Esteban
- Department of Cell and Systems Biology/Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Ontario M5S 3B2, Canada
| | - Nicholas J Provart
- Department of Cell and Systems Biology/Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Ontario M5S 3B2, Canada
| | - Friedrich Kragler
- Max Planck Institute of Molecular Plant Physiology, 14476 Potsdam, Germany
| | - Alisdair Fernie
- Max Planck Institute of Molecular Plant Physiology, 14476 Potsdam, Germany
| | - Takayuki Tohge
- Max Planck Institute of Molecular Plant Physiology, 14476 Potsdam, Germany
- Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan
| | - Marek Mutwil
- Max Planck Institute of Molecular Plant Physiology, 14476 Potsdam, Germany
- School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
| |
Collapse
|
|
10
|
Silva AM, Silva SC, Soares JP, Martins-Gomes C, Teixeira JP, Leal F, Gaivão I. Ginkgo biloba L. Leaf Extract Protects HepG2 Cells Against Paraquat-Induced Oxidative DNA Damage. PLANTS 2019; 8:plants8120556. [PMID: 31795413 PMCID: PMC6963582 DOI: 10.3390/plants8120556] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/23/2019] [Accepted: 11/27/2019] [Indexed: 02/07/2023]
Abstract
Ginkgo biloba L. leaf extracts and herbal infusions are used worldwide due to the health benefits that are attributed to its use, including anti-neoplastic, anti-aging, neuro-protection, antioxidant and others. The aim of this study was to evaluate the effect of an aqueous Ginkgo biloba extract on HepG2 cell viability, genotoxicity and DNA protection against paraquat-induced oxidative damage. Exposure to paraquat (PQ), over 24 h incubation at 1.0 and 1.5 µM, did not significantly reduce cell viability but induced concentration and time-dependent oxidative DNA damage. Ginkgo biloba leaf extract produced dose-dependent cytotoxicity (IC50 = 540.8 ± 40.5 µg/mL at 24 h exposure), and short incubations (1 h) produced basal and oxidative DNA damage (>750 and 1500 µg/mL, respectively). However, lower concentrations (e.g., 75 µg/mL) of Ginkgo biloba leaf extract were not cytotoxic and reduced basal DNA damage, indicating a protective effect at incubations up to 4 h. On the other hand, longer incubations (24 h) induced oxidative DNA damage. Co-incubation of HepG2 cells for 4 h, with G. biloba leaf extract (75 µg/mL) and PQ (1.0 or 1.5 µM) significantly reduced PQ-induced oxidative DNA damage. In conclusion, the consumption of Ginkgo biloba leaf extract for long periods at high doses/concentrations is potentially toxic; however, low doses protect the cells against basal oxidative damage and against environmentally derived toxicants that induce oxidative DNA damage.
Collapse
Affiliation(s)
- Amélia M. Silva
- Department of Biology and Environment, University of Trás-os-Montes e Alto Douro (ECVA, UTAD), Quinta de Prados, 5001-801 Vila Real, Portugal; (S.C.S.); (C.M.-G.)
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences, (CITAB-UTAD), Quinta de Prados, 5001-801 Vila-Real, Portugal
- Correspondence: (A.M.S.); (I.G.); Tel.: +351-259350921 (A.M.S.); +351-259350734 (I.G.)
| | - Sandra C. Silva
- Department of Biology and Environment, University of Trás-os-Montes e Alto Douro (ECVA, UTAD), Quinta de Prados, 5001-801 Vila Real, Portugal; (S.C.S.); (C.M.-G.)
- Department of Genetic and Biotechnology, (ECVA, UTAD), Quinta de Prados, 5001-801 Vila-Real, Portugal;
| | - Jorge P. Soares
- Research Center in Sports, Health Sciences and Human Development, ECVA, UTAD, Quinta de Prados, 5001-801 Vila Real, Portugal
| | - Carlos Martins-Gomes
- Department of Biology and Environment, University of Trás-os-Montes e Alto Douro (ECVA, UTAD), Quinta de Prados, 5001-801 Vila Real, Portugal; (S.C.S.); (C.M.-G.)
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences, (CITAB-UTAD), Quinta de Prados, 5001-801 Vila-Real, Portugal
| | - João Paulo Teixeira
- National Health Institute Dr. Ricardo Jorge (INSA), Rua Alexandre Herculano 321, 4000-055 Porto, Portugal;
- EPIUnit—Instituto de Saúde Pública da Universidade do Porto, Rua das Taipas, 135, 4050-091 Porto, Portugal
| | - Fernanda Leal
- Department of Genetic and Biotechnology, (ECVA, UTAD), Quinta de Prados, 5001-801 Vila-Real, Portugal;
- BioISI—Biosystems & Integrative Sciences Institute, University of Trás-os-Montes and Alto Douro (BioISI-UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal
| | - Isabel Gaivão
- Department of Genetic and Biotechnology, (ECVA, UTAD), Quinta de Prados, 5001-801 Vila-Real, Portugal;
- The Veterinary and Animal Research Centre, (CECAV-UTAD), 5000-801 Vila Real, Portugal
- Correspondence: (A.M.S.); (I.G.); Tel.: +351-259350921 (A.M.S.); +351-259350734 (I.G.)
| |
Collapse
|
|
11
|
Hu WH, Chan GKL, Duan R, Wang HY, Kong XP, Dong TTX, Tsim KWK. Synergy of Ginkgetin and Resveratrol in Suppressing VEGF-Induced Angiogenesis: A Therapy in Treating Colorectal Cancer. Cancers (Basel) 2019; 11:cancers11121828. [PMID: 31757048 PMCID: PMC6966653 DOI: 10.3390/cancers11121828] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 10/18/2019] [Accepted: 10/21/2019] [Indexed: 12/22/2022] Open
Abstract
Ginkgetin, a biflavone from Ginkgo biloba leaf, and resveratrol, a polyphenol found in grape and wine, are two phytochemicals being identified for its binding to vascular endothelial growth factor (VEGF): the binding, therefore, resulted in the alteration of the physiological roles of VEGF-mediated angiogenesis. The bindings of ginkgetin and resveratrol were proposed on different sites of VEGF, but both of them suppressed the angiogenic properties of VEGF. The suppressive activities of ginkgetin and resveratrol in VEGF-mediated angiogenesis were supported by several lines of evidence including (i) inhibiting the formation of sub-intestinal vessel in zebrafish embryos and microvascular sprouting in rat aortic ring; and (ii) suppressing the phosphorylations of VEGFR2, Akt, eNOS, and Erk as well as expressions of matrix metalloproteinases (MMPs), MMP-2, and MMP-9 in human umbilical vein endothelial cells (HUVECs). Here, we showed the synergy of ginkgetin and resveratrol in suppressing the VEGF-induced endothelial cell proliferation, migration, invasion, and tube formation. The synergy of ginkgetin and resveratrol was further illustrated in HT-29 colon cancer xenograft nude mice. Ginkgetin and resveratrol, when applied together, exerted a synergistic anti-tumor effect of 5-fluorouracil with decreasing microvessel density of tumors. In parallel, the combination of ginkgetin and resveratrol synergistically relieved the 5-fluorouracil-induced inflammatory response by suppressing expressions of COX-2 and inflammatory cytokines. Thus, the anti-angiogenic roles of ginkgetin and/or resveratrol could provide effective therapeutic strategy in cancer, similar to that of Avastin, in suppressing the VEGF-mediated angiogenesis during cancer development.
