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1
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Wang TY, Zhu XY, Jia HR, Zhu YX, Zhou YX, Li YH, Gao CZ, Pan GY, Wu FG. Devastating the Supply Wagons: Multifaceted Liposomes Capable of Exhausting Tumor to Death via Triple Energy Depletion. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2308861. [PMID: 38372029 DOI: 10.1002/smll.202308861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 01/08/2024] [Indexed: 02/20/2024]
Abstract
The anabolism of tumor cells can not only support their proliferation, but also endow them with a steady influx of exogenous nutrients. Therefore, consuming metabolic substrates or limiting access to energy supply can be an effective strategy to impede tumor growth. Herein, a novel treatment paradigm of starving-like therapy-triple energy-depleting therapy-is illustrated by glucose oxidase (GOx)/dc-IR825/sorafenib liposomes (termed GISLs), and such a triple energy-depleting therapy exhibits a more effective tumor-killing effect than conventional starvation therapy that only cuts off one of the energy supplies. Specifically, GOx can continuously consume glucose and generate toxic H2O2 in the tumor microenvironment (including tumor cells). After endocytosis, dc-IR825 (a near-infrared cyanine dye) can precisely target mitochondria and exert photodynamic and photothermal activities upon laser irradiation to destroy mitochondria. The anti-angiogenesis effect of sorafenib can further block energy and nutrition supply from blood. This work exemplifies a facile and safe method to exhaust the energy in a tumor from three aspects and starve the tumor to death and also highlights the importance of energy depletion in tumor treatment. It is hoped that this work will inspire the development of more advanced platforms that can combine multiple energy depletion therapies to realize more effective tumor treatment.
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Affiliation(s)
- Tian-Yu Wang
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, 2 Southeast University Road, Nanjing, 211189, P. R. China
| | - Xiao-Yu Zhu
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, 2 Southeast University Road, Nanjing, 211189, P. R. China
| | - Hao-Ran Jia
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, 2 Southeast University Road, Nanjing, 211189, P. R. China
| | - Ya-Xuan Zhu
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, 2 Southeast University Road, Nanjing, 211189, P. R. China
| | - Yong-Xi Zhou
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, 2 Southeast University Road, Nanjing, 211189, P. R. China
| | - Yan-Hong Li
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, 2 Southeast University Road, Nanjing, 211189, P. R. China
| | - Cheng-Zhe Gao
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, 2 Southeast University Road, Nanjing, 211189, P. R. China
| | - Guang-Yu Pan
- School of Intelligent Medicine and Biotechnology, Guilin Medical University, Guilin, 541100, P. R. China
| | - Fu-Gen Wu
- State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, 2 Southeast University Road, Nanjing, 211189, P. R. China
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2
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Qian Y, Lu S, Meng J, Chen W, Li J. Thermo-Responsive Hydrogels Coupled with Photothermal Agents for Biomedical Applications. Macromol Biosci 2023; 23:e2300214. [PMID: 37526220 DOI: 10.1002/mabi.202300214] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 07/04/2023] [Indexed: 08/02/2023]
Abstract
Intelligent hydrogels are materials with abilities to change their chemical nature or physical structure in response to external stimuli showing promising potential in multitudinous applications. Especially, photo-thermo coupled responsive hydrogels that are prepared by encapsulating photothermal agents into thermo-responsive hydrogel matrix exhibit more attractive advantages in biomedical applications owing to their spatiotemporal control and precise therapy. This work summarizes the latest progress of the photo-thermo coupled responsive hydrogel in biomedical applications. Three major elements of the photo-thermo coupled responsive hydrogel, i.e., thermo-responsive hydrogel matrix, photothermal agents, and construction methods are introduced. Furthermore, the recent developments of these hydrogels for biomedical applications are described with some selected examples. Finally, the challenges and future perspectives for photo-thermo coupled responsive hydrogels are outlined.
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Affiliation(s)
- Yafei Qian
- Hunan Provincial Key Laboratory of Micro & Nano Materials Interface Science, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, 410008, China
| | - Sha Lu
- Hunan Provincial Key Laboratory of Micro & Nano Materials Interface Science, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, 410008, China
| | - Jianqiang Meng
- Hunan Provincial Key Laboratory of Micro & Nano Materials Interface Science, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, 410008, China
| | - Wansong Chen
- Hunan Provincial Key Laboratory of Micro & Nano Materials Interface Science, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, 410008, China
| | - Juan Li
- Hunan Provincial Key Laboratory of Micro & Nano Materials Interface Science, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, 410008, China
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3
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Cheng HB, Cao X, Zhang S, Zhang K, Cheng Y, Wang J, Zhao J, Zhou L, Liang XJ, Yoon J. BODIPY as a Multifunctional Theranostic Reagent in Biomedicine: Self-Assembly, Properties, and Applications. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2207546. [PMID: 36398522 DOI: 10.1002/adma.202207546] [Citation(s) in RCA: 85] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 10/18/2022] [Indexed: 05/05/2023]
Abstract
The use of boron dipyrromethene (BODIPY) in biomedicine is reviewed. To open, its synthesis and regulatory strategies are summarized, and inspiring cutting-edge work in post-functionalization strategies is highlighted. A brief overview of assembly model of BODIPY is then provided: BODIPY is introduced as a promising building block for the formation of single- and multicomponent self-assembled systems, including nanostructures suitable for aqueous environments, thereby showing the great development potential of supramolecular assembly in biomedicine applications. The frontier progress of BODIPY in biomedical application is thereafter described, supported by examples of the frontiers of biomedical applications of BODIPY-containing smart materials: it mainly involves the application of materials based on BODIPY building blocks and their assemblies in fluorescence bioimaging, photoacoustic imaging, disease treatment including photodynamic therapy, photothermal therapy, and immunotherapy. Lastly, not only the current status of the BODIPY family in the biomedical field but also the challenges worth considering are summarized. At the same time, insights into the future development prospects of biomedically applicable BODIPY are provided.
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Affiliation(s)
- Hong-Bo Cheng
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, 15 North Third Ring Road, Beijing, 100029, P. R. China
| | - Xiaoqiao Cao
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, 15 North Third Ring Road, Beijing, 100029, P. R. China
| | - Shuchun Zhang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, 15 North Third Ring Road, Beijing, 100029, P. R. China
| | - Keyue Zhang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, 15 North Third Ring Road, Beijing, 100029, P. R. China
| | - Yang Cheng
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, 15 North Third Ring Road, Beijing, 100029, P. R. China
| | - Jiaqi Wang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, 15 North Third Ring Road, Beijing, 100029, P. R. China
| | - Jing Zhao
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, 15 North Third Ring Road, Beijing, 100029, P. R. China
| | - Liming Zhou
- Henan Provincial Key Laboratory of Surface and Interface Science, School of Material and Chemical Engineering, Zhengzhou University of Light Industry, Zhengzhou, 450002, China
| | - Xing-Jie Liang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, No. 11, First North Road, Zhongguancun, Beijing, 100190, China
- School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, 510260, P. R. China
| | - Juyoung Yoon
- Department of Chemistry and Nanoscience, Ewha Womans University, Seoul, 03760, South Korea
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4
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Chen L, Yuan M, Zhang X, Li Y, Feng Y, Yu J, Coudyzer W, Xie Y, Xu J, Li Y, Li Y, Ni Y. Exploration of Chick Embryo and Chorioallantoic Membrane on Imaging Navigated Platforms for Anticancer Pharmaceutical Evaluations. Technol Cancer Res Treat 2023; 22:15330338231206985. [PMID: 37844882 PMCID: PMC10585999 DOI: 10.1177/15330338231206985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/29/2023] [Accepted: 09/25/2023] [Indexed: 10/18/2023] Open
Abstract
Conforming to the current replace-reduce-refine 3Rs' guidelines in animal experiments, a series of explorative efforts have been made to set up operable biomedical imaging-guided platforms for qualitative and quantitative evaluations on pharmacological effects of tumor vascular-disrupting agents (VDAs), based on the chick embryos (CEs) with its chorioallantoic membrane (CAM), in this overview. The techniques and platforms have been hierarchically elaborated, from macroscopic to microscopic and from overall to specific aspects. A protocol of LED lamplight associated with a new deep-learning algorithm was consolidated to screen out weak CEs by using the CAM vasculature imaging. 3D magnetic resonance imaging (MRI) and laser speckle contrast imaging (LSCI) to monitor the evolution of CE and vascular changes in CAM are introduced. A LSCI-CAM platform for studying the effects of VDAs on normal and cancerous vasculature of CAM and possible molecular mechanisms has been demonstrated. Finally, practical challenges and future perspectives are highlighted. The aim of this article is to help peers in biomedical research to familiarize with the CAM platform and to optimize imaging protocols for the evaluation of vasoactive pharmaceuticals, especially anticancer vascular targeted therapy.
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Affiliation(s)
- Lei Chen
- KU Leuven, Biomedical Group, Leuven, Belgium
| | - Mingyuan Yuan
- Department of Radiology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Xinqi Zhang
- Airport Division, Tianjin Cancer Hospital, Tianjin, China
| | - Yongsheng Li
- Airport Division, Tianjin Cancer Hospital, Tianjin, China
| | - Yuanbo Feng
- KU Leuven, Biomedical Group, Leuven, Belgium
| | - Jie Yu
- KU Leuven, Biomedical Group, Leuven, Belgium
| | - Walter Coudyzer
- Department of Radiology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Yiyang Xie
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Jiayue Xu
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Yuzhen Li
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Yue Li
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Yicheng Ni
- KU Leuven, Biomedical Group, Leuven, Belgium
- Department of Radiology, Zhongda Hospital, Southeast University, Nanjing, China
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5
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Vascular disrupting agent-induced amplification of tumor targeting and prodrug activation boosts anti-tumor efficacy. Sci China Chem 2022. [DOI: 10.1007/s11426-022-1347-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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6
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Ghollasi M, Ghasembaglou S, Rahban D, Korani M, Motallebnezhad M, Asadi M, Zarredar H, Salimi A. Prospects for Manipulation of Mesenchymal Stem Cells in Tumor Therapy: Anti-Angiogenesis Property on the Spotlight. Int J Stem Cells 2021; 14:351-365. [PMID: 34456189 PMCID: PMC8611310 DOI: 10.15283/ijsc20146] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 06/01/2021] [Accepted: 06/16/2021] [Indexed: 11/10/2022] Open
Abstract
The interactions between the tumor microenvironment and the tumor cells confers a condition that accelerate or decelerate the development of tumor. Of these cells, mesenchymal stem cells (MSCs) have the potential to modulate the tumor cells. MSCs have been established with double functions, whereby contribute to a tumorigenic or anti-tumor setting. Clinical studies have indicated the potential of MSCs to be used as tool in treating the human cancer cells. One of the advantageous features of MSCs that make them as a well-suited tool for cancer therapy is the natural tumor-trophic migration potential. A key specification of the tumor development has been stablished to be angiogenesis. As a result, manipulation of angiogenesis has become an attractive approach for cancer therapy. This review article will seek to clarify the anti-angiogenesis strategy in modulating the MSCs to treat the tumor cells.
