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Zhao Y, Yuan C, Shi Y, Liu X, Luo L, Zhang L, Pešić M, Yao H, Li L. Drug screening approaches for small-molecule compounds in cancer-targeted therapy. J Drug Target 2025; 33:368-383. [PMID: 39575843 DOI: 10.1080/1061186x.2024.2427185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 09/30/2024] [Accepted: 10/27/2024] [Indexed: 02/08/2025]
Abstract
Small-molecule compounds exhibit distinct pharmacological properties and clinical effectiveness. Over the past decade, advances in covalent drug discovery have led to successful small-molecule drugs, such as EGFR, BTK, and KRAS (G12C) inhibitors, for cancer therapy. Researchers are paying more attention to refining drug screening methods aiming for high throughput, fast speed, high specificity, and accuracy. Therefore, the discovery and development of small-molecule drugs has been facilitated by significantly reducing screening time and financial resources, and increasing promising lead compounds compared with traditional methods. This review aims to introduce classical and emerging methods for screening small-molecule compounds in targeted cancer therapy. It includes classification, principles, advantages, disadvantages, and successful applications, serving as valuable references for subsequent researchers.
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Affiliation(s)
- Yelin Zhao
- State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Biotechnology for Microbial Drugs, Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chenyu Yuan
- State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Biotechnology for Microbial Drugs, Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuchen Shi
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaohong Liu
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Xicheng District, Beijing, China
| | - Liaoxin Luo
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Li Zhang
- State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Biotechnology for Microbial Drugs, Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Milica Pešić
- Department of Neurobiology, Institute for Biological Research, 'Siniša Stanković'- National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Hongjuan Yao
- State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Biotechnology for Microbial Drugs, Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liang Li
- State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Biotechnology for Microbial Drugs, Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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2
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Shikai Y, Kawai S, Katsuyama Y, Ohnishi Y. In vitro characterization of nonribosomal peptide synthetase-dependent O-(2-hydrazineylideneacetyl)serine synthesis indicates a stepwise oxidation strategy to generate the α-diazo ester moiety of azaserine. Chem Sci 2023; 14:8766-8776. [PMID: 37621439 PMCID: PMC10445470 DOI: 10.1039/d3sc01906c] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 07/02/2023] [Indexed: 08/26/2023] Open
Abstract
Azaserine, a natural product containing a diazo group, exhibits anticancer activity. In this study, we investigated the biosynthetic pathway to azaserine. The putative azaserine biosynthetic gene (azs) cluster, which contains 21 genes, including those responsible for hydrazinoacetic acid (HAA) synthesis, was discovered using bioinformatics analysis of the Streptomyces fragilis genome. Azaserine was produced by the heterologous expression of the azs cluster in Streptomyces albus. In vitro enzyme assays using recombinant Azs proteins revealed the azaserine biosynthetic pathway as follows. AzsSPTF and carrier protein (CP) AzsQ are used to synthesize the 2-hydrazineylideneacetyl (HDA) moiety attached to AzsQ from HAA. AzsD transfers the HDA moiety to the C-terminal CP domain of AzsN. The heterocyclization (Cy) domain of the nonribosomal peptide synthetase AzsO synthesizes O-(2-hydrazineylideneacetyl)serine (HDA-Ser) attached to its CP domain from l-serine and HDA moiety-attached AzsN. The thioesterase AzsB hydrolyzes it to yield HDA-Ser, which appears to be converted to azaserine by oxidation. Bioinformatics analysis of the Cy domain of AzsO showed that it has a conserved DxxxxD motif; however, two conserved amino acid residues (Thr and Asp) important for heterocyclization are substituted for Asn. Site-directed mutagenesis of two Asp residues in the DxxxxD motif (D193 and D198) and two substituted Asn residues (N414 and N447) indicated that these four residues are important for ester bond synthesis. These results showed that the diazo ester of azasrine is synthesized by the stepwise oxidation of the HAA moiety and provided another strategy to biosynthesize the diazo group.