Collapse
Affiliation(s)
- Wei-Hui Hu
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518057, China; (W.-H.H.); (G.K.-L.C.); (R.D.); (H.-Y.W.); (X.-P.K.); (T.T.-X.D.)
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong 999077, China
| | - Gallant Kar-Lun Chan
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518057, China; (W.-H.H.); (G.K.-L.C.); (R.D.); (H.-Y.W.); (X.-P.K.); (T.T.-X.D.)
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong 999077, China
| | - Ran Duan
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518057, China; (W.-H.H.); (G.K.-L.C.); (R.D.); (H.-Y.W.); (X.-P.K.); (T.T.-X.D.)
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong 999077, China
| | - Huai-You Wang
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518057, China; (W.-H.H.); (G.K.-L.C.); (R.D.); (H.-Y.W.); (X.-P.K.); (T.T.-X.D.)
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong 999077, China
| | - Xiang-Peng Kong
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518057, China; (W.-H.H.); (G.K.-L.C.); (R.D.); (H.-Y.W.); (X.-P.K.); (T.T.-X.D.)
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong 999077, China
| | - Tina Ting-Xia Dong
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518057, China; (W.-H.H.); (G.K.-L.C.); (R.D.); (H.-Y.W.); (X.-P.K.); (T.T.-X.D.)
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong 999077, China
| | - Karl Wah-Keung Tsim
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518057, China; (W.-H.H.); (G.K.-L.C.); (R.D.); (H.-Y.W.); (X.-P.K.); (T.T.-X.D.)
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong 999077, China
- Correspondence: ; Tel.: +852-2358-7332; Fax: +852-2358-1552
| |
Collapse
|
|
12
|
Yao W, Lin Z, Shi P, Chen B, Wang G, Huang J, Sui Y, Liu Q, Li S, Lin X, Liu Q, Yao H. Delicaflavone induces ROS-mediated apoptosis and inhibits PI3K/AKT/mTOR and Ras/MEK/Erk signaling pathways in colorectal cancer cells. Biochem Pharmacol 2019; 171:113680. [PMID: 31669234 DOI: 10.1016/j.bcp.2019.113680] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 10/13/2019] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors worldwide and tends to have drug resistance. Delicaflavone (DLF), a novel anticancer agent of biflavonoid from Selaginella doederleinii Hieron, showed strong anti-CRC activities, which has not yet been reported. In this study, we investigated the effects and possible anti-CRC mechanism of DLF in vitro and in vivo. It was shown that DLF significantly inhibited the cells viability and induced G2/M phase arrest, apoptosis, the loss of mitochondrial membrane potential (Δψm), generation of ROS and increase of intracellular Ca2+ in HT29 and HCT116 cells by MTT assay, TEM, flow cytometry and inverted fluorescence microscope. Western blot and qPCR assays results further confirmed DLF induced caspase-dependent apoptosis and inhibited PI3K/AKT/mTOR and Ras/MEK/Erk signaling pathways in CRC cells. Meanwhile, DLF significantly suppressed the tumor growth via activation of Caspase-9 and Caspase-3 protein and decrease of ki67 and CD34 protein without apparent side effects in vivo. In summary, these results indicated DLF induced ROS-mediated cell cycle arrest and apoptosis through ER stress and mitochondrial pathway accompanying with the inhibition of PI3K/AKT/mTOR and Ras/MEK/Erk signaling cascade. Thus DLF could be a potential therapeutic agent for CRC.
Collapse
Affiliation(s)
- Wensong Yao
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, China; College of Medical Sciences, Ningde Normal University, Ningde 352100, China
| | - Zhen Lin
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, China
| | - Peiying Shi
- Department of Traditional Chinese Medicine Resource and Bee Products, Bee Science College, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Bing Chen
- Nano Medical Technology Research Institute, Fujian Medical University, Fuzhou 350122, China
| | - Gang Wang
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, China
| | - Jianyong Huang
- Department of Pharmaceutics, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Yuxia Sui
- Department of Pharmacy, Provincial Clinical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China
| | - Qicai Liu
- Department of Reproductive Medicine Centre, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| | - Shaoguang Li
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, China.
| | - Xinhua Lin
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, China; Nano Medical Technology Research Institute, Fujian Medical University, Fuzhou 350122, China; Higher Educational Key Laboratory for Nano Biomedical Technology of Fujian Province, Fujian Medical University, Fuzhou 350122, China.
| | - Qicai Liu
- Nano Medical Technology Research Institute, Fujian Medical University, Fuzhou 350122, China
| | - Hong Yao
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, China; Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, Fujian Medical University, Fuzhou 350122, China.
| |
Collapse
|
|
13
|
Wang HY, Zhang YQ. The main active constituents and detoxification process of Ginkgo biloba seeds and their potential use in functional health foods. J Food Compost Anal 2019. [DOI: 10.1016/j.jfca.2019.103247] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
|
|
14
|
Qiao Y, Liu X, Li X, Wang X, Li C, Khutsishvili M, Alizade V, Atha D, Zhang Y, Borris RP. Biflavonoids from Juniperus oblonga inhibit organic anion transporter 3. Biochem Biophys Res Commun 2019; 509:931-936. [PMID: 30648554 DOI: 10.1016/j.bbrc.2019.01.039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Accepted: 01/08/2019] [Indexed: 01/04/2023]
Abstract
Organic anion transporters (OATs in humans, Oats in rodents) play an important role in the distribution and excretion of numerous endogenous metabolic products and exogenous organic anions, including a host of widely prescribed drugs. Their ligand recognition is also important for drug therapy and development. In this study, the n-butanol and dichloromethane soluble fractions of Juniperus oblonga were found to inhibit OAT3 in vitro and three biflavonoids were found to be responsible for this activity. One of these compounds, amentoflavone exhibited stronger inhibition than probenecid, a known strong inhibitor of OAT3. Biological characterization of amentoflavone in vivo also showed inhibition of Oat3. Preliminary observations of structure-activity relationships suggest that the biflavonoids are more potent inhibitors of this transporter than their corresponding monomer, and that methylation of even a single hydroxyl group results in a substantial decrease in activity. This greater potency of the biflavonoids may indicate the need for a more in-depth investigation of the distribution of biflavonoids in plants used as foodstuffs and herbal medicines, due to their potential for causing interactions with OAT3 substrate drugs.