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Affiliation(s)
- Marzieh Ghollasi
- Department of Cell and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran
| | - Shahram Ghasembaglou
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Dariush Rahban
- Department of Nanomedicine, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Korani
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Morteza Motallebnezhad
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Milad Asadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Basic Oncology, Ege University, Institute of Health Sciences, Izmir, Turkey
| | - Habib Zarredar
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Ali Salimi
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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7
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Mesenchymal stem cells and cancer therapy: insights into targeting the tumour vasculature. Cancer Cell Int 2021; 21:158. [PMID: 33685452 PMCID: PMC7938588 DOI: 10.1186/s12935-021-01836-9] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 02/15/2021] [Indexed: 12/27/2022] Open
Abstract
A crosstalk established between tumor microenvironment and tumor cells leads to contribution or inhibition of tumor progression. Mesenchymal stem cells (MSCs) are critical cells that fundamentally participate in modulation of the tumor microenvironment, and have been reported to be able to regulate and determine the final destination of tumor cell. Conflicting functions have been attributed to the activity of MSCs in the tumor microenvironment; they can confer a tumorigenic or anti-tumor potential to the tumor cells. Nonetheless, MSCs have been associated with a potential to modulate the tumor microenvironment in favouring the suppression of cancer cells, and promising results have been reported from the preclinical as well as clinical studies. Among the favourable behaviours of MSCs, are releasing mediators (like exosomes) and their natural migrative potential to tumor sites, allowing efficient drug delivering and, thereby, efficient targeting of migrating tumor cells. Additionally, angiogenesis of tumor tissue has been characterized as a key feature of tumors for growth and metastasis. Upon introduction of first anti-angiogenic therapy by a monoclonal antibody, attentions have been drawn toward manipulation of angiogenesis as an attractive strategy for cancer therapy. After that, a wide effort has been put on improving the approaches for cancer therapy through interfering with tumor angiogenesis. In this article, we attempted to have an overview on recent findings with respect to promising potential of MSCs in cancer therapy and had emphasis on the implementing MSCs to improve them against the suppression of angiogenesis in tumor tissue, hence, impeding the tumor progression.
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Shiah HS, Chiang NJ, Lin CC, Yen CJ, Tsai HJ, Wu SY, Su WC, Chang KY, Wang CC, Chang JY, Chen LT. Phase I Dose-Escalation Study of SCB01A, a Microtubule Inhibitor with Vascular Disrupting Activity, in Patients with Advanced Solid Tumors. Oncologist 2020; 26:e567-e579. [PMID: 33245172 DOI: 10.1002/onco.13612] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 11/15/2020] [Indexed: 11/10/2022] Open
Abstract
LESSONS LEARNED SCB01A is a novel microtubule inhibitor with vascular disrupting activity. This first-in-human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity. SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity. BACKGROUND SCB01A, a novel microtubule inhibitor, has vascular disrupting activity. METHODS In this phase I dose-escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m2 to the maximum tolerated dose (MTD) based on dose-limiting toxicity (DLT). SCB01A-induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints. RESULTS Treatment-related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m2 cohort; grade 3 gastric hemorrhage in the 6.5 mg/m2 cohort; grade 2 thromboembolic event in the 24 mg/m2 cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m2 cohort. The MTD was 24 mg/m2 , and average half-life was ~2.5 hours. The area under the curve-dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A-induced neurotoxicity was reversible in vitro. CONCLUSION The MTD of SCB01A was 24 mg/m2 every 21 days; it is safe and tolerable in patients with solid tumors.
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Affiliation(s)
- Her-Shyong Shiah
- Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.,Division of Hematology and Oncology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
| | - Nai-Jung Chiang
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.,Division of Oncology-Hematology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Chi Lin
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chia-Jui Yen
- Division of Oncology-Hematology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hui-Jen Tsai
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.,Division of Oncology-Hematology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Shang-Yin Wu
- Division of Oncology-Hematology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wu-Chou Su
- Division of Oncology-Hematology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kwang-Yu Chang
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.,Division of Oncology-Hematology, Department of Internal Medicine, National Cheng Kung University, Tainan, Taiwan
| | | | - Jang-Yang Chang
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.,Division of Oncology-Hematology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.,Division of Oncology-Hematology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Internal Medicine, Kaohisung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
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9
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Schuemann J, Bagley AF, Berbeco R, Bromma K, Butterworth KT, Byrne HL, Chithrani BD, Cho SH, Cook JR, Favaudon V, Gholami YH, Gargioni E, Hainfeld JF, Hespeels F, Heuskin AC, Ibeh UM, Kuncic Z, Kunjachan S, Lacombe S, Lucas S, Lux F, McMahon S, Nevozhay D, Ngwa W, Payne JD, Penninckx S, Porcel E, Prise KM, Rabus H, Ridwan SM, Rudek B, Sanche L, Singh B, Smilowitz HM, Sokolov KV, Sridhar S, Stanishevskiy Y, Sung W, Tillement O, Virani N, Yantasee W, Krishnan S. Roadmap for metal nanoparticles in radiation therapy: current status, translational challenges, and future directions. Phys Med Biol 2020; 65:21RM02. [PMID: 32380492 DOI: 10.1088/1361-6560/ab9159] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
This roadmap outlines the potential roles of metallic nanoparticles (MNPs) in the field of radiation therapy. MNPs made up of a wide range of materials (from Titanium, Z = 22, to Bismuth, Z = 83) and a similarly wide spectrum of potential clinical applications, including diagnostic, therapeutic (radiation dose enhancers, hyperthermia inducers, drug delivery vehicles, vaccine adjuvants, photosensitizers, enhancers of immunotherapy) and theranostic (combining both diagnostic and therapeutic), are being fabricated and evaluated. This roadmap covers contributions from experts in these topics summarizing their view of the current status and challenges, as well as expected advancements in technology to address these challenges.
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Affiliation(s)
- Jan Schuemann
- Department of Radiation Oncology, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, United States of America
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10
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Olatunde OZ, Yong J, Lu C. The Progress of the Anticancer Agents Related to the Microtubules Target. Mini Rev Med Chem 2020; 20:2165-2192. [PMID: 32727327 DOI: 10.2174/1389557520666200729162510] [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: 03/31/2020] [Revised: 05/11/2020] [Accepted: 05/22/2020] [Indexed: 11/22/2022]
Abstract
Anticancer drugs based on the microtubules target are potent mitotic spindle poison agents, which interact directly with the microtubules, and were classified as microtubule-stabilizing agents and microtubule-destabilizing agents. Researchers have worked tremendously towards the improvements of anticancer drugs, in terms of improving the efficacy, solubility and reducing the side effects, which brought about advancement in chemotherapy. In this review, we focused on describing the discovery, structures and functions of the microtubules as well as the progress of anticancer agents related to the microtubules, which will provide adequate references for researchers.
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Affiliation(s)
- Olagoke Zacchaeus Olatunde
- CAS Key Laboratory of Desing and Assembly of Functional Nanostructures, and Fujian Provincial Key Laboratory of Nanomaterials, Fujian Institute of Research on the Structures of Matter, Chinese Academy of Sciences. Fuzhou, Fujian, 350002, China
| | - Jianping Yong
- Xiamen Institute of Rare-Earth Materials, Chinese Academy of Sciences, Xiamen, Fujian, 361021, China
| | - Canzhong Lu
- CAS Key Laboratory of Desing and Assembly of Functional Nanostructures, and Fujian Provincial Key Laboratory of Nanomaterials, Fujian Institute of Research on the Structures of Matter, Chinese Academy of Sciences. Fuzhou, Fujian, 350002, China
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11
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Li X, Wang C. The potential biomedical platforms based on the functionalized Gd@C
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nanomaterials. VIEW 2020. [DOI: 10.1002/viw2.7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Xue Li
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Molecular Nanostructure and Nanotechnology, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of ChemistryChinese Academy of Sciences Beijing China
- University of Chinese Academy of Sciences Beijing China
| | - Chunru Wang
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Molecular Nanostructure and Nanotechnology, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of ChemistryChinese Academy of Sciences Beijing China
- University of Chinese Academy of Sciences Beijing China
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12
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Predicting Clinical Efficacy of Vascular Disrupting Agents in Rodent Models of Primary and Secondary Liver Cancers: An Overview with Imaging-Histopathology Correlation. Diagnostics (Basel) 2020; 10:diagnostics10020078. [PMID: 32024029 PMCID: PMC7168934 DOI: 10.3390/diagnostics10020078] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 01/24/2020] [Accepted: 01/28/2020] [Indexed: 12/16/2022] Open
Abstract
Vascular disrupting agents (VDAs) have entered clinical trials for over 15 years. As the leading VDA, combretastatin A4 phosphate (CA4P) has been evaluated in combination with chemotherapy and molecular targeting agents among patients with ovarian cancer, lung cancer and thyroid cancer, but still remains rarely explored in human liver cancers. To overcome tumor residues and regrowth after CA4P monotherapy, a novel dual targeting pan-anticancer theragnostic strategy, i.e., OncoCiDia, has been developed and shown promise previously in secondary liver tumor models. Animal model of primary liver cancer is time consuming to induce, but of value for more closely mimicking human liver cancers in terms of tumor angiogenesis, histopathological heterogeneity, cellular differentiation, tumor components, cancer progression and therapeutic response. Being increasingly adopted in VDA researches, multiparametric magnetic resonance imaging (MRI) provides imaging biomarkers to reflect in vivo tumor responses to drugs. In this article as a chapter of a doctoral thesis, we overview the construction and clinical relevance of primary and secondary liver cancer models in rodents. Target selection for CA4P therapy assisted by enhanced MRI using hepatobiliary contrast agents (CAs), and therapeutic efficacy evaluated by using MRI with a non-specific contrast agent, dynamic contrast enhanced (DCE) imaging, diffusion weighted imaging (DWI) are also described. We then summarize diverse responses among primary hepatocellular carcinomas (HCCs), secondary liver and pancreatic tumors to CA4P, which appeared to be related to tumor size, vascularity, and cellular differentiation. In general, imaging-histopathology correlation studies allow to conclude that CA4P tends to be more effective in secondary liver tumors and in more differentiated HCCs, but less effective in less differentiated HCCs and implanted pancreatic tumor. Notably, cirrhotic liver may be responsive to CA4P as well. All these could be instructive for future clinical trials of VDAs.
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Microtubule inhibitors containing immunostimulatory agents promote cancer immunochemotherapy by inhibiting tubulin polymerization and tryptophan-2,3-dioxygenase. Eur J Med Chem 2019; 187:111949. [PMID: 31830637 DOI: 10.1016/j.ejmech.2019.111949] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 12/02/2019] [Accepted: 12/02/2019] [Indexed: 01/06/2023]
Abstract
A combination therapeutic regimen via introducing tryptophan 2,3-dioxygenase inhibitors into microtubule inhibitors was performed and evaluated for their antitumor activity. Thereinto, HT2, composed of combretastatin A-4 (CA-4) and tryptophan-2,3-dioxygenase (TDO) inhibitor by a linker, displayed the most potent activity with 10-fold higher than its parent CA-4 against HepG2, A549 and HCT-116 cancer cell lines. Mechanism studies suggested that HT2 inhibited tubulin polymerization and cell migration, caused G2 phase arrest, induced apoptosis by mitochondrial mediated apoptotic pathway, concurrent depolarized the mitochondria membrane potentials and caused reactive oxygen species (ROS) production in HepG2 cells. Moreover, HT2 could enhance T-cell immune responses in vitro by releasing a TDO inhibitor to suppress TDO expression and blockade kynurenine production. As expected, HT2 could remarkably promote the antitumor activity of CA-4 in either immunocompetent H22 or immunodeficient A549 tumor xenograft models without observable toxic effects. More importantly, HT2 increased the level of splenic and tumor-infiltrated T cells and in turn effectively boosted the inhibition effect in H22 xenografted tumor growth. Collectively, this immunochemotherapeutic strategy can be applied to promote chemotherapeutic effect.
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14
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Yu S, Chen Z, Zeng X, Chen X, Gu Z. Advances in nanomedicine for cancer starvation therapy. Theranostics 2019; 9:8026-8047. [PMID: 31754379 PMCID: PMC6857045 DOI: 10.7150/thno.38261] [Citation(s) in RCA: 149] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 09/25/2019] [Indexed: 12/24/2022] Open
Abstract
Abnormal cell metabolism with vigorous nutrition consumption is one of the major physiological characteristics of cancers. As such, the strategy of cancer starvation therapy through blocking the blood supply, depleting glucose/oxygen and other critical nutrients of tumors has been widely studied to be an attractive way for cancer treatment. However, several undesirable properties of these agents, such as low targeting efficacy, undesired systemic side effects, elevated tumor hypoxia, induced drug resistance, and increased tumor metastasis risk, limit their future applications. The recent development of starving-nanotherapeutics combined with other therapeutic methods displayed the promising potential for overcoming the above drawbacks. This review highlights the recent advances of nanotherapeutic-based cancer starvation therapy and discusses the challenges and future prospects of these anticancer strategies.