Collapse
Affiliation(s)
- Yilin Qiao
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 30072, China
| | - Xueling Liu
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 30072, China
| | - Xue Li
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 30072, China
| | - Xue Wang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 30072, China
| | - Caiyu Li
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 30072, China
| | - Manana Khutsishvili
- National Herbarium of Georgia, Ilia State University, Tbilisi, 100995, Georgia
| | - Valida Alizade
- Institute of Botany, Azerbaijan National Academy of Sciences, Baku, AZ, 1102, Azerbaijan
| | - Daniel Atha
- New York Botanical Garden, Bronx, 10041, NY, USA
| | - Youcai Zhang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 30072, China
| | - Robert P Borris
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 30072, China.
| |
Collapse
|
|
15
|
Pan LL, Wu WJ, Zheng GF, Han XY, He JS, Cai Z. Ginkgetin inhibits proliferation of human leukemia cells via the TNF-α signaling pathway. ACTA ACUST UNITED AC 2018; 72:441-447. [PMID: 28902633 DOI: 10.1515/znc-2016-0210] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 07/27/2017] [Indexed: 01/14/2023]
Abstract
Ginkgetin is known to be an anticancer agent in many studies. However, its effectiveness in treating chronic myeloid leukemia [corrected] remains unknown. The present study aimed to evaluate the effects of ginkgetin on the growth of the K562 cell line. The MTT assay was employed to examine the proliferation of K562, and a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining was conducted to detect the apoptotic rates. Furthermore, changes of tumor necrosis factor-α (TNF-α) were detected by Western blot analysis. Ginkgetin inhibited the proliferation of K562 cells in a dose- and time-dependent manner. Concentrations of ginkgetin required to induce 50% death of K562 at 24, 48 and 72 h were 38.9, 31.3 and 19.2 μM, respectively. Moreover, treatment of ginkgetin increased K562 apoptosis in vitro along with increased levels of TNF-α. Interestingly, anti-TNF-α antibody prevented ginkgetin-induced K562 cell apoptosis and growth inhibition via deactivation of caspase-8, caspase-9 and caspase-3. Concomitantly, downregulation of TNF-α by etanercept in vivo attenuated ginkgetin-induced inhibitory effects on the tumor growth in an xenograft mouse model. Our results indicate that ginkgetin effectively inhibits K562 cell proliferation, and TNF-α plays a key role in ginkgetin-induced cell apoptosis.
Collapse
|
|
16
|
Baskaran XR, Geo Vigila AV, Zhang SZ, Feng SX, Liao WB. A review of the use of pteridophytes for treating human ailments. J Zhejiang Univ Sci B 2018; 19:85-119. [PMID: 29405039 PMCID: PMC5833325 DOI: 10.1631/jzus.b1600344] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 03/05/2017] [Indexed: 01/29/2023]
Abstract
The aim of this review was to explore the pharmacological activity of early tracheophytes (pteridophytes) as an alternative medicine for treating human ailments. As the first vascular plants, pteridophytes (aka, ferns and fern allies) are an ancient lineage, and human beings have been exploring and using taxa from this lineage for over 2000 years because of their beneficial properties. We have documented the medicinal uses of pteridophytes belonging to thirty different families. The lycophyte Selaginella sp. was shown in earlier studies to have multiple pharmacological activity, such as antioxidant, anti-inflammatory, anti-cancer, antidiabetic, antiviral, antimicrobial, and anti-Alzheimer properties. Among all the pteridophytes examined, taxa from the Pteridaceae, Polypodiaceae, and Adiantaceae exhibited significant medicinal activity. Based on our review, many pteridophytes have properties that could be used in alternative medicine for treatment of various human illnesses. Biotechnological tools can be used to preserve and even improve their bioactive molecules for the preparation of medicines against illness. Even though several studies have reported medicinal uses of ferns, the possible bioactive compounds of several pteridophytes have not been identified. Furthermore, their optimal dosage level and treatment strategies still need to be determined. Finally, the future direction of pteridophyte research is discussed.
Collapse
Affiliation(s)
- Xavier-ravi Baskaran
- State Key Laboratory of Biocontrol and Guangdong Key Laboratory of Plant Resources, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
- Shenzhen Key Laboratory of Southern Subtropical Plant Diversity, Fairy Lake Botanical Garden /Chinese Academy of Sciences, Shenzhen 518004, China
| | | | - Shou-zhou Zhang
- Shenzhen Key Laboratory of Southern Subtropical Plant Diversity, Fairy Lake Botanical Garden /Chinese Academy of Sciences, Shenzhen 518004, China
| | - Shi-xiu Feng
- Shenzhen Key Laboratory of Southern Subtropical Plant Diversity, Fairy Lake Botanical Garden /Chinese Academy of Sciences, Shenzhen 518004, China
| | - Wen-bo Liao
- State Key Laboratory of Biocontrol and Guangdong Key Laboratory of Plant Resources, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
| |
Collapse
|
|
17
|
Liu T, Zhang J, Chai Z, Wang G, Cui N, Zhou B. Ginkgo biloba extract EGb 761-induced upregulation of LincRNA-p21 inhibits colorectal cancer metastasis by associating with EZH2. Oncotarget 2017; 8:91614-91627. [PMID: 29207671 PMCID: PMC5710951 DOI: 10.18632/oncotarget.21345] [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: 06/28/2017] [Accepted: 07/26/2017] [Indexed: 12/31/2022] Open
Abstract
EGb 761, the standard ginkgo biloba extract, is frequently prescribed in traditional Chinese medicine. Currently, there is no research focusing on its role in human colorectal cancer progression. In our study, we determined the anti-metastatic effect of EGb 761 on colorectal cancer cells and further explored the potential underlying regulatory mechanism. The cell migration and invasion assay indicated that EGb 761 treatment of colorectal cancer cells induced inhibition of cell migration and invasion ability in a concentration-dependent manner. To further explore the underlying regulatory mechanisms that may account for these findings, we performed quantitative real-time PCR (RT-qPCR), western blotting and immunoprecipitation analysis. The results showed that EGb 761 induced upregulation of LincRNA-p21 expression in a dose- and time-dependent manner. Overexpression of LincRNA-p21 also suppressed colorectal cancer cell metastasis. Furthermore, EGb 761 as well as LincRNA-p21 inhibited the expression of extracellular matrix protein, fibronectin. More importantly, RNA immunoprecipitation (RIP) and Chromatin immunoprecipitation (ChIP) assays showed that LincRNA-p21 directly interacted with EZH2, and this interaction suppressed the expression of fibronectin. Finally, the gain and loss function assay revealed that EGb 761 inhibited migration, invasion and fibronctin expression by the LincRNA-p21/EZH2 pathway in colorectal cancer cells. Hence, EGb 761 may be a promising treatment regimen for colorectal cancer and restoration of LincRNA-p21 levels may be helpful for enhancing the anti-cancer effect of EGb 761.
Collapse
Affiliation(s)
- Tingting Liu
- Department of Integrated Chinese and Western Medicine Surgery, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Department of Anorectal Surgery, Tianjin Binhai New Area Traditional Chinese Medicine Hospital, Tianjin, China
| | - Junzhong Zhang
- Department of Anorectal Surgery, Tianjin Binhai New Area Traditional Chinese Medicine Hospital, Tianjin, China
| | - Zhongqiu Chai
- Department of Science and Education, Tianjin Binhai New Area Traditional Chinese Medicine Hospital, Tianjin, China
| | - Gang Wang
- Department of Oncology, Ruijin Hospital of Shanghai Jiaotong University, Shanghai, China
| | - Naiqiang Cui
- Department of Integrated Chinese and Western Medicine Surgery, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Bing Zhou
- Department of Integrated Chinese and Western Medicine Surgery, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| |
Collapse
|
|
18
|
Cao J, Tong C, Liu Y, Wang J, Ni X, Xiong MM. Ginkgetin inhibits growth of breast carcinoma via regulating MAPKs pathway. Biomed Pharmacother 2017; 96:450-458. [PMID: 29031204 DOI: 10.1016/j.biopha.2017.09.077] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 09/09/2017] [Accepted: 09/18/2017] [Indexed: 02/07/2023] Open
Abstract
The purpose of present study was to investigate anti-tumor activity of Ginkgetin (GK) and its mechanism of action in breast cancer. The effects of GK on growth of human breast cancer cell lines MDA-MB-231, BT-474 and MCF-7 were examined by MTT assay. Cells apoptosis in MCF-7 cells were analyzed by TUNEL staining and annexin-V and propidium iodide double staining. The effects of GK on expression of apoptotic associated proteins and mitogen-activated protein kinases (MAPKs) were determined by western blotting. The results showed that GK significantly inhibited proliferation of MDA-MB-231, BT-474 and MCF-7 cells in vitro with time and dose dependent manners and induced apoptosis in MCF-7 cells. GK treatment obviously induced the tumor cells apoptosis and inhibited tumor growth in the MCF-7 xenograft nude mice. GK increased expression of Bax, cleaved-caspase-3, cleaved-caspase-8, cleaved-caspase-9, cleaved-PARP, and decreased the levels of Bcl-2 and survivin in MCF-7 cells. Moreover, GK treatment up-regulated expression of phospho extracellular-related kinase (p-ERK), p-p38 and phospho Jun-amino-terminal kinase (p-JNK) in MCF-7 cells in vitro, and increased numbers of p-p38, p-JNK and p-ERK positive cells in the tumor tissue in vivo. Strikingly, treatment of p38 inhibitor (or JNK inhibitor; ERK inhibitor) significantly prevented GK induced growth inhibition and apoptosis in MCF-7 cells. Collectively, our data exhibit GK exerts well anticancer effects in breast cancer cells, which at least in part, is via activation of the MAPKs. Our results provide a new approach for the treatment of breast cancer.
Collapse
Affiliation(s)
- Jun Cao
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Department of General Surgery, The Third Affiliated Hospital of Anhui Medical University, Hefei 230032,China
| | - Chuang Tong
- Department of General Surgery, The Third Affiliated Hospital of Anhui Medical University, Hefei 230032,China
| | - Yanyan Liu
- Department of General Surgery, The Third Affiliated Hospital of Anhui Medical University, Hefei 230032,China
| | - Jianguo Wang
- Department of General Surgery, The Third Affiliated Hospital of Anhui Medical University, Hefei 230032,China
| | - Xiaoyan Ni
- Anke Biotechnology Co. LTD, Hefei 230088, China
| | - Mao-Ming Xiong
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
| |
Collapse
|
|
19
|
Park Y, Woo SH, Seo SK, Kim H, Noh WC, Lee JK, Kwon BM, Min KN, Choe TB, Park IC. Ginkgetin induces cell death in breast cancer cells via downregulation of the estrogen receptor. Oncol Lett 2017; 14:5027-5033. [PMID: 29085516 DOI: 10.3892/ol.2017.6742] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 06/15/2017] [Indexed: 01/08/2023] Open
Abstract
Ginkgetin is a natural biflavonoid isolated from the leaves of Ginkgo biloba, and is characterized by its anti-inflammatory and anti-viral activities. Although numerous studies state that it has also antitumor activity, the anti-proliferative effect of ginkgetin and the underlying mechanism in breast cancer cells have not yet been investigated. In the present study, ginkgetin inhibited the cell viability of MCF-7 and T-47D cells dose-dependently, and suppressed the expression of the estrogen receptor (ER) at the mRNA and protein levels. Among the targets of the ER, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), cyclin D1 and survivin were also downregulated by ginkgetin treatment. The anti-proliferative effects of ginkgetin were sufficient to suppress the growth by estradiol stimulation. However, ginkgetin did not significantly affect the viability of MDA-MB-231 cells, which are ER-negative cells. Furthermore, the knockdown of the ER and an inhibitor of PFKFB3 significantly sensitized MCF-7 and T-47D cells to ginkgetin. These findings suggest that ginkgetin induces cell death in ER-positive breast cancer cells via the inhibition of ER expression and that it is a promising agent for breast cancer treatment.
Collapse
Affiliation(s)
- Yoonhwa Park
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon, Seoul, Gyeonggi 01812, Republic of Korea.,School of Life Science and Biotechnology, Korea University, Seongbuk, Seoul, Gyeonggi 02841, Republic of Korea
| | - Sang Hyeok Woo
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon, Seoul, Gyeonggi 01812, Republic of Korea.,KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Nowon, Seoul, Gyeonggi 01812, Republic of Korea
| | - Sung-Keum Seo
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon, Seoul, Gyeonggi 01812, Republic of Korea
| | - Hyunggee Kim
- School of Life Science and Biotechnology, Korea University, Seongbuk, Seoul, Gyeonggi 02841, Republic of Korea
| | - Woo Chul Noh
- Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Nowon, Seoul, Gyeonggi 01812, Republic of Korea
| | - Jin Kyung Lee
- KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Nowon, Seoul, Gyeonggi 01812, Republic of Korea
| | - Byoung-Mog Kwon
- Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Yuseong, Daejeon, Chungcheong 34141, Republic of Korea
| | - Kyung Nam Min
- Department of Microbiological Engineering, Kon-Kuk University, Gwangjin, Seoul, Gyeonggi 05029, Republic of Korea
| | - Tae-Boo Choe
- Department of Microbiological Engineering, Kon-Kuk University, Gwangjin, Seoul, Gyeonggi 05029, Republic of Korea
| | - In-Chul Park
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon, Seoul, Gyeonggi 01812, Republic of Korea
| |
Collapse
|
|
20
|
A Review on Platelet Activating Factor Inhibitors: Could a New Class of Potent Metal-Based Anti-Inflammatory Drugs Induce Anticancer Properties? Bioinorg Chem Appl 2017; 2017:6947034. [PMID: 28458618 PMCID: PMC5387815 DOI: 10.1155/2017/6947034] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Accepted: 02/27/2017] [Indexed: 12/12/2022] Open
Abstract
In this minireview, we refer to recent results as far as the Platelet Activating Factor (PAF) inhibitors are concerned. At first, results of organic compounds (natural and synthetic ones and specific and nonspecific) as inhibitors of PAF are reported. Emphasis is given on recent results about a new class of the so-called metal-based inhibitors of PAF. A small library of 30 metal complexes has been thus created; their anti-inflammatory activity has been further evaluated owing to their inhibitory effect against PAF in washed rabbit platelets (WRPs). In addition, emphasis has also been placed on the identification of preliminary structure-activity relationships for the different classes of metal-based inhibitors.