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Affiliation(s)
- Shuangjiang Yu
- College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 311121, P. R. China
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China. E-mail:
| | - Zhaowei Chen
- Department of Bioengineering, Jonsson Comprehensive Cancer Center, California Nanosystems Institute (CNSI), and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA 90095, USA
| | - Xuan Zeng
- Department of Bioengineering, Jonsson Comprehensive Cancer Center, California Nanosystems Institute (CNSI), and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA 90095, USA
| | - Xuesi Chen
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China. E-mail:
| | - Zhen Gu
- Department of Bioengineering, Jonsson Comprehensive Cancer Center, California Nanosystems Institute (CNSI), and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA 90095, USA
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15
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Jiang J, Shen N, Song W, Yu H, Sakurai K, Tang Z, Li G. Combretastatin A4 nanodrug combined plerixafor for inhibiting tumor growth and metastasis simultaneously. Biomater Sci 2019; 7:5283-5291. [PMID: 31603448 DOI: 10.1039/c9bm01418g] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Inhibition of tumor growth and metastasis simultaneously is an important issue for tumor therapy. The CXCR4/CXCL12 axis plays a crucial role in cancer metastasis, and the blocking of the CXCR4/CXCL12 axis is an effective way of inhibiting cancer metastasis. Combretastatin A4 nanodrug (CA4-NPs), a neogenesis blood vascular disrupting agent, can accumulate around blood vessels and disrupt tumor neogenesis of blood vessels more efficaciously than typical small molecular drug combretastatin A4 phosphate (CA4P). However, in this work, we find that the CXCR4 expression is significantly enhanced in CA4-NPs-treated tumor tissues in a metastatic orthotopic 4T1 mammary adenocarcinoma mouse model. Considering that the overexpression of CXCR4 can promote tumor cell metastasis, a novel cooperative strategy that utilizes plerixafor (PLF, CXCR4 antagonist) with CA4-NPs for inhibiting tumor growth and metastasis simultaneously is developed. The combination of CA4-NPs (60 mg kg-1 on CA4 basis) + PLF shows remarkably enhanced antitumor efficacy. The tumor growth inhibition rate of the combination group reaches 91.3%, significantly higher than those of non-cooperative groups. In addition, the number of lung metastasis foci of the combination group is least among all groups. This cooperative strategy provides a useful method for inhibiting tumor growth and metastasis simultaneously, and gives the evidence to support the clinical use of the combination of vascular disruption agents and CXCR4 antagonists.
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Affiliation(s)
- Jian Jiang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China. and School of Applied Chemistry and Engineering, University of Sciences and Technology of China, Hefei 230026, P. R. China and Jilin Biomedical Polymers Engineering Laboratory, Changchun, 130022, P. R. China
| | - Na Shen
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China. and Jilin Biomedical Polymers Engineering Laboratory, Changchun, 130022, P. R. China
| | - Wantong Song
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China. and Jilin Biomedical Polymers Engineering Laboratory, Changchun, 130022, P. R. China
| | - Haiyang Yu
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China. and Jilin Biomedical Polymers Engineering Laboratory, Changchun, 130022, P. R. China
| | - Kazuo Sakurai
- The University of Kitakyushu, Department of Chemistry and Biochemistry, 1-1, Hibikino, Wakamatsu-ku, Kitakyushu, Fukuoka, 808-0135, Japan
| | - Zhaohui Tang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China. and Jilin Biomedical Polymers Engineering Laboratory, Changchun, 130022, P. R. China
| | - Gao Li
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China. and Jilin Biomedical Polymers Engineering Laboratory, Changchun, 130022, P. R. China
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16
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Javan MR, Khosrojerdi A, Moazzeni SM. New Insights Into Implementation of Mesenchymal Stem Cells in Cancer Therapy: Prospects for Anti-angiogenesis Treatment. Front Oncol 2019; 9:840. [PMID: 31555593 PMCID: PMC6722482 DOI: 10.3389/fonc.2019.00840] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 08/15/2019] [Indexed: 12/12/2022] Open
Abstract
Tumor microenvironment interacts with tumor cells, establishing an atmosphere to contribute or suppress the tumor development. Among the cells which play a role in the tumor microenvironment, mesenchymal stem cells (MSCs) have been demonstrated to possess the ability to orchestrate the fate of tumor cells, drawing the attention to the field. MSCs have been considered as cells with double-bladed effects, implicating either tumorigenic or anti-tumor activity. On the other side, the promising potential of MSCs in treating human cancer cells has been observed from the clinical studies. Among the beneficial characteristics of MSCs is the natural tumor-trophic migration ability, providing facility for drug delivery and, therefore, targeted treatment to detach tumor and metastatic cells. Moreover, these cells have been the target of engineering approaches, due to their easily implemented traits, in order to obtain the desired expression of anti-angiogenic, anti-proliferative, and pro-apoptotic properties, according to the tumor type. Tumor angiogenesis is the key characteristic of tumor progression and metastasis. Manipulation of angiogenesis has become an attractive approach for cancer therapy since the introduction of the first angiogenesis inhibitor, namely bevacizumab, for metastatic colorectal cancer therapy. This review tries to conclude the approaches, with focus on anti-angiogenesis approach, in implementing the MSCs to combat against tumor cell progression.
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Affiliation(s)
- Mohammad Reza Javan
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Arezou Khosrojerdi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Mohammad Moazzeni
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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17
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Safety and Tolerability of Anti-Angiogenic Protein Kinase Inhibitors and Vascular-Disrupting Agents in Cancer: Focus on Gastrointestinal Malignancies. Drug Saf 2019; 42:159-179. [PMID: 30649744 DOI: 10.1007/s40264-018-0776-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Angiogenesis is an essential process for tumor growth and metastasis. Inhibition of angiogenesis as an anticancer strategy has shown significant results in a plethora of tumors. Anti-angiogenic agents are currently part of many standard-of-care options for several metastatic gastrointestinal cancers. Bevacizumab, aflibercept, ramucirumab, and regorafenib have significantly improved both progression-free and overall survival in different lines of treatment in metastatic colorectal cancer. Second-line ramucirumab and third-line apatinib are effective anti-angiogenic treatments for patients with metastatic gastric cancer. Unfortunately, the anti-angiogenic strategy has major practical limitations: resistance inevitably develops through redundancy of signaling pathways and selection for subclonal populations adapted for hypoxic conditions. Anti-angiogenic agents may be more effective in combination therapies, with not only cytotoxics but also other emerging compounds in the anti-angiogenic class or in the separate class of the so-called vascular-disrupting agents. This review aims to provide an overview of the approved and "under development" anti-angiogenic compounds as well as the vascular-disrupting agents in the treatment of gastrointestinal cancers, focusing on the actual body of knowledge available on therapy challenges, pharmacodynamic and pharmacokinetic mechanisms, safety profiles, promising predictive biomarkers, and future perspectives.
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18
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Liang Y, Hao Y, Wu Y, Zhou Z, Li J, Sun X, Liu YN. Integrated Hydrogel Platform for Programmed Antitumor Therapy Based on Near Infrared-Triggered Hyperthermia and Vascular Disruption. ACS APPLIED MATERIALS & INTERFACES 2019; 11:21381-21390. [PMID: 31141335 DOI: 10.1021/acsami.9b05536] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Complete tumor regression is a great challenge faced by single therapy of near-infrared (NIR)-triggered hyperthermia or vascular disrupting agents. An injectable nanocomposite (NC) hydrogel is rationally designed for combined anticancer therapy based on NIR-triggered hyperthermia and vascular disruption. The NC hydrogel, codelivered with Prussian blue (PB) nanoparticles and combretastatin A4 (CA4), has good shear-thinning, self-recovery, and excellent photothermal properties. Because of the remarkable tumor-site retention and sustained release of CA4 (about 10% over 12 days), the NC hydrogel has a tumor suppression rate of 99.6%. The programmed combinational therapy conveys the concept of "attack + guard", where PB-based NIR irradiation imposes intensive attack on most of cancer cells, and CA4 serves as a guard against the tumor growth by cutting off the energy supply. Moreover, the biosafety and eco-friendliness of the hydrogel platform pave the way toward clinical applications.
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19
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Ma Y, Xiu Z, Zhou Z, Huang B, Liu J, Wu X, Li S, Tang X. Cytochalasin H Inhibits Angiogenesis via the Suppression of HIF-1α Protein Accumulation and VEGF Expression through PI3K/AKT/P70S6K and ERK1/2 Signaling Pathways in Non-Small Cell Lung Cancer Cells. J Cancer 2019; 10:1997-2005. [PMID: 31205560 PMCID: PMC6548170 DOI: 10.7150/jca.29933] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 03/10/2019] [Indexed: 02/07/2023] Open
Abstract
Our previous study has demonstrated that cytochalasin H (CyH) isolated from mangrove-derived endophytic fungus induces apoptosis and inhibits migration in A549 non-small cell lung cancer (NSCLC) cells. In this study, we further explored the effect of CyH on angiogenesis in NSCLC cells and the underlying molecular mechanisms. A549 and H460 NSCLC cells were treated with different concentrations of CyH for 24 h. The effects of CyH on NSCLC angiogenesis in vitro and in vivo were investigated. Hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression in xenografted NSCLC of nude mice was analyzed by immunohistochemistry. ELISA was used to analyze the concentration of VEGF in the conditioned media derived from treated and untreated NSCLC cells. Western blot was performed to detect the levels of HIF-1α, p-AKT, p-P70S6K, and p-ERK1/2 proteins, and RT-qPCR was used to determine the levels of HIF-1α and VEGF mRNA in A549 and H460 cells. Our results showed that CyH significantly inhibited angiogenesis in vitro and in vivo, and suppressed the hemoglobin content and HIF-1α and VEGF protein expression in xenografted NSCLC tissues of nude mice. Meanwhile, CyH inhibited the secretion of VEGF protein and the expression of HIF-1α protein in A549 and H460 cells. Moreover, CyH had a significant inhibitory effect on VEGF mRNA expression but had no effect on HIF-1α mRNA expression, and CyH inhibited HIF-1α protein expression by promoting the degradation of HIF-1α protein in A549 and H460 cells. Additionally, CyH dramatically inhibited AKT, P70S6K, and ERK1/2 activation in A549 and H460 cells. Taken together, our results suggest that CyH can inhibit NSCLC angiogenesis by the suppression of HIF-1α protein accumulation and VEGF expression through PI3K/AKT/P70S6K and ERK1/2 signaling pathways.
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Affiliation(s)
- Yuefan Ma
- Collaborative innovation center for antitumor active substance research and development, Guangdong Medical University, Zhanjiang 524023, P.R. China.,Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Zihan Xiu
- Collaborative innovation center for antitumor active substance research and development, Guangdong Medical University, Zhanjiang 524023, P.R. China.,Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Zhiyuan Zhou
- Collaborative innovation center for antitumor active substance research and development, Guangdong Medical University, Zhanjiang 524023, P.R. China.,Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Bingyu Huang
- Collaborative innovation center for antitumor active substance research and development, Guangdong Medical University, Zhanjiang 524023, P.R. China.,Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Jiao Liu
- Collaborative innovation center for antitumor active substance research and development, Guangdong Medical University, Zhanjiang 524023, P.R. China.,Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Xiaofeng Wu
- Collaborative innovation center for antitumor active substance research and development, Guangdong Medical University, Zhanjiang 524023, P.R. China.,Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Sanzhong Li
- Collaborative innovation center for antitumor active substance research and development, Guangdong Medical University, Zhanjiang 524023, P.R. China.,Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Xudong Tang
- Collaborative innovation center for antitumor active substance research and development, Guangdong Medical University, Zhanjiang 524023, P.R. China.,Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, P.R. China.,Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang 524023, P.R. China.,Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, P.R. China
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20
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Yang S, Tang Z, Hu C, Zhang D, Shen N, Yu H, Chen X. Selectively Potentiating Hypoxia Levels by Combretastatin A4 Nanomedicine: Toward Highly Enhanced Hypoxia-Activated Prodrug Tirapazamine Therapy for Metastatic Tumors. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2019; 31:e1805955. [PMID: 30680816 DOI: 10.1002/adma.201805955] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 01/13/2019] [Indexed: 06/09/2023]
Abstract
Hypoxia-activated prodrugs (HAPs) have the potential to selectively kill hypoxic cells and convert tumor hypoxia from a problem to a selective treatment advantage. However, HAPs are unsuccessful in most clinical trials owing to inadequate hypoxia within the treated tumors, as implied by a further substudy of a phase II clinical trial. Here, a novel strategy for the combination of HAPs plus vascular disrupting agent (VDA) nanomedicine for efficacious solid tumor therapy is developed. An effective VDA nanomedicine of poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4 (CA4-NPs) is prepared and can selectively enhance tumor hypoxia and boost a typical HAP tirapazamine (TPZ) therapy against metastatic 4T1 breast tumors. After treatment with the combination of TPZ plus CA4-NPs, complete tumor reduction is observed in 4T1 xenograft mice (initial tumor volume is 180 mm3 ), and significant tumor shrinkage and antimetastatic effects are observed in challenging large tumors with initial volume of 500 mm3 . The report here highlights the potential of using a combination of HAPs plus VDA nanomedicine in solid tumor therapy.