Collapse
|
|
21
|
Mei N, Guo X, Ren Z, Kobayashi D, Wada K, Guo L. Review of Ginkgo biloba-induced toxicity, from experimental studies to human case reports. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART C, ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS 2017; 35:1-28. [PMID: 28055331 PMCID: PMC6373469 DOI: 10.1080/10590501.2016.1278298] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
Ginkgo biloba seeds and leaves have been used as a traditional herbal remedy for thousands of years, and its leaf extract has been consumed as a botanical dietary supplement for decades. Ginkgo biloba extract is a complex mixture with numerous components, including flavonol glycosides and terpene lactones, and is one of the most widely sold botanical dietary supplements worldwide. Concerns about potential health risks for the general population have been raised because of the widespread human exposure to Ginkgo biloba and its potential toxic and carcinogenic activities in rodents. The National Toxicology Program conducted 2-year gavage studies on one Ginkgo biloba leaf extract and concluded that there was clear evidence of carcinogenic activity of this extract in mice based on an increased incidence of hepatocellular carcinoma and hepatoblastoma. Recently, Ginkgo biloba leaf extract has been classified as a possible human carcinogen (Group 2B) by the International Agency for Research on Cancer. This review presents updated information on the toxicological effects from experimental studies both in vitro and in vivo to human case reports (caused by ginkgo seeds or leaves), and also summarizes the negative results from relatively large clinical trials.
Collapse
Affiliation(s)
- Nan Mei
- a Division of Genetic and Molecular Toxicology , National Center for Toxicological Research , Jefferson , Arkansas , USA
| | - Xiaoqing Guo
- a Division of Genetic and Molecular Toxicology , National Center for Toxicological Research , Jefferson , Arkansas , USA
| | - Zhen Ren
- b Division of Biochemical Toxicology , National Center for Toxicological Research , Jefferson , Arkansas , USA
| | - Daisuke Kobayashi
- c Department of Food and Chemical Toxicology , Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido , Hokkaido , Japan
| | - Keiji Wada
- c Department of Food and Chemical Toxicology , Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido , Hokkaido , Japan
| | - Lei Guo
- b Division of Biochemical Toxicology , National Center for Toxicological Research , Jefferson , Arkansas , USA
| |
Collapse
|
|
22
|
Lin CM, Lin YL, Ho SY, Chen PR, Tsai YH, Chung CH, Hwang CH, Tsai NM, Tzou SC, Ke CY, Chang J, Chan YL, Wang YS, Chi KH, Liao KW. The inhibitory effect of 7,7″-dimethoxyagastisflavone on the metastasis of melanoma cells via the suppression of F-actin polymerization. Oncotarget 2016; 8:60046-60059. [PMID: 28947953 PMCID: PMC5601121 DOI: 10.18632/oncotarget.10960] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 06/29/2016] [Indexed: 11/25/2022] Open
Abstract
7,7″-Dimethoxyagastisflavone (DMGF), a biflavonoid isolated from Taxus × media cv. Hicksii, induces apoptotic and autophagic cell death. However, whether DMGF suppresses tumor metastasis is unclear. The aim of this study was to investigate the anti-metastatic activities of DMGF on the metastatic processes of melanoma cells in vivo and in vitro. A transwell assay showed that DMGF could effectively attenuate the motility of B16F10 cells, and the results of real-time PCR revealed that DMGF also suppressed the expressions of matrix metalloproteinase-2 (MMP-2). Moreover, DMGF did not influence tube formation but inhibited the migration of endothelial cells. Furthermore, animal models were used to monitor the effects of DMGF on tumor metastasis, and all models showed that DMGF significantly suppressed the metastatic behaviors of B16F10 cells, including intravasation, colonization, and invasion of the lymphatic duct. In addition, DMGF could also reduce the densities of the blood vessels in the tumor area in vivo. Further investigation of the molecular mechanisms of anti-metastatic activity revealed that DMGF can down-regulate the levels of key modulators of the Cdc42/Rac1 pathway to interfere in F-actin polymerization and suppress the formation of lamellipodia by reducing the phosphorylation of CREB. These data suggested that DMGF presents anti-metastatic activities in B16F10 melanoma cells. Here, we demonstrated that DMGF can inhibit the metastasis of highly invasive melanoma cancer cells through the down-regulation of F-actin polymerization. Considering these findings, DMGF may be further developed to serve as a chemoprevention drug for patients with metastatic melanoma.
Collapse
Affiliation(s)
- Ching-Min Lin
- Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan
| | - Yu-Ling Lin
- Center for Bioinformatics Research, National Chiao Tung University, Hsinchu, Taiwan.,Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
| | - Shu-Yi Ho
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
| | - Pin-Rong Chen
- Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan
| | - Yi-Hsuan Tsai
- Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan
| | - Chen-Han Chung
- Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan
| | | | - Nu-Man Tsai
- Department of Medical and Laboratory Biotechnology, Chung Shan Medical University, Taichung, Taiwan.,Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shey-Cherng Tzou
- Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan.,Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
| | - Chun-Yen Ke
- Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan
| | - Jung Chang
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
| | - Yi-Lin Chan
- Department of Life Science, Chinese Culture University, Taichung, Taiwan
| | - Yu-Shan Wang
- Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Kwan-Hwa Chi
- Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Kuang-Wen Liao
- Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan.,Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.,Graduate Institut of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| |
Collapse
|
|
23
|
Baek SH, Lee JH, Ko JH, Lee H, Nam D, Lee SG, Yang WM, Um JY, Lee J, Kim SH, Shim BS, Ahn KS. Ginkgetin Blocks Constitutive STAT3 Activation and Induces Apoptosis through Induction of SHP-1 and PTEN Tyrosine Phosphatases. Phytother Res 2016; 30:567-76. [PMID: 27059688 DOI: 10.1002/ptr.5557] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 11/26/2015] [Accepted: 12/04/2015] [Indexed: 11/06/2022]
Abstract
Ginkgetin, a biflavone from Ginkgo biloba leaves, is known to exhibit antiinflammatory, antifungal, neuroprotective, and antitumor activities, but its precise mechanism of action has not been fully elucidated. Because the aberrant activation of STAT3 has been linked with regulation of inflammation, proliferation, invasion, and metastasis of tumors, we hypothesized that ginkgetin modulates the activation of STAT3 in tumor cells. We found that ginkgetin clearly suppressed constitutive phosphorylation of STAT3 through inhibition of the activation of upstream JAK1 and c-Src kinases and nuclear translocation of STAT3 on both A549 and FaDu cells. Treatment with sodium pervanadate reversed the ginkgetin-induced down-modulation of STAT3, thereby indicating a critical role for a PTP. We also found that ginkgetin strongly induced the expression of the SHP-1 and PTEN proteins and its mRNAs. Further, deletion of SHP-1 and PTEN genes by siRNA suppressed the induction of SHP-1 and PTEN, and reversed the inhibition of STAT3 activation. Ginkgetin induced apoptosis as characterized by an increased accumulation of cells in subG1 phase, positive Annexin V binding, loss of mitochondrial membrane potential, down-regulation of STAT3-regulated gene products, and cleavage of PARP. Overall, ginkgetin abrogates STAT3 signaling pathway through induction of SHP-1 and PTEN proteins, thus attenuating STAT3 phosphorylation and tumorigenesis.