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Affiliation(s)
- Shengcai Yang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
- College of Chemistry, Jilin University, Changchun, 130012, P. R. China
| | - Zhaohui Tang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
| | - Chenyang Hu
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
| | - Dawei Zhang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
| | - Na Shen
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
| | - Haiyang Yu
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
| | - Xuesi Chen
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
- College of Chemistry, Jilin University, Changchun, 130012, P. R. China
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21
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Schmitt F, Gold M, Rothemund M, Andronache I, Biersack B, Schobert R, Mueller T. New naphthopyran analogues of LY290181 as potential tumor vascular-disrupting agents. Eur J Med Chem 2019; 163:160-168. [PMID: 30503940 DOI: 10.1016/j.ejmech.2018.11.055] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 10/04/2018] [Accepted: 11/22/2018] [Indexed: 10/27/2022]
Abstract
A series of 19 analogues of the antiproliferative naphthopyran LY290181 were prepared for structure-activity relationship studies. We found the best activities for test compounds bearing small substituents at the meta position of the phenyl ring. The mode of action of LY290181 and eight new analogues was studied in detail. The compounds were highly anti-proliferative with IC50 values in the sub-nanomolar to triple-digit nanomolar range. The new analogues led to G2/M arrest due to interruption of the microtubule dynamics. In 518A2 melanoma cells they caused a mitotic catastrophe which eventually led to apoptosis. The naphthopyrans also induced a disruption of the vasculature in the chorioallantoic membrane (CAM) of fertilized chicken eggs as well as in xenograft tumors in mice. In a preliminary therapy trial, the difluoro derivative 2b retarded the growth of resistant xenograft tumors in mice.
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Affiliation(s)
- Florian Schmitt
- Department of Chemistry, University Bayreuth, Universitaetsstrasse 30, 95440, Bayreuth, Germany
| | - Madeleine Gold
- Department of Chemistry, University Bayreuth, Universitaetsstrasse 30, 95440, Bayreuth, Germany
| | - Matthias Rothemund
- Department of Chemistry, University Bayreuth, Universitaetsstrasse 30, 95440, Bayreuth, Germany
| | - Ion Andronache
- University of Bucharest, Research Center for Integrated Analysis and Territorial Management, 4-12, Regina Elisabeta Avenue, Bucharest, 3rd District, 030018, Romania
| | - Bernhard Biersack
- Department of Chemistry, University Bayreuth, Universitaetsstrasse 30, 95440, Bayreuth, Germany
| | - Rainer Schobert
- Department of Chemistry, University Bayreuth, Universitaetsstrasse 30, 95440, Bayreuth, Germany.
| | - Thomas Mueller
- Department of Internal Medicine IV, Oncology/Hematology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, 06120, Halle, Germany
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22
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Liu J, Jiang M, Li Z, Zhang X, Li X, Hao Y, Su X, Zhu J, Zheng C, Xiao W, Wang Y. A Novel Systems Pharmacology Method to Investigate Molecular Mechanisms of Scutellaria barbata D. Don for Non-small Cell Lung Cancer. Front Pharmacol 2018; 9:1473. [PMID: 30618763 PMCID: PMC6304355 DOI: 10.3389/fphar.2018.01473] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 11/30/2018] [Indexed: 12/15/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most ordinary type of lung cancer which leads to 1/3 of all cancer deaths. At present, cytotoxic chemotherapy, surgical resection, radiation, and photodynamic therapy are the main strategies for NSCLC treatment. However, NSCLC is relatively resistant to the above therapeutic strategies, resulting in a rather low (20%) 5-year survival rate. Therefore, there is imperative to identify or develop efficient lead compounds for the treatment of NSCLC. Here, we report that the herb Scutellaria barbata D. Don (SBD) can effectively treat NSCLC by anti-inflammatory, promoting apoptosis, cell cycle arrest, and angiogenesis. In this work, we analyze the molecular mechanism of SBD for NSCLC treatment by applying the systems pharmacology strategy. This method combines pharmacokinetics analysis with pharmacodynamics evaluation to screen out the active compounds, predict the targets and assess the networks and pathways. Results show that 33 compounds were identified with potential anti-cancer effects. Utilizing these active compounds as probes, we predicted that 145 NSCLC related targets mainly involved four aspects: apoptosis, inflammation, cell cycle, and angiogenesis. And in vitro experiments were managed to evaluate the reliability of some vital active compounds and targets. Overall, a complete overview of the integrated systems pharmacology method provides a precise probe to elucidate the molecular mechanisms of SBD for NSCLC. Moreover, baicalein from SBD effectively inhibited tumor growth in an LLC tumor-bearing mice models, demonstrating the anti-tumor effects of SBD. Our findings further provided experimental evidence for the application in the treatment of NSCLC.
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Affiliation(s)
- Jianling Liu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi’an, China
| | - Meng Jiang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi’an, China
| | - Zhihua Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi’an, China
| | - Xia Zhang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi’an, China
| | - XiaoGang Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi’an, China
| | - Yuanyuan Hao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi’an, China
| | - Xing Su
- Pharmacology Department, School of Pharmacy, Shihezi University, Shihezi, China
| | - Jinglin Zhu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi’an, China
| | - Chunli Zheng
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi’an, China
| | - Wei Xiao
- State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Parmaceutical, Co., Ltd., Lianyungang, China
| | - Yonghua Wang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi’an, China
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23
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Liu YW, De Keyzer F, Feng YB, Chen F, Song SL, Swinnen J, Bormans G, Oyen R, Huang G, Ni YC. Intra-individual comparison of therapeutic responses to vascular disrupting agent CA4P between rodent primary and secondary liver cancers. World J Gastroenterol 2018; 24:2710-2721. [PMID: 29991876 PMCID: PMC6034151 DOI: 10.3748/wjg.v24.i25.2710] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 04/01/2018] [Accepted: 04/09/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To compare therapeutic responses of a vascular-disrupting-agent, combretastatin-A4-phosphate (CA4P), among hepatocellular carcinomas (HCCs) and implanted rhabdomyosarcoma (R1) in the same rats by magnetic-resonance-imaging (MRI), microangiography and histopathology.
METHODS Thirty-six HCCs were created by diethylnitrosamine gavage in 14 rats that were also intrahepatically implanted with one R1 per rat as monitored by T2-/T1-weighted images (T2WI/T1WI) on a 3.0T clinical MRI-scanner. Vascular response and tumoral necrosis were detected by dynamic contrast-enhanced (DCE-) and CE-MRI before, 1 h after and 12 h after CA4P iv at 10 mg/kg (treatment group n = 7) or phosphate-buffered saline at 1.0 mL/kg (control group n = 7). Tumor blood supply was calculated by a semiquantitative DCE parameter of area under the time signal intensity curve (AUC30). In vivo MRI findings were verified by postmortem techniques.
RESULTS On CE-T1WIs, unlike the negative response in all tumors of control animals, in treatment group CA4P caused rapid extensive vascular shutdown in all R1-tumors, but mildly or spottily in HCCs at 1 h. Consequently, tumor necrosis occurred massively in R1-tumors but patchily in HCCs at 12 h. AUC30 revealed vascular closure (66%) in R1-tumors at 1 h (P < 0.05), followed by further perfusion decrease at 12 h (P < 0.01), while less significant vascular clogging occurred in HCCs. Histomorphologically, CA4P induced more extensive necrosis in R1-tumors (92.6%) than in HCCs (50.2%) (P < 0.01); tumor vascularity heterogeneously scored +~+++ in HCCs but homogeneously scored ++ in R1-tumors.
CONCLUSION This study suggests superior performance of CA4P in metastatic over primary liver cancers, which could guide future clinical applications of vascular-disrupting-agents.
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MESH Headings
- Angiography
- Animals
- Antineoplastic Agents, Phytogenic/pharmacology
- Antineoplastic Agents, Phytogenic/therapeutic use
- Carcinoma, Hepatocellular/blood supply
- Carcinoma, Hepatocellular/chemically induced
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/pathology
- Contrast Media/administration & dosage
- Diethylnitrosamine/toxicity
- Humans
- Liver/diagnostic imaging
- Liver/pathology
- Liver Neoplasms/blood supply
- Liver Neoplasms/chemically induced
- Liver Neoplasms/drug therapy
- Liver Neoplasms/pathology
- Liver Neoplasms, Experimental/chemically induced
- Liver Neoplasms, Experimental/diagnostic imaging
- Liver Neoplasms, Experimental/drug therapy
- Liver Neoplasms, Experimental/pathology
- Magnetic Resonance Imaging/methods
- Male
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/pathology
- Rats
- Rhabdomyosarcoma/blood supply
- Rhabdomyosarcoma/drug therapy
- Rhabdomyosarcoma/pathology
- Rhabdomyosarcoma/secondary
- Stilbenes/pharmacology
- Stilbenes/therapeutic use
- Treatment Outcome
- Tumor Microenvironment/drug effects
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Ye-Wei Liu
- Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
- Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, China
| | | | - Yuan-Bo Feng
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | - Feng Chen
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | - Shao-Li Song
- Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Johan Swinnen
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | - Guy Bormans
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | - Raymond Oyen
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | - Gang Huang
- Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
- Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, China
| | - Yi-Cheng Ni
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
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24
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Liu Y, De Keyzer F, Wang Y, Wang F, Feng Y, Chen F, Yu J, Liu J, Song S, Swinnen J, Bormans G, Oyen R, Huang G, Ni Y. The first study on therapeutic efficacies of a vascular disrupting agent CA4P among primary hepatocellular carcinomas with a full spectrum of differentiation and vascularity: Correlation of MRI-microangiography-histopathology in rats. Int J Cancer 2018; 143:1817-1828. [PMID: 29707770 DOI: 10.1002/ijc.31567] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 03/27/2018] [Accepted: 04/10/2018] [Indexed: 12/19/2022]
Abstract
To better inform the next clinical trials of vascular disrupting agent combretastatin-A4-phosphate (CA4P) in patients with hepatic malignancies, this preclinical study aimed at evaluating CA4P therapeutic efficacy in rats with primary hepatocellular carcinomas (HCCs) of a full spectrum of differentiation and vascularity by magnetic resonance imaging (MRI), microangiography and histopathology. Ninety-six HCCs were raised in 25 rats by diethylnitrosamine gavage. Tumor growth was monitored by T2-/T1-weighted-MRI (T2WI, T1WI) using a 3.0 T scanner. Early vascular response and later intratumoral necrosis were detected by dynamic-contrast-enhanced (DCE) MRI and diffusion-weighted-imaging (DWI) before, 1 and 12 hr after CA4P iv-administration. In vivo MRI-findings were validated by postmortem-techniques. Multi-parametric MRI revealed rapid CA4P-induced tumor vascular shutdown within 1 hr, followed by variable intratumoral necrosis at 12 hr. Tumor volumes decreased by 10% at 1 hr (p < 0.05), but resumed at 12 hr. Correlations of semi-quantitative DCE parameter initial-area-under-the-gadolinium-curve (IAUGC30) with histopathology proved partial vascular closure and compensational reopening (p < 0.05). The higher grades of vascularity prevented those residual tumor tissues from CA4P-caused ischemic necrosis. By histopathology using a 4-scale cellular-differentiation criteria and a 4-grade tumor-vascularity classification, percentage of CA4P-induced necrosis negatively correlated with HCC differentiation (r = -0.404, p < 0.001) and tumor vascularity (r = -0.370, p < 0.001). Ordinal-logistic-regression helped to predict early tumor responses to CA4P in terms of tumoral differentiation and vascularity. Our study demonstrated that CA4P could induce vascular shutdown in primary HCCs within 1 hr, resulting in various degrees of tumor necrosis at 12 hr. MRI as a real-time imaging biomarker may help to define tumor vascularity and differentiation and further to predict CA4P therapeutic outcomes.
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Affiliation(s)
- Yewei Liu
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium.,Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China.,Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China
| | | | - Yixin Wang
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Fengna Wang
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Yuanbo Feng
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Feng Chen
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Jie Yu
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Jianjun Liu
- Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shaoli Song
- Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Johan Swinnen
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Guy Bormans
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Raymond Oyen
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Gang Huang
- Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China.,Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China
| | - Yicheng Ni
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
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25
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Huang SW, Lien JC, Kuo SC, Huang TF. DDA suppresses angiogenesis and tumor growth of colorectal cancer in vivo through decreasing VEGFR2 signaling. Oncotarget 2018; 7:63124-63137. [PMID: 27517319 PMCID: PMC5325351 DOI: 10.18632/oncotarget.11152] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 07/26/2016] [Indexed: 12/12/2022] Open
Abstract
As angiogenesis is required for tumor growth and metastasis, suppressing angiogenesis is a promising strategy in limiting tumor progression. Vascular endothelial growth factor (VEGF)-A, a critical pro-angiogenic factor, has thus become an attractive target for therapeutic interventions in cancer. In this study, we explored the underlying mechanisms of a novel anthraquinone derivative DDA in suppressing angiogenesis. DDA inhibited VEGF-A-induced proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs). DDA also reduced VEGF-A-induced microvessel sprouting from aortic rings ex vivo and suppressed neovascularization in vivo. VEGF-A-induced VEGFR1, VEGFR2, FAK, Akt, ERK1/2 or STAT3 phosphorylation was reduced in the presence of DDA. In addition, NRP-1 siRNA reduced VEGF-A's enhancing effects in VEGFR2, FAK and Akt phosphorylation and cell proliferation in HUVECs. DDA disrupted VEGF-A-induced complex formation between NRP-1 and VEGFR2. Furthermore, systemic administration of DDA was shown to suppress tumor angiogenesis and growth in in vivo mouse xenograft models. Taken together, we demonstrated in this study that DDA exhibits anti-angiogenic properties through suppressing VEGF-A signaling. These observations also suggest that DDA might be a potential drug candidate for developing anti-angiogenic agent in the field of cancer and angiogenesis-related diseases.
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Affiliation(s)
- Shiu-Wen Huang
- Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jin-Cherng Lien
- Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan
| | - Sheng-Chu Kuo
- Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan
| | - Tur-Fu Huang
- Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
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26
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Liu Y, Yin T, Keyzer FD, Feng Y, Chen F, Liu J, Song S, Yu J, Vandecaveye V, Swinnen J, Bormans G, Himmelreich U, Oyen R, Zhang J, Huang G, Ni Y. Micro-HCCs in rats with liver cirrhosis: paradoxical targeting effects with vascular disrupting agent CA4P. Oncotarget 2017; 8:55204-55215. [PMID: 28903414 PMCID: PMC5589653 DOI: 10.18632/oncotarget.19339] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 06/27/2017] [Indexed: 12/11/2022] Open
Abstract
We sought to investigate anticancer efficacy of a vascular disrupting agent (VDA) combretastatin A-4 phosphate (CA4P) in relation to tumor size among hepatocellular carcinomas (HCCs) in rats using magnetic resonance imaging (MRI) and postmortem techniques. Nineteen rats with 43 chemically-induced HCCs of 2.8–20.9 mm in size on liver cirrhosis received CA4P intravenously at 10 mg/kg. Tumor-diameter was measured by T2-weighted imaging (T2WI) to define microcancers (< 5 mm) versus larger HCCs. Vascular responses and tissue necrosis were detected by diffusion-weighted imaging (DWI), contrast-enhanced T1-weighted imaging (CE-T1WI) and dynamic contrast enhanced (DCE-) MRI, which were validated by microangiography and histopathology. MRI revealed nearly complete necrosis in 5 out of 7 micro-HCCs, but diverse therapeutic necrosis in larger HCCs with a positive correlation with tumor size. Necrosis in micro-HCCs was 36.9% more than that in larger HCCs. While increased diffusion coefficient (ADCdiff) suggested tumor necrosis, perfusion coefficient (ADCperf) indicated sharply decreased blood perfusion in cirrhotic liver together with a reduction in micro-HCCs. DCE revealed lowered tumor blood flow from intravascular into extravascular extracellular space (EES). Microangiography and histopathology revealed hypo- and hypervascularity in 4 and 3 micro-HCCs, massive, partial and minor degrees of tumoral necrosis in 5, 1 and 1 micro-HCCs respectively, and patchy necrotic foci in cirrhotic liver. CD34-PAS staining implicated that poorly vascularized micro-HCCs growing on liver cirrhosis tended to respond better to CA4P treatment. In this study, more complete CA4P-response occurred unexpectedly in micro-HCCs in rats, along with CA4P-induced necrotic foci in cirrhotic liver. These may help to plan clinical applications of VDAs in patients with HCCs and liver cirrhosis.
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Affiliation(s)
- Yewei Liu
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium.,Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.,Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.,Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, China
| | - Ting Yin
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | | | - Yuanbo Feng
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | - Feng Chen
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | - Jianjun Liu
- Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Shaoli Song
- Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Jie Yu
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | | | - Johan Swinnen
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | - Guy Bormans
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | - Uwe Himmelreich
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | - Raymond Oyen
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | - Jian Zhang
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China
| | - Gang Huang
- Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.,Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.,Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, China
| | - Yicheng Ni
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium.,Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China
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27
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Yang MH, Chang KJ, Zheng JC, Huang H, Sun GY, Zhao XW, Li B, Xiu QY. Anti-angiogenic effect of arsenic trioxide in lung cancer via inhibition of endothelial cell migration, proliferation and tube formation. Oncol Lett 2017; 14:3103-3109. [PMID: 28928847 DOI: 10.3892/ol.2017.6518] [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: 09/22/2015] [Accepted: 03/10/2017] [Indexed: 12/20/2022] Open
Abstract
Arsenic trioxide (As2O3) exhibits a remarkable effect on leukemia treatment; however, its effect on solid tumors remains poorly explored. The present study demonstrated the inhibitory effect of As2O3 on lung cancer and explored its possible mechanism. It was observed that As2O3 significantly inhibited the growth of lung cancer xenografts and tumor angiogenesis in vivo. The inhibitory effect of As2O3 on cell proliferation in vitro was more remarkable in vascular endothelial cells than in lung cancer cells. It was also observed that As2O3 inhibited the migration of vascular endothelial cells and disrupted vascular tube formation on Matrigel assays. In addition, a series of key signaling factors involved in multiple stages of angiogenesis, including matrix metalloproteinase (MMP)-2, MMP-9, platelet-derived growth factor (PDGF)-BB/PDGF receptor-β, vascular endothelial growth factor (VEGF)-A/VEGF receptor-2, basic fibroblast growth factor (FGF)/FGF receptor-1 and delta like canonical Notch ligand 4/Notch-1, were regulated by As2O3. These findings suggested that anti-angiogenesis may be an underlying mechanism of As2O3 anticancer activity in lung cancer.
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Affiliation(s)
- Meng-Hang Yang
- Department of Respiratory Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Ke-Jie Chang
- Department of Respiratory Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Jin-Cheng Zheng
- Department of Respiratory Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Hai Huang
- Department of Respiratory Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Guang-Yuan Sun
- Department of Thoracic Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Xue-Wei Zhao
- Department of Thoracic Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Bing Li
- Department of Respiratory Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Qing-Yu Xiu
- Department of Respiratory Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
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28
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Chen X. Prediction of optimal gene functions for osteosarcoma using network-based- guilt by association method based on gene oncology and microarray profile. J Bone Oncol 2017; 7:18-22. [PMID: 28443230 PMCID: PMC5396855 DOI: 10.1016/j.jbo.2017.04.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 04/05/2017] [Accepted: 04/06/2017] [Indexed: 01/21/2023] Open
Abstract
In the current study, we planned to predict the optimal gene functions for osteosarcoma (OS) by integrating network-based method with guilt by association (GBA) principle (called as network-based gene function inference approach) based on gene oncology (GO) data and gene expression profile. To begin with, differentially expressed genes (DEGs) were extracted using linear models for microarray data (LIMMA) package. Then, construction of differential co-expression network (DCN) relying on DEGs was implemented, and sub-DCN was identified using Spearman correlation coefficient (SCC). Subsequently, GO annotations for OS were collected according to known confirmed database and DEGs. Ultimately, gene functions were predicted by means of GBA principle based on the area under the curve (AUC) for GO terms, and we determined GO terms with AUC >0.7 as the optimal gene functions for OS. Totally, 123 DEGs and 137 GO terms were obtained for further analysis. A DCN was constructed, which included 123 DEGs and 7503 interactions. A total of 105 GO terms were identified when the threshold was set as AUC >0.5, which had a good classification performance. Among these 105 GO terms, 2 functions had the AUC >0.7 and were determined as the optimal gene functions including angiogenesis (AUC =0.767) and regulation of immune system process (AUC =0.710). These gene functions appear to have potential for early detection and clinical treatment of OS in the future.
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29
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Chen L, Li J, Wang F, Dai C, Wu F, Liu X, Li T, Glauben R, Zhang Y, Nie G, He Y, Qin Z. Tie2 Expression on Macrophages Is Required for Blood Vessel Reconstruction and Tumor Relapse after Chemotherapy. Cancer Res 2016; 76:6828-6838. [PMID: 27758887 DOI: 10.1158/0008-5472.can-16-1114] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 08/18/2016] [Accepted: 09/14/2016] [Indexed: 11/16/2022]
Abstract
Tumor relapse after chemotherapy is a major hurdle for successful cancer therapy. Chemotherapeutic drugs select for resistant tumor cells and reshape tumor microenvironment, including the blood supply system. Using animal models, we observed on macrophages in tumor tissue a close correlation between upregulated Tie2 expression and tumor relapse upon chemotherapy. Conditional deletion of Tie2 expression in macrophages significantly prohibited blood supply and regrowth of tumors. Tie2+ macrophages were derived from tumor-infiltrating Tie2-CD11b+ cells and hypoxia-induced Tie2 expression on these cells. Mechanistically, expression of Tie2 prevented macrophages from apoptosis in stress conditions via the AKT-dependent signaling pathway. Together, these results demonstrate that Tie2 expression by macrophages is necessary and sufficient to promote the reconstruction of blood vessels after chemotherapy, shedding new light on developing novel strategies to inhibit tumor relapse. Cancer Res; 76(23); 6828-38. ©2016 AACR.
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Affiliation(s)
- Lin Chen
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Jie Li
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Fei Wang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Chengliang Dai
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Fan Wu
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Xiaoman Liu
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Taotao Li
- Laboratory of Vascular and Cancer Biology, Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Thrombosis and Hemostasis Key Lab of the Ministry of Health, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, China
| | - Rainer Glauben
- Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Medical Department I, Berlin, Germany
| | - Yi Zhang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Guangjun Nie
- National Centre for Nanoscience and Technology of China, Beijing, China
| | - Yulong He
- Laboratory of Vascular and Cancer Biology, Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Thrombosis and Hemostasis Key Lab of the Ministry of Health, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, China.
| | - Zhihai Qin
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
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30
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Kunjachan S, Detappe A, Kumar R, Ireland T, Cameron L, Biancur DE, Motto-Ros V, Sancey L, Sridhar S, Makrigiorgos GM, Berbeco RI. Nanoparticle Mediated Tumor Vascular Disruption: A Novel Strategy in Radiation Therapy. NANO LETTERS 2015; 15:7488-96. [PMID: 26418302 PMCID: PMC5507193 DOI: 10.1021/acs.nanolett.5b03073] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
More than 50% of all cancer patients receive radiation therapy. The clinical delivery of curative radiation dose is strictly restricted by the proximal healthy tissues. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. The resulting tumor vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/nanoparticle toxicity, extending its utility to intransigent or nonresectable tumors that barely respond to standard therapies.