Collapse
Affiliation(s)
- Seung Ho Baek
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea
| | - Jae Hwi Lee
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea
| | - Jeong-Hyeon Ko
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea
| | - Hanwool Lee
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea
| | - Dongwoo Nam
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea
| | - Seok Geun Lee
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea
| | - Woong Mo Yang
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea
| | - Jae-Young Um
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea
| | - Junhee Lee
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea
| | - Sung-Hoon Kim
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea
| | - Bum Sang Shim
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea
| | - Kwang Seok Ahn
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea
| |
Collapse
|
|
24
|
XIONG MIN, WANG LIN, YU HUALONG, HAN HENG, MAO DAN, CHEN JIE, ZENG YUN, HE NING, LIU ZHIGANG, WANG ZHIYONG, XU SHOUJIA, GUO LEYUN, WANG YONGAN. Ginkgetin exerts growth inhibitory and apoptotic effects on osteosarcoma cells through inhibition of STAT3 and activation of caspase-3/9. Oncol Rep 2015; 35:1034-40. [DOI: 10.3892/or.2015.4427] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 07/13/2015] [Indexed: 11/06/2022] Open
|
|
25
|
Jeon YJ, Jung SN, Yun J, Lee CW, Choi J, Lee YJ, Han DC, Kwon BM. Ginkgetin inhibits the growth of DU-145 prostate cancer cells through inhibition of signal transducer and activator of transcription 3 activity. Cancer Sci 2015; 106:413-20. [PMID: 25611086 PMCID: PMC4409885 DOI: 10.1111/cas.12608] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Revised: 01/07/2015] [Accepted: 01/09/2015] [Indexed: 12/26/2022] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in human cancers. Therefore, STAT3 is a therapeutic target of cancer drug discovery. We previously reported that natural products inhibited constitutively activated STAT3 in human prostate tumor cells. We used a dual-luciferase assay to screen 200 natural products isolated from herbal medicines and we identified ginkgetin obtained from the leaves of Ginkgo biloba L. as a STAT3 inhibitor. Ginkgetin inhibited both inducible and constitutively activated STAT3 and blocked the nuclear translocation of p-STAT3 in DU-145 prostate cancer cells. Furthermore, ginkgetin selectively inhibited the growth of prostate tumor cells stimulated with activated STAT3. Ginkgetin induced STAT3 dephosphorylation at Try705 and inhibited its localization to the nucleus, leading to the inhibition of expression of STAT3 target genes such as cell survival-related genes (cyclin D1 and survivin) and anti-apoptotic proteins (Bcl-2 and Bcl-xL). Therefore, ginkgetin inhibited the growth of STAT3-activated tumor cells. We also found that ginkgetin inhibited tumor growth in xenografted nude mice and downregulated p-STAT3(Tyr705) and survivin in tumor tissues. This is the first report that ginkgetin exerts antitumor activity by inhibiting STAT3. Therefore, ginkgetin is a good STAT3 inhibitor and may be a useful lead molecule for development of a therapeutic STAT3 inhibitor.
Collapse
Affiliation(s)
- Yoon Jung Jeon
- Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea; Korea University of Science and Technology, Daejeon, Korea
| | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Li J, Lei X, Chen KL. Comparison of cytotoxic activities of extracts from Selaginella species. Pharmacogn Mag 2014; 10:529-35. [PMID: 25422557 PMCID: PMC4239734 DOI: 10.4103/0973-1296.141794] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 11/15/2013] [Accepted: 09/26/2014] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Selaginella species are resurrection plants, which are known, possess various molecular bioactivities depending on species, but only a few species have been detailed observe in the advanced research. OBJECTIVE The objective of the following study is to compare the chemical profiles of different species of Selaginella and to investigate cytotoxicity and induction of apoptosis activities of some species of Selaginella. MATERIALS AND METHODS The high-performance liquid chromatography (HPLC) method was developed for chemical analysis. Ethyl acetate, ethanol and water-soluble extracts from seven Selaginella species were submitted to 3-(4,5-dimenthyl thizol-2-yl)-2,5-diphenyl tetrazolium bromide assay, flow cytometry, deoxyribonucleic acid (DNA) laddering analysis and caspase-3 expression using Bel-7402, HT-29 and HeLa cells. RESULTS The HPLC analysis revealed two major common peaks, which were identified as amentoflavone and robustaflavone and another three main peaks in their chromatograms. The results showed that S. labordei, Selaginella tamariscina and Selaginella uncinata had relatively stronger activities on Bel-7402 and HeLa cells and Selaginella moellendorfii had moderate antiproliferation activities, but Selaginella remotifolia and Selaginella pulvinata had almost no inhibitory activities. The main active components were in the ethyl acetate extracts which had abundant biflavonoids. The effects of these extracts on cell proliferation and apoptosis in different cells were not the same, they were more apparent on HeLa cells than on HT-29 cells. The assay of DNA laddering analysis and caspase-3 expression further confirmed that inducing cell apoptosis was one of antitumor mechanisms and antitumor activities of Selaginella species were related to apoptosis induced by caspase family. CONCLUSION S. labordei, S. tamariscina and S. uncinata would be potential antitumor agents.