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Affiliation(s)
- Sijumon Kunjachan
- Department of Radiation Oncology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Alexandre Detappe
- Department of Radiation Oncology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, United States
- Institut Lumière Matière, Université Claude Bernard Lyon1-CNRS, Université de Lyon, 69007 Lyon, France
| | - Rajiv Kumar
- Department of Radiation Oncology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, United States
- Nanomedicine Science and Technology Center and Department of Physics, Northeastern University, Boston, Massachusetts 02115, United States
| | - Thomas Ireland
- LA-ICP-MS and ICP-ES Laboratories, Boston University, Boston, Massachusetts 02215, United States
| | - Lisa Cameron
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
| | - Douglas E. Biancur
- Department of Radiation Oncology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Vincent Motto-Ros
- Institut Lumière Matière, Université Claude Bernard Lyon1-CNRS, Université de Lyon, 69007 Lyon, France
| | - Lucie Sancey
- Institut Lumière Matière, Université Claude Bernard Lyon1-CNRS, Université de Lyon, 69007 Lyon, France
| | - Srinivas Sridhar
- Department of Radiation Oncology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, United States
- Nanomedicine Science and Technology Center and Department of Physics, Northeastern University, Boston, Massachusetts 02115, United States
| | - G. Mike Makrigiorgos
- Department of Radiation Oncology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Ross I. Berbeco
- Department of Radiation Oncology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, United States
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31
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Kawczyk-Krupka A, Wawrzyniec K, Musiol SK, Potempa M, Bugaj AM, Sieroń A. Treatment of localized prostate cancer using WST-09 and WST-11 mediated vascular targeted photodynamic therapy-A review. Photodiagnosis Photodyn Ther 2015; 12:567-74. [PMID: 26467273 DOI: 10.1016/j.pdpdt.2015.10.001] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Revised: 09/23/2015] [Accepted: 10/06/2015] [Indexed: 10/22/2022]
Abstract
BACKGROUND Photodynamic therapy (PDT) is well known for its direct cytotoxicity of the free radical-producing photochemical reaction, indirect mechanisms of action including modulation of intrinsic anti-tumour immune activity, and occlusion of pathologically altered tumour vessels leading to tumour ischaemia. The aim of this work is to critically review the evidence base for the use of vascular targeted PDT (VTP) to treat low-risk prostate cancer, and to discuss perspectives and challenges yet to be overcome. A brief general overview of focal prostate cancer therapy was provided, followed by a discussion of both basic and clinical research pertaining to prostate cancer VTP, with a focus on the palladium-based WST-09 and WST-11 photosensitisers. MATERIALS AND METHOD Literature on VTP for prostate cancer with the fallowing medical subject headings search terms: prostate cancer, photodynamic therapy, vascular targeted photodynamic therapy, bacteriopheophorbide were reviewed. The articles were selected by their relevance to the topic. RESULTS The clinical and basic research data available to date show much promise for WST-09, and WST-11 based VTP eventually joining the standard urologist's armamentarium against prostate cancer. With good reported tolerability and efficacy VTP can be proposed as an intermediate treatment for local low risk disease, halfway between watchful waiting and radical therapy.
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Affiliation(s)
- A Kawczyk-Krupka
- School of Medicine with the Division of Dentistry in Zabrze, Department and Clinic of Internal Diseases, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia, Batorego Street 15, 41-902 Bytom, Poland.
| | - K Wawrzyniec
- Department of Internal Diseases, 11 Listopada 48, 28-200 Staszów, Poland
| | - S K Musiol
- School of Clinical Medicine, University of Cambridge, Cambridge, Addenbrooke's Hospital, Hills Rd, Cambridge CB2 OSP, United Kingdom
| | - M Potempa
- School of Medicine with the Division of Dentistry in Zabrze, Department and Clinic of Internal Diseases, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia, Batorego Street 15, 41-902 Bytom, Poland
| | - A M Bugaj
- School of Medicine with the Division of Dentistry in Zabrze, Department and Clinic of Internal Diseases, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia, Batorego Street 15, 41-902 Bytom, Poland; College of Health, Beauty Care and Education, Brzeźnicka 3, 60-133 Poznań, Poland
| | - A Sieroń
- School of Medicine with the Division of Dentistry in Zabrze, Department and Clinic of Internal Diseases, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia, Batorego Street 15, 41-902 Bytom, Poland
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32
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Liang F, Han Y, Gao H, Xin S, Chen S, Wang N, Qin W, Zhong H, Lin S, Yao X, Li S. Kaempferol Identified by Zebrafish Assay and Fine Fractionations Strategy from Dysosma versipellis Inhibits Angiogenesis through VEGF and FGF Pathways. Sci Rep 2015; 5:14468. [PMID: 26446489 PMCID: PMC4597183 DOI: 10.1038/srep14468] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Accepted: 08/28/2015] [Indexed: 11/09/2022] Open
Abstract
Natural products are a rich resource for the discovery of therapeutic substances. By directly using 504 fine fractions from isolated traditional Chinese medicine plants, we performed a transgenic zebrafish based screen for anti-angiogenesis substances. One fraction, DYVE-D3, was found to inhibit the growth of intersegmental vessels in the zebrafish vasculature. Bioassay-guided isolation of DYVE-D3 indicates that the flavonoid kaempferol was the active substance. Kaempferol also inhibited the proliferation and migration of HUVECs in vitro. Furthermore, we found that kaempferol suppressed angiogenesis through inhibiting VEGFR2 expression, which can be enhanced by FGF inhibition. In summary, this study shows that the construction of fine fraction libraries allows efficient identification of active substances from natural products.
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Affiliation(s)
- Fang Liang
- Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, 518055, China
| | - Yuxiang Han
- Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, 518055, China
| | - Hao Gao
- Institute of Traditional Chinese Medicine &Natural Products, College of Pharmacy, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Shengchang Xin
- Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, 518055, China
| | - Shaodan Chen
- Institute of Traditional Chinese Medicine &Natural Products, College of Pharmacy, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Nan Wang
- Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, 518055, China
| | - Wei Qin
- Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, 518055, China
| | - Hanbing Zhong
- Department of Biology, South University of Science and Technology of China, Shenzhen, 518055, China
| | - Shuo Lin
- Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, 518055, China.,Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Xinsheng Yao
- Institute of Traditional Chinese Medicine &Natural Products, College of Pharmacy, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Song Li
- Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, 518055, China
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Huang SW, Lien JC, Kuo SC, Huang TF. PPemd26, an anthraquinone derivative, suppresses angiogenesis via inhibiting VEGFR2 signalling. Br J Pharmacol 2015; 171:5728-42. [PMID: 25091695 DOI: 10.1111/bph.12872] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 07/25/2014] [Accepted: 07/29/2014] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND PURPOSE Angiogenesis contributes to coronary heart disease, immune disorders and numerous malignancies. VEGF-A and its receptors (VEGFRs) play a pivotal role in regulating angiogenesis. In an effort to discover more effective inhibitors of tumour angiogenesis, we have analysed the actions of a novel anthraquinone derivative, PPemd26, and explored its anti-angiogenic mechanisms. EXPERIMENTAL APPROACH The effects of PPemd26 were evaluated in vitro using HUVEC cultures to assess proliferation, migration, invasion and tube formation. Immunoblotting was used to analyse phosphorylation of signalling kinases. Effects in vivo were assayed using Matrigel plug and xenograft mouse models. KEY RESULTS PPemd26 significantly inhibited VEGF-A-induced proliferation, migration, invasion and tube formation of HUVECs. PPemd26 also attenuated VEGF-A-induced microvessel sprouting from rat aortic rings ex vivo and suppressed formation of new blood vessels in implanted Matrigel plugs in models of angiogenesis in vivo. In addition, PPemd26 inhibited VEGF-A-induced phosphorylation of VEGFR2 and its downstream protein kinases including Akt, focal adhesion kinase, ERK and Src. Furthermore, systemic administration of PPemd26 suppressed the growth of s.c. xenografts of human colon carcinoma in vivo. Histochemical analysis of the xenografts revealed a marked reduction in stainingfor the vascular marker CD31 and proliferation marker Ki-67. CONCLUSIONS AND IMPLICATIONS This study provides evidence that PPemd26 suppressed tumour angiogenesis through inhibiting VEGFR2 signalling pathways, suggesting that PPemd26 is a potential drug candidate for developing anti-angiogenic agents for the treatment of cancer and angiogenesis-related diseases.
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Affiliation(s)
- S W Huang
- Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
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Fotopoulou C, Coleman RL. International Gynecologic Cancer Society (IGCS) 2014: Meeting report. Gynecol Oncol 2015. [DOI: 10.1016/j.ygyno.2015.01.527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Peripherally cross-linking the shell of core-shell polymer micelles decreases premature release of physically loaded combretastatin A4 in whole blood and increases its mean residence time and subsequent potency against primary murine breast tumors after IV administration. Pharm Res 2014; 32:1028-44. [PMID: 25223962 DOI: 10.1007/s11095-014-1515-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2014] [Accepted: 09/05/2014] [Indexed: 01/16/2023]
Abstract
PURPOSE Determine the feasibility and potential benefit of peripherally cross-linking the shell of core-shell polymer micelles on the premature release of physically loaded hydrophobic drug in whole blood and subsequent potency against solid tumors. METHODS Individual Pluronic F127 polymer micelles (F127 PM) peripherally cross-linked with ethylenediamine at 76% of total PEO blocks (X-F127 PM) were physically loaded with combretastatin A4 (CA4) by the solid dispersion method and compared to CA4 physically loaded in uncross-linked F127 PM, CA4 in DMSO in vitro, or water-soluble CA4 phosphate (CA4P) in vivo. RESULTS X-F127 PM had similar CA4 loading and aqueous solubility as F127 PM up to 10 mg CA4 / mL at 22.9 wt% and did not aggregate in PBS or 90% (v/v) human serum at 37°C for at least 24 h. In contrast, X-F127 PM decreased the unbound fraction of CA4 in whole blood (fu) and increased the mean plasma residence time and subsequent potency of CA4 against the vascular function and growth of primary murine 4T1 breast tumors over CA4 in F127 PM and water-soluble CA4P after IV administration. CONCLUSIONS Given that decreasing the fu is an indication of decreased drug release, peripherally cross-linking the shell of core-shell polymer micelles may be a simple approach to decrease premature release of physically loaded hydrophobic drug in the blood and increase subsequent potency in solid tumors.
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Ngwa W, Kumar R, Sridhar S, Korideck H, Zygmanski P, Cormack RA, Berbeco R, Makrigiorgos GM. Targeted radiotherapy with gold nanoparticles: current status and future perspectives. Nanomedicine (Lond) 2014; 9:1063-82. [PMID: 24978464 PMCID: PMC4143893 DOI: 10.2217/nnm.14.55] [Citation(s) in RCA: 130] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Radiation therapy (RT) is the treatment of cancer and other diseases with ionizing radiation. The ultimate goal of RT is to destroy all the disease cells while sparing healthy tissue. Towards this goal, RT has advanced significantly over the past few decades in part due to new technologies including: multileaf collimator-assisted modulation of radiation beams, improved computer-assisted inverse treatment planning, image guidance, robotics with more precision, better motion management strategies, stereotactic treatments and hypofractionation. With recent advances in nanotechnology, targeted RT with gold nanoparticles (GNPs) is actively being investigated as a means to further increase the RT therapeutic ratio. In this review, we summarize the current status of research and development towards the use of GNPs to enhance RT. We highlight the promising emerging modalities for targeted RT with GNPs and the corresponding preclinical evidence supporting such promise towards potential clinical translation. Future prospects and perspectives are discussed.
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Affiliation(s)
- Wilfred Ngwa
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham & Women’s Hospital & Harvard Medical School, Boston, MA 02215, USA
| | - Rajiv Kumar
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham & Women’s Hospital & Harvard Medical School, Boston, MA 02215, USA
- Electronic Materials Research Institute & Department of Physics, Northeastern University, Boston, MA 02115, USA
| | - Srinivas Sridhar
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham & Women’s Hospital & Harvard Medical School, Boston, MA 02215, USA
- Electronic Materials Research Institute & Department of Physics, Northeastern University, Boston, MA 02115, USA
| | - Houari Korideck
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham & Women’s Hospital & Harvard Medical School, Boston, MA 02215, USA
| | - Piotr Zygmanski
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham & Women’s Hospital & Harvard Medical School, Boston, MA 02215, USA
| | - Robert A Cormack
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham & Women’s Hospital & Harvard Medical School, Boston, MA 02215, USA
| | - Ross Berbeco
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham & Women’s Hospital & Harvard Medical School, Boston, MA 02215, USA
| | - G Mike Makrigiorgos
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham & Women’s Hospital & Harvard Medical School, Boston, MA 02215, USA
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Kretzschmann VK, Gellrich D, Ullrich A, Zahler S, Vollmar AM, Kazmaier U, Fürst R. Novel Tubulin Antagonist Pretubulysin Displays Antivascular Properties In Vitro and In Vivo. Arterioscler Thromb Vasc Biol 2014; 34:294-303. [DOI: 10.1161/atvbaha.113.302155] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Objective—
Pretubulysin (PT) is a novel, synthetically accessible myxobacterial compound that acts as a tubulin-depolymerizing agent and inhibits cancer cell growth in vitro and in vivo. Moreover, PT was found to attenuate tumor angiogenesis. Here, we hypothesized that PT could exert antivascular activities on existing tumor vessels.
Approach and Results—
We aimed to characterize the antivascular effects of PT and to elucidate the underlying mechanisms in endothelial cells. In vitro, PT rapidly induced endothelial hyperpermeability and a concentration-dependent disassembly of established endothelial tubes on Matrigel and in an ex vivo aortic ring model. It disrupted endothelial cell junctions and triggered F-actin stress fiber formation and cell contraction by the RhoA/Rho-associated protein kinase pathway without causing cell death. In vivo, using a hamster dorsal skinfold chamber preparation, PT significantly decreased blood flow and vessel diameter in hamster A-Mel-3 amelanotic melanoma tumors but not in the neighboring healthy tissue. In a second tumor model using mice with subcutaneous murine B16 melanoma tumors, a single dose of PT (10 mg/kg) caused a shut down of tumor blood flow and a strong central tumor cell necrosis within 24 hours. Repeated PT administration significantly decelerates tumor growth and seems to be well tolerated.
Conclusions—
In summary, we could show for the first time that the antitumor effect of PT is, at least in part, mediated via its antivascular activities on existing tumor vessels.
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Affiliation(s)
- Verena K. Kretzschmann
- From the Department of Pharmacy, Pharmaceutical Biology (V.K.K., S.Z., A.M.V.) and Walter-Brendel-Center for Experimental Medicine (D.G.), University of Munich, Munich, Germany; Institute of Organic Chemistry, Saarland University, Saarbrücken, Germany (A.U., U.K.); and Institute of Pharmaceutical Biology, Biocenter, Goethe-University Frankfurt, Frankfurt am Main, Germany (V.K.K., R.F.)
| | - Donata Gellrich
- From the Department of Pharmacy, Pharmaceutical Biology (V.K.K., S.Z., A.M.V.) and Walter-Brendel-Center for Experimental Medicine (D.G.), University of Munich, Munich, Germany; Institute of Organic Chemistry, Saarland University, Saarbrücken, Germany (A.U., U.K.); and Institute of Pharmaceutical Biology, Biocenter, Goethe-University Frankfurt, Frankfurt am Main, Germany (V.K.K., R.F.)
| | - Angelika Ullrich
- From the Department of Pharmacy, Pharmaceutical Biology (V.K.K., S.Z., A.M.V.) and Walter-Brendel-Center for Experimental Medicine (D.G.), University of Munich, Munich, Germany; Institute of Organic Chemistry, Saarland University, Saarbrücken, Germany (A.U., U.K.); and Institute of Pharmaceutical Biology, Biocenter, Goethe-University Frankfurt, Frankfurt am Main, Germany (V.K.K., R.F.)
| | - Stefan Zahler
- From the Department of Pharmacy, Pharmaceutical Biology (V.K.K., S.Z., A.M.V.) and Walter-Brendel-Center for Experimental Medicine (D.G.), University of Munich, Munich, Germany; Institute of Organic Chemistry, Saarland University, Saarbrücken, Germany (A.U., U.K.); and Institute of Pharmaceutical Biology, Biocenter, Goethe-University Frankfurt, Frankfurt am Main, Germany (V.K.K., R.F.)
| | - Angelika M. Vollmar
- From the Department of Pharmacy, Pharmaceutical Biology (V.K.K., S.Z., A.M.V.) and Walter-Brendel-Center for Experimental Medicine (D.G.), University of Munich, Munich, Germany; Institute of Organic Chemistry, Saarland University, Saarbrücken, Germany (A.U., U.K.); and Institute of Pharmaceutical Biology, Biocenter, Goethe-University Frankfurt, Frankfurt am Main, Germany (V.K.K., R.F.)
| | - Uli Kazmaier
- From the Department of Pharmacy, Pharmaceutical Biology (V.K.K., S.Z., A.M.V.) and Walter-Brendel-Center for Experimental Medicine (D.G.), University of Munich, Munich, Germany; Institute of Organic Chemistry, Saarland University, Saarbrücken, Germany (A.U., U.K.); and Institute of Pharmaceutical Biology, Biocenter, Goethe-University Frankfurt, Frankfurt am Main, Germany (V.K.K., R.F.)
| | - Robert Fürst
- From the Department of Pharmacy, Pharmaceutical Biology (V.K.K., S.Z., A.M.V.) and Walter-Brendel-Center for Experimental Medicine (D.G.), University of Munich, Munich, Germany; Institute of Organic Chemistry, Saarland University, Saarbrücken, Germany (A.U., U.K.); and Institute of Pharmaceutical Biology, Biocenter, Goethe-University Frankfurt, Frankfurt am Main, Germany (V.K.K., R.F.)
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Anti-cancer activity of an osthole derivative, NBM-T-BMX-OS01: targeting vascular endothelial growth factor receptor signaling and angiogenesis. PLoS One 2013; 8:e81592. [PMID: 24312323 PMCID: PMC3842266 DOI: 10.1371/journal.pone.0081592] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Accepted: 10/15/2013] [Indexed: 12/27/2022] Open
Abstract
Angiogenesis occurs during tissue growth, development and wound healing. It is also required for tumor progression and represents a rational target for therapeutic intervention. NBM-T-BMX-OS01 (BMX), derived from the semisynthesis of osthole, an active ingredient isolated from Chinese herb Cnidium monnieri (L.) Cuss., was recently shown to enhance learning and memory in rats. In this study, we characterized the anti-angiogenic activities of NBM-T-BMX-OS01 (BMX) in an effort to develop novel inhibitors to suppress angiogenesis and tumor growth. BMX inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration and endothelial tube formation in human umbilical endothelial cells (HUVECs). BMX also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo and reduced HCT116 colorectal cancer cells-induced angiogenesis in vivo. Moreover, BMX inhibited the phosphorylation of VEGFR2, FAK, Akt and ERK in HUVECs exposed to VEGF. BMX was also shown to inhibit HCT116 cell proliferation and to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. Taken together, this study provides evidence that BMX modulates vascular endothelial cell remodeling and leads to the inhibition of tumor angiogenesis. These results also support the role of BMX as a potential drug candidate and warrant the clinical development in the treatment of cancer.
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El Kaffas A, Al-Mahrouki A, Tran WT, Giles A, Czarnota GJ. Sunitinib effects on the radiation response of endothelial and breast tumor cells. Microvasc Res 2013; 92:1-9. [PMID: 24215790 DOI: 10.1016/j.mvr.2013.10.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Revised: 10/04/2013] [Accepted: 10/31/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND Endothelial cells are suggested regulators of tumor response to radiation. Anti-vascular targeting agents can enhance tumor response by targeting endothelial cells. Here, we have conducted experiments in vitro to discern the effects of radiation combined with the anti-angiogenic Sunitinib on endothelial (HUVEC) and tumor (MDA-MB-231) cells, and further compared findings to results obtained in vivo. METHODS In vitro and in vivo treatments consisted of single dose radiation therapy of 2, 4, 8 or 16 Gy administered alone or in combination with bFGF or Sunitinib. In vitro, in situ end labeling (ISEL) was used to assess 24-hour apoptotic cell death, and clonogenic assays were used to assess long-term response. In vivo MDA-MB-231 tumors were grown in CB-17 SCID mice. The vascular marker CD31 was used to assess 24-hour acute response while tumor clonogenic assays were used to assess long-term tumor cell viability following treatments. RESULTS Using in vitro studies, we observed an enhanced endothelial cell response to radiation doses of 8 and 16 Gy when compared to tumor cells. Administering Sunitinib alone significantly increased HUVEC cell death, while having modest additive effects when combined with radiation. Sunitinib also increased tumor cell death when combined with 8 and 16 Gy radiation doses. In comparison, we found that the clonogenic response of in vivo treated tumor cells more closely resembled that of in vitro treated endothelial cells than in vitro treated tumor cells. CONCLUSION Our results indicate that the endothelium is an important regulator of tumor response to radiotherapy, and that Sunitinib can enhance tumor radiosensitivity. To the best of our knowledge, this is the first time that Sunitinib is investigated in combination with radiotherapy on the MDA-MB-231 breast cancer cell line.
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Affiliation(s)
- Ahmed El Kaffas
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Azza Al-Mahrouki
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - William T Tran
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Anoja Giles
- Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Gregory J Czarnota
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
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Denaro N, Nigro CL, Russi EG, Merlano MC. The role of chemotherapy and latest emerging target therapies in anaplastic thyroid cancer. Onco Targets Ther 2013; 9:1231-41. [PMID: 24092989 PMCID: PMC3787923 DOI: 10.2147/ott.s46545] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Anaplastic thyroid cancer represents 1%–2% of thyroid cancers. For its aggressiveness, it
is considered a systemic disease at the time of diagnosis. Surgery remains the cornerstone of
therapy in resectable tumor. Traditional chemotherapy has little effect on metastatic disease. A
multimodality approach, incorporating cytoreductive surgical resection, chemoradiation, either
concurrently or sequentially, and new promising target therapies is advisable. Doxorubicin is the
most commonly used agent, with a response rate of 22%. Recently, other chemotherapy agents have been
used, such as paclitaxel and gemcitabine, with superimposable activity and response rates of
10%–20%. However, survival of patients with anaplastic thyroid cancer has changed little in
the past 50 years, despite more aggressive systemic and radiotherapies. Several new agents are
currently under investigation. Some of them, such as sorafenib, imatinib, and axitinib have been
tested in small clinical trials, showing promising disease control rates ranging from
35%–75%. Referral of patients for participation in clinical trials is needed.