Collapse
Affiliation(s)
- Juan Li
- Department of Identification and Assessment of TCM, Hubei College of Traditional Chinese Medicine, Key Laboratory of TCM Resource and TCM Compound Co-constructed by Hubei Province and Ministry of Education, Wuhan 430065, Hubei Province, China ; Department of Phytochemistry, Guangxi Institute of Botany, Guangxi Zhuang Autonomous Region and the Chinese Academy of Sciences, Guilin 541006, Guangxi Province, China
| | - Xiang Lei
- Department of Identification and Assessment of TCM, Hubei College of Traditional Chinese Medicine, Key Laboratory of TCM Resource and TCM Compound Co-constructed by Hubei Province and Ministry of Education, Wuhan 430065, Hubei Province, China
| | - Ke-Li Chen
- Department of Identification and Assessment of TCM, Hubei College of Traditional Chinese Medicine, Key Laboratory of TCM Resource and TCM Compound Co-constructed by Hubei Province and Ministry of Education, Wuhan 430065, Hubei Province, China
| |
Collapse
|
|
27
|
Masi S, Gustafsson E, Saint Jalme M, Narat V, Todd A, Bomsel MC, Krief S. Unusual feeding behavior in wild great apes, a window to understand origins of self-medication in humans: role of sociality and physiology on learning process. Physiol Behav 2011; 105:337-49. [PMID: 21888922 DOI: 10.1016/j.physbeh.2011.08.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2011] [Revised: 08/04/2011] [Accepted: 08/09/2011] [Indexed: 11/16/2022]
Abstract
Certain toxic plants are beneficial for health if small amounts are ingested infrequently and in a specific context of illness. Among our closest living relatives, chimpanzees are found to consume plants with pharmacological properties. Providing insight on the origins of human self-medication, this study investigates the role social systems and physiology (namely gut specialization) play on learning mechanisms involved in the consumption of unusual and potentially bioactive foods by two great ape species. We collected data from a community of 41-44 wild chimpanzees in Uganda (11 months, 2008), and a group of 11-13 wild western gorillas in Central African Republic (10 months, 2008-2009). During feeding, we recorded food consumed, its availability, and social interactions (including observers watching conspecifics and the observers' subsequent activity). Unusual food consumption in chimpanzees was twice higher than in gorillas. Additionally chimpanzees relied more on social information with vertical knowledge transmission on unusual foods by continually acquiring information during their life through mostly observing the fittest (pre-senescent) adults. In contrast, in gorillas observational learning primarily occurred between related immatures, showing instead the importance of horizontal knowledge transmission. As chimpanzees' guts are physiologically less specialized than gorillas (more capable of detoxifying harmful compounds), unusual-food consumption may be more risky for chimpanzees and linked to reasons other than nutrition (like self-medication). Our results show that differences in sociality and physiology between the two species may influence mechanisms that discriminate between plants for nutrition and plants with potential therapeutic dietary components. We conclude that self-medication may have appeared in our ancestors in association with high social tolerance and lack of herbivorous gut specialization.
Collapse
Affiliation(s)
- Shelly Masi
- Muséum national d'histoire naturelle, Département Hommes, Natures, Sociétés UMR 7206 Éco-anthropologie et Ethnobiologie, CP 135, 43 rue Buffon, 75 005 Paris, France.
| | | | | | | | | | | | | |
Collapse
|
|
28
|
Research strategies in the study of the pro-oxidant nature of polyphenol nutraceuticals. J Toxicol 2011; 2011:467305. [PMID: 21776260 PMCID: PMC3135211 DOI: 10.1155/2011/467305] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Accepted: 04/12/2011] [Indexed: 12/13/2022] Open
Abstract
Polyphenols of phytochemicals are thought to exhibit chemopreventive effects against cancer. These plant-derived antioxidant polyphenols have a dual nature, also acting as pro-oxidants, generating reactive oxygen species (ROS), and causing oxidative stress. When studying the overall cytotoxicity of polyphenols, research strategies need to distinguish the cytotoxic component derived from the polyphenol per se from that derived from the generated ROS. Such strategies include (a) identifying hallmarks of oxidative damage, such as depletion of intracellular glutathione and lipid peroxidation, (b) classical manipulations, such as polyphenol exposures in the absence and presence of antioxidant enzymes (i.e., catalase and superoxide dismutase) and of antioxidants (e.g., glutathione and N-acetylcysteine) and cotreatments with glutathione depleters, and (c) more recent manipulations, such as divalent cobalt and pyruvate to scavenge ROS. Attention also must be directed to the influence of iron and copper ions and to the level of polyphenols, which mediate oxidative stress.
Collapse
|
|
29
|
|
|
30
|
Babich H, Ackerman NJ, Burekhovich F, Zuckerbraun HL, Schuck AG. Gingko biloba leaf extract induces oxidative stress in carcinoma HSC-2 cells. Toxicol In Vitro 2009; 23:992-9. [DOI: 10.1016/j.tiv.2009.06.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2009] [Revised: 05/21/2009] [Accepted: 06/23/2009] [Indexed: 12/01/2022]
|
|
31
|
Abstract
Selaginella (spikemoss) is an enigma in the plant kingdom. Although a fascination to botanists at the turn of the twentieth century, members of this genus are unremarkable in appearance, never flower, and are of no agronomic value. However, members of this genus are relicts from ancient times, and one has to marvel at how this genus has survived virtually unchanged in appearance for hundreds of millions of years. In light of the recent completion of the Selaginella moellendorffii genome sequence, this review is intended to survey what is known about Selaginella, with a special emphasis on recent inquiries into its unique biology and importance in understanding the early evolution of vascular plants.
Collapse
Affiliation(s)
- Jo Ann Banks
- Department of Botany and Plant Pathology, Purdue University, West Lafayette, Indiana 47907, USA.
| |
Collapse
|
|
32
|
Biochemical pharmacology of biflavonoids: Implications for anti-inflammatory action. Arch Pharm Res 2008; 31:265-73. [DOI: 10.1007/s12272-001-1151-3] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2007] [Indexed: 11/26/2022]
|
|
33
|
Zhang Y, Chen AY, Li M, Chen C, Yao Q. Ginkgo biloba extract kaempferol inhibits cell proliferation and induces apoptosis in pancreatic cancer cells. THE JOURNAL OF SURGICAL RESEARCH 2008. [PMID: 18570926 DOI: 10.1016/j.jss.2008.02.036s0022-4804(08)00140-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Kaempferol is one of the most important constituents in ginkgo flavonoids. Recent studies indicate kaempferol may have antitumor activities. The objective of this study was to determine the effect and mechanisms of kaempferol on pancreatic cancer cell proliferation and apoptosis. MATERIALS AND METHODS Pancreatic cancer cell lines MIA PaCa-2 and Panc-1 were treated with kaempferol, and the inhibitory effects of kaempferol on pancreatic cancer cell proliferation were examined by direct cell counting, 3H-thymidine incorporation, and MTS assay. Lactate dehydrogenase release from cells was determined as an index of cytotoxicity. Apoptosis was analyzed by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay. RESULTS Upon the treatment with 70 microm kaempferol for 4 days, MIA PaCa-2 cell proliferation was significantly inhibited by 79% and 45.7% as determined by direct cell counting and MTS assay, respectively, compared with control cells (P < 0.05). Similarly, the treatment with kaempferol significantly inhibited Panc-1 cell proliferation. Kaempferol treatment also significantly reduced 3H-thymidine incorporation in both MIA PaCa-2 and Panc-1 cells. Combination treatment of low concentrations of kaempferol and 5-fluorouracil showed an additive effect on the inhibition of MIA PaCa-2 cell proliferation. Furthermore, kaempferol had significantly less cytotoxicity than 5-fluorouracil in normal human pancreatic ductal epithelial cells (P = 0.029). In both MIA PaCa-2 and Panc-1 cells, apoptotic cell population was increased when treated with kaempferol in a concentration-dependent manner. CONCLUSIONS Ginkgo biloba extract kaempferol effectively inhibits pancreatic cancer cell proliferation and induces cancer cell apoptosis, which may sensitize pancreatic tumor cells to chemotherapy. Kaempferol may have clinical applications as adjuvant therapy in the treatment of pancreatic cancer.