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Affiliation(s)
- Nerina Denaro
- Oncology Department, AO S Croce e Carle, Messina, Italy ; Human Pathology Department, Messina University, Messina, Italy
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Li J, Oyen R, Verbruggen A, Ni Y. Small Molecule Sequential Dual-Targeting Theragnostic Strategy (SMSDTTS): from Preclinical Experiments towards Possible Clinical Anticancer Applications. J Cancer 2013; 4:133-45. [PMID: 23412554 PMCID: PMC3572405 DOI: 10.7150/jca.5635] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Accepted: 01/03/2013] [Indexed: 01/02/2023] Open
Abstract
Hitting the evasive tumor cells proves challenging in targeted cancer therapies. A general and unconventional anticancer approach namely small molecule sequential dual-targeting theragnostic strategy (SMSDTTS) has recently been introduced with the aims to target and debulk the tumor mass, wipe out the residual tumor cells, and meanwhile enable cancer detectability. This dual targeting approach works in two steps for systemic delivery of two naturally derived drugs. First, an anti-tubulin vascular disrupting agent, e.g., combretastatin A4 phosphate (CA4P), is injected to selectively cut off tumor blood supply and to cause massive necrosis, which nevertheless always leaves peripheral tumor residues. Secondly, a necrosis-avid radiopharmaceutical, namely 131I-hypericin (131I-Hyp), is administered the next day, which accumulates in intratumoral necrosis and irradiates the residual cancer cells with beta particles. Theoretically, this complementary targeted approach may biologically and radioactively ablate solid tumors and reduce the risk of local recurrence, remote metastases, and thus cancer mortality. Meanwhile, the emitted gamma rays facilitate radio-scintigraphy to detect tumors and follow up the therapy, hence a simultaneous theragnostic approach. SMSDTTS has now shown promise from multicenter animal experiments and may demonstrate unique anticancer efficacy in upcoming preliminary clinical trials. In this short review article, information about the two involved agents, the rationale of SMSDTTS, its preclinical antitumor efficacy, multifocal targetability, simultaneous theragnostic property, and toxicities of the dose regimens are summarized. Meanwhile, possible drawbacks, practical challenges and future improvement with SMSDTTS are discussed, which hopefully may help to push forward this strategy from preclinical experiments towards possible clinical applications.
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Affiliation(s)
- Junjie Li
- 1. Department of Imaging and Pathology, Biomedical Sciences Group; KU Leuven, Belgium. ; 2. Molecular Small Animal Imaging Center, Faculty of Medicine; KU Leuven, Belgium
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Mita MM, Sargsyan L, Mita AC, Spear M. Vascular-disrupting agents in oncology. Expert Opin Investig Drugs 2013; 22:317-28. [PMID: 23316880 DOI: 10.1517/13543784.2013.759557] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
INTRODUCTION Vascular-disrupting agents (VDAs) are a new class of oncology drugs, which specifically target established tumor neovasculature and have a relatively low toxicity profile. VDAs generally have non-overlapping side effects when concomitantly used with conventional cytotoxics. Several members of the VDA class have recently progressed through mid-to-late stages of clinical trials. AREAS COVERED We examined recent publications on preclinical findings and Phase I/II/III clinical trial data on mechanisms of actions, toxicities, and optimal use of VDA class drugs. It is becoming apparent that VDAs should be used in combination with other classes of cytotoxic agents for the optimization of their effect in treating various cancers. In this article we describe doses, timing of delivery, and sequence of combined therapy. We also address the combined mechanisms of actions of VDAs and conventional cytotoxic medications. EXPERT OPINION Vascular-disrupting agents represent a new class of promising anticancer agents, which exhibit synergistic and/or additive effects in combination with many conventional cytotoxics. Pharmacological evaluation of the optimal combinations of VDAs with agents of other classes and drug interactions need to be continued. Further clinical and preclinical studies are required for distinguishing cancer patients' subpopulations that would most benefit from VDAs, identifying tumor biomarkers predictive of response as well as reliable and reproducible imaging and/or biological assays indicative of pharmacodynamic effects, and establishing clinical algorithms for treatment.
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Affiliation(s)
- Monica M Mita
- Experimental Theraputics Program, Samuel Oschin Comprehensive Cancer Center, Cedars Sinai Medical Center, LA, CA, USA.
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Asfour W, Almadi S, Haffar L. Thymoquinone Suppresses Cellular Proliferation, Inhibits VEGF Production and Obstructs Tumor Progression and Invasion in the Rat Model of DMH-Induced Colon Carcinogenesis. ACTA ACUST UNITED AC 2013. [DOI: 10.4236/pp.2013.41002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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PENG LEI, LIU AN, SHEN YUE, XU HUAZI, YANG SHIZHOU, YING XIAOZHOU, LIAO WEI, LIU HAIXIAO, LIN ZHONGQIN, CHEN QINGYU, CHENG SHAOWEN, SHEN WEIDONG. Antitumor and anti-angiogenesis effects of thymoquinone on osteosarcoma through the NF-κB pathway. Oncol Rep 2012; 29:571-8. [DOI: 10.3892/or.2012.2165] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Accepted: 10/29/2012] [Indexed: 11/06/2022] Open
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Mechanisms of tumor resistance to small-molecule vascular disrupting agents: treatment and rationale of combination therapy. J Formos Med Assoc 2012; 112:115-24. [PMID: 23473523 DOI: 10.1016/j.jfma.2012.09.017] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Revised: 09/19/2012] [Accepted: 09/21/2012] [Indexed: 12/13/2022] Open
Abstract
Small-molecule vascular disrupting agents (VDAs) target the established tumor blood vessels, resulting in rapidly and selectively widespread ischemia and necrosis of central tumor; meanwhile, blood flow in normal tissues is relatively unaffected. Although VDAs therapy is considered an important option for treatment, its use is still limited. The tumor cells at the periphery are less sensitive to vascular shutdown than those at the center, and subsequently avoid a nutrient-deprived environment. This phenomenon is referred to as tumor resistance to VDAs treatment. The viable periphery rim of tumor cells contributes to tumor regeneration, metastasis, and ongoing progression. However, there is no systematic review of the plausible mechanisms of repopulation of the viable tumor cells following VDAs therapy. The purpose of this review is to provide insights into mechanisms of tumor surviving small-molecule VDAs therapy, and the synergetic treatment to the remaining viable tumor cells at the periphery.
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El Kaffas A, Tran W, Czarnota GJ. Vascular Strategies for Enhancing Tumour Response to Radiation Therapy. Technol Cancer Res Treat 2012; 11:421-32. [DOI: 10.7785/tcrt.2012.500265] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Radiation therapy is prescribed to more than 50% of patients diagnosed with cancer. Although mechanisms of interaction between radiation and tumour cells are well understood on a molecular level, much remains uncertain concerning the interaction of radiation with the tumour as a whole. Recent studies have demonstrated that single large doses of radiation (8–20 Gy) may primarily target tumour endothelial cells, leading to secondary tumour clonogenic cell death. These studies suggest that blood vessels play an important role in radiation response. As a result, various strategies have been proposed to effectively combine radiation with vascular targeting agents. While most proposed schemes focus on methods to disrupt tumour blood vessels, recent evidence supporting that some anti-angiogenic agents may “normalize” tumour blood vessels, in turn enhancing tumour oxygenation and radiosensitivity, indicates that there may be more efficient strategies. Furthermore, vascular targeting agents have recently been demonstrated to enhance radiation therapy by targeting endothelial cells. When combined with radiation, these agents are believed to cause even more localized vascular destruction followed by tumour clonogenic cell death. Taken together, it is now crucial to elucidate the role of tumour blood vessels in radiation therapy response, in order to make use of this knowledge in developing therapeutic strategies that target tumour vasculature above and beyond classic clonogenic tumour cell death. In this report, we review some major developments in understanding the importance of tumour blood vessels during radiation therapy. A discussion of current imaging modalities used for studying vascular response to treatments will also be presented.
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Affiliation(s)
- Ahmed El Kaffas
- Department of Imaging Research, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Toronto, ON, Canada M4N 3M5
- Department of Medical Biophysics, University of Toronto, 2075 Bayview Ave., Toronto, ON, Canada M4N 3M5
| | - William Tran
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Toronto, ON, Canada M4N 3M5
| | - Gregory J. Czarnota
- Department of Imaging Research, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Toronto, ON, Canada M4N 3M5
- Department of Medical Biophysics, University of Toronto, 2075 Bayview Ave., Toronto, ON, Canada M4N 3M5
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Toronto, ON, Canada M4N 3M5
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Tran WT, Iradji S, Sofroni E, Giles A, Eddy D, Czarnota GJ. Microbubble and ultrasound radioenhancement of bladder cancer. Br J Cancer 2012; 107:469-76. [PMID: 22790798 PMCID: PMC3405216 DOI: 10.1038/bjc.2012.279] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Revised: 05/29/2012] [Accepted: 05/30/2012] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Tumour vasculature is an important component of tumour growth and survival. Recent evidence indicates tumour vasculature also has an important role in tumour radiation response. In this study, we investigated ultrasound and microbubbles to enhance the effects of radiation. METHODS Human bladder cancer HT-1376 xenografts in severe combined immuno-deficient mice were used. Treatments consisted of no, low and high concentrations of microbubbles and radiation doses of 0, 2 and 8 Gy in short-term and longitudinal studies. Acute response was assessed 24 h after treatment and longitudinal studies monitored tumour response weekly up to 28 days using power Doppler ultrasound imaging for a total of 9 conditions (n=90 animals). RESULTS Quantitative analysis of ultrasound data revealed reduced blood flow with ultrasound-microbubble treatments alone and further when combined with radiation. Tumours treated with microbubbles and radiation revealed enhanced cell death, vascular normalisation and areas of fibrosis. Longitudinal data demonstrated a reduced normalised vascular index and increased tumour cell death in both low and high microbubble concentrations with radiation. CONCLUSION Our study demonstrated that ultrasound-mediated microbubble exposure can enhance radiation effects in tumours, and can lead to enhanced tumour cell death.
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Affiliation(s)
- W T Tran
- Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
- Department of Imaging Research, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada
- Department of Radiotherapy and Oncology, Sheffield Hallam University, Howard Street, Sheffield, South Yorkshire S1 1WB, UK
| | - S Iradji
- Department of Imaging Research, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada
| | - E Sofroni
- Department of Imaging Research, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada
| | - A Giles
- Department of Imaging Research, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada
| | - D Eddy
- Department of Radiotherapy and Oncology, Sheffield Hallam University, Howard Street, Sheffield, South Yorkshire S1 1WB, UK
| | - G J Czarnota
- Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
- Department of Imaging Research, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
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Barbigerone, an isoflavone, inhibits tumor angiogenesis and human non-small-cell lung cancer xenografts growth through VEGFR2 signaling pathways. Cancer Chemother Pharmacol 2012; 70:425-37. [DOI: 10.1007/s00280-012-1923-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2012] [Accepted: 07/05/2012] [Indexed: 01/08/2023]
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Kim JW, Jung SY, Kwon YH, Lee JH, Lee YM, Lee BY, Kwon SM. Ginsenoside Rg3 attenuates tumor angiogenesis via inhibiting bioactivities of endothelial progenitor cells. Cancer Biol Ther 2012; 13:504-15. [PMID: 22406998 DOI: 10.4161/cbt.19599] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Accumulating evidence suggests that Ginsenoside Rg3 appears to inhibit tumor growth including Lewis lung carcinoma, intestinal adenocarcinomas or B16 melanoma by inhibiting cell proliferation, tumor cell invasion and metastasis. Endothelial progenitor cells (EPCs) appear to play a key role in the growth of early tumors by intervening with the angiogenic switch promoting tumor neovessel formation by producing angiogenic cytokines during tumor progression. This paper reports a novel mechanism of Ginsenoside Rg3, a candidate anticancer bio-molecule, on tumor angiogenesis by inhibiting the multiple bioactivities of EPCs. When Ginsenoside Rg3 was applied to the ex vivo cultured outgrowth ECs, a type of EPCs, it inhibited the cell proliferation, cell migration and tubular formation of EPCs. Importantly, Ginsenoside Rg3 attenuated the phosphorylation cascade of the VEGF dependent p38/ERK signaling in vitro. The xenograft tumor model clearly showed that Ginsenoside Rg3 suppresses tumor growth and tumor angiogenesis by inhibiting the mobilization of EPCs from the bone marrow microenvironment to the peripheral circulation and modulates VEGF-dependent tumor angiogenesis. In conclusion, this study provides a potential therapeutic molecule, Ginsenoside Rg3, as an anticancer drug by inhibiting the EPC bioactivities.
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Affiliation(s)
- Jae-Won Kim
- Department of Biomedical Science, Laboratory for Functional Foods & Nutrigenomics, CHA University, Seoul, Korea
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