Collapse
Affiliation(s)
- Yuqing Zhang
- Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA
| | | | | | | | | |
Collapse
|
|
34
|
Ginkgo biloba extract kaempferol inhibits cell proliferation and induces apoptosis in pancreatic cancer cells. J Surg Res 2008; 148:17-23. [PMID: 18570926 DOI: 10.1016/j.jss.2008.02.036] [Citation(s) in RCA: 123] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2007] [Revised: 02/12/2008] [Accepted: 02/20/2008] [Indexed: 12/26/2022]
Abstract
BACKGROUND Kaempferol is one of the most important constituents in ginkgo flavonoids. Recent studies indicate kaempferol may have antitumor activities. The objective of this study was to determine the effect and mechanisms of kaempferol on pancreatic cancer cell proliferation and apoptosis. MATERIALS AND METHODS Pancreatic cancer cell lines MIA PaCa-2 and Panc-1 were treated with kaempferol, and the inhibitory effects of kaempferol on pancreatic cancer cell proliferation were examined by direct cell counting, 3H-thymidine incorporation, and MTS assay. Lactate dehydrogenase release from cells was determined as an index of cytotoxicity. Apoptosis was analyzed by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay. RESULTS Upon the treatment with 70 microm kaempferol for 4 days, MIA PaCa-2 cell proliferation was significantly inhibited by 79% and 45.7% as determined by direct cell counting and MTS assay, respectively, compared with control cells (P < 0.05). Similarly, the treatment with kaempferol significantly inhibited Panc-1 cell proliferation. Kaempferol treatment also significantly reduced 3H-thymidine incorporation in both MIA PaCa-2 and Panc-1 cells. Combination treatment of low concentrations of kaempferol and 5-fluorouracil showed an additive effect on the inhibition of MIA PaCa-2 cell proliferation. Furthermore, kaempferol had significantly less cytotoxicity than 5-fluorouracil in normal human pancreatic ductal epithelial cells (P = 0.029). In both MIA PaCa-2 and Panc-1 cells, apoptotic cell population was increased when treated with kaempferol in a concentration-dependent manner. CONCLUSIONS Ginkgo biloba extract kaempferol effectively inhibits pancreatic cancer cell proliferation and induces cancer cell apoptosis, which may sensitize pancreatic tumor cells to chemotherapy. Kaempferol may have clinical applications as adjuvant therapy in the treatment of pancreatic cancer.
Collapse
|
|
35
|
Hsiao HL, Wang WS, Chen PM, Su Y. Overexpression of thymosin β-4 renders SW480 colon carcinoma cells more resistant to apoptosis triggered by FasL and two topoisomerase II inhibitors via downregulating Fas and upregulating Survivin expression, respectively. Carcinogenesis 2005; 27:936-44. [PMID: 16364925 DOI: 10.1093/carcin/bgi316] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The present work was conducted to further examine the effects of thymosin beta-4 (Tbeta4) upregulation on the apoptosis of SW480 colon cancer cells induced by T cells and various chemotherapeutic agents because reduced susceptibility to the cytotoxicity of an anti-Fas IgM (CH-11) in Tbeta4-overexpressing cells has previously been reported by us. As expected, Tbeta4 overexpressers were also more resistant to the killing effect of FasL-bearing Jurkat T cells. On the other hand, pretreating these cells with an MMP inhibitor restored not only their Fas levels but also their sensitivity to CH-11, suggesting a pivotal role of MMP in downregulating Fas in Tbeta4 overexpressers. Interestingly, while the susceptibilities of Tbeta4 overexpressers to 5-FU and irinotecan remained unchanged, they were more resistant to doxorubicin and etoposide which triggered apoptosis via a mitochondrial pathway. Concordantly, activation of both caspases 9 and 3 in Tbeta4 overexpressers by the two aforementioned topoisomerase II inhibitors was dramatically abrogated which could be accounted mainly by an increased expression of Survivin, a critical anti-apoptotic factor. Finally, poor survival was found in stage III colon cancer patients whose tumors were stained positively by the anti-Survivin antibody. Thus, advantages such as immune evasion and resistance to anticancer drug-induced apoptosis acquired by colon cancer cells through Tbeta4 overexpression might facilitate their survival during metastasis and chemotherapy.
Collapse
Affiliation(s)
- Hung-Liang Hsiao
- Institute of Pharmacology, College of Medicine, National Yang-Ming University, Shih-Pai, Taipei 11221, Taiwan, R.O. China
| | | | | | | |
Collapse
|
|
36
|
Chao JCJ, Chu CC. Effects of Ginkgo biloba extract on cell proliferation and cytotoxicity in human hepatocellular carcinoma cells. World J Gastroenterol 2004; 10:37-41. [PMID: 14695765 PMCID: PMC4717074 DOI: 10.3748/wjg.v10.i1.37] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To study the effect of Ginkgo biloba extract (EGb 761) containing 22%-27% flavonoids (ginkgo-flavone glycosides) and 5%-7% terpenoids (ginkgolides and bilobalides) on cell proliferation and cytotoxicity in human hepatocellular carcinoma (HCC) cells.
METHODS: Human HCC cell lines (HepG2 and Hep3B) were incubated with various concentrations (0-1000 mg/L) of EGb 761 solution. After 24 h incubation, cell proliferation and cytotoxicity were determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and lactate dehydrogenase (LDH) release, respectively. After 48 h incubation, the expression of proliferating cell nuclear antigen (PCNA) and p53 protein was measured by Western blotting.
RESULTS: The results showed that EGb 761 (50-1000 mg/L) significantly suppressed cell proliferation and increased LDH release (P < 0.05) in HepG2 and Hep3B cells compared with the control group. The cell proliferation of HepG2 and Hep3B cells treated with EGb 761 (1000 mg/L) was 45% and 39% of the control group (P < 0.05), respectively. LDH release of HepG2 cells without and with EGb 761 (1000 mg/L) treatment was 6.7% and 37.7%, respectively, and that of Hep3B cells without and with EGb 761 (1000 mg/L) treatment was 7.2% and 40.3%, respectively. The expression of PCNA and p53 protein in HepG2 cells treated with EGb 761 (1000 mg/L) was 85% and 174% of the control group, respectively.
CONCLUSION: Ginkgo biloba extract significantly can suppress proliferation and increase cytotoxicity in HepG2 and Hep3B cells. Additionally, Ginkgo biloba extract can decrease PCNA and increase p53 expression in HepG2 cells.
Collapse
Affiliation(s)
- Jane C J Chao
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei 110, Taiwan, China.
| | | |
Collapse
|