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Affiliation(s)
- Yusuke Shikai
- Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo 1-1-1 Yayoi, Bunkyo-ku Tokyo 113-8657 Japan
| | - Seiji Kawai
- Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo 1-1-1 Yayoi, Bunkyo-ku Tokyo 113-8657 Japan
| | - Yohei Katsuyama
- Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo 1-1-1 Yayoi, Bunkyo-ku Tokyo 113-8657 Japan
- Collaborative Research Institute for Innovative Microbiology, The University of Tokyo Bunkyo-ku Tokyo 113-8657 Japan
| | - Yasuo Ohnishi
- Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo 1-1-1 Yayoi, Bunkyo-ku Tokyo 113-8657 Japan
- Collaborative Research Institute for Innovative Microbiology, The University of Tokyo Bunkyo-ku Tokyo 113-8657 Japan
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Ekeuku SO, Etim EP, Pang KL, Chin KY, Mai CW. Vitamin E in the management of pancreatic cancer: A scoping review. World J Gastrointest Oncol 2023; 15:943-958. [PMID: 37389119 PMCID: PMC10302993 DOI: 10.4251/wjgo.v15.i6.943] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 02/03/2023] [Accepted: 04/07/2023] [Indexed: 06/14/2023] Open
Abstract
Pancreatic cancer is the leading cause of cancer mortality worldwide. Research investigating effective management strategies for pancreatic cancer is ongoing. Vitamin E, consisting of both tocopherol and tocotrienol, has demonstrated debatable effects on pancreatic cancer cells. Therefore, this scoping review aims to summarize the effects of vitamin E on pancreatic cancer. In October 2022, a literature search was conducted using PubMed and Scopus since their inception. Original studies on the effects of vitamin E on pancreatic cancer, including cell cultures, animal models and human clinical trials, were considered for this review. The literature search found 75 articles on this topic, but only 24 articles met the inclusion criteria. The available evidence showed that vitamin E modulated proliferation, cell death, angiogenesis, metastasis and inflammation in pancreatic cancer cells. However, the safety and bioavailability concerns remain to be answered with more extensive preclinical and clinical studies. More in-depth analysis is necessary to investigate further the role of vitamin E in the management of pancreatic cancers.
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Affiliation(s)
- Sophia Ogechi Ekeuku
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Effiong Paul Etim
- Faculty of Applied Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
| | - Kok-Lun Pang
- Newcastle University Medicine Malaysia, Iskandar Puteri 79200, Johor, Malaysia
| | - Kok-Yong Chin
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Chun-Wai Mai
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
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Chen H, Zheng M, Zhang W, Long Y, Xu Y, Yuan M. Research Status of Mouse Models for Non-Small-Cell Lung Cancer (NSCLC) and Antitumor Therapy of Traditional Chinese Medicine (TCM) in Mouse Models. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:6404853. [PMID: 36185084 PMCID: PMC9519343 DOI: 10.1155/2022/6404853] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 08/31/2022] [Indexed: 11/25/2022]
Abstract
Non-small-cell lung cancer (NSCLC) is known as one of the most lethal cancers, causing more than 1 million deaths annually worldwide. Therefore, the development of novel therapeutic drugs for NSCLC has become an urgent need. Herein, various mouse models provide great convenience not only for researchers but also for the development of antitumor drug. Meanwhile, TCM, as a valuable and largely untapped resource pool for modern medicine, provides research resources for the treatment of various diseases. Until now, cell-derived xenograft (CDX) model, patient-derived xenograft (PDX) model, syngeneic model, orthotopic model, humanized mouse model (HIS), and genetically engineered mouse models (GEMMs) have been reported in TCM evaluation. This review shows the role and current status of kinds of mouse models in antitumor research and summarizes the application progress of TCM including extracts, formulas, and isolated single molecules for NSCLC therapy in various mouse models; more importantly, it provides a theoretical exploration of what kind of mouse models is ideal for TCM efficacy evaluation in future. However, there are still huge challenges and limitations in the development of mouse models specifically for the TCM research, and none of the available models are perfectly matching the characteristics of TCM, which suppress the tumor growth through various mechanisms, especially by regulating immune function. Nevertheless, with fully functional immune system existing in syngeneic model and humanized mouse model (HIS), it is still suggested that these two models are more suitable for development of TCM especially for TCM extracts or formulas. Moreover, continued efforts are needed to generate more reliable mouse models to test TCM formulas in future research.
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Affiliation(s)
- Hongkui Chen
- Shanghai Lidebiotech Co. Ltd., Shanghai 201203, China
| | - Min Zheng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wenhui Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203, China
| | - Yuan Long
- Shanghai Lidebiotech Co. Ltd., Shanghai 201203, China
| | - Yu Xu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203, China
| | - Man Yuan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203, China
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Li J, Chen H, Zhao S, Wen D, Bi L. Patient-derived intrafemoral orthotopic xenografts of peripheral blood or bone marrow from acute myeloid and acute lymphoblastic leukemia patients: clinical characterization, methodology, and validation. Clin Exp Med 2022:10.1007/s10238-022-00884-3. [PMID: 36121505 PMCID: PMC10390355 DOI: 10.1007/s10238-022-00884-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 08/27/2022] [Indexed: 11/27/2022]
Abstract
Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are malignant clonal diseases of the hematopoietic system with an unsatisfactory overall prognosis. The main obstacle is the increased resistance of AML and ALL cells to chemotherapy. The development and validation of new therapeutic strategies for acute leukemia require preclinical models that accurately recapitulate the genetic, pathological, and clinical features of acute leukemia. A patient-derived orthotopic xenograft (PDOX) model is established using surgical orthotopic implantation. They closely resemble human tumor progression and microenvironment and are more reliable translational research tools than subcutaneous-transplant models. In this study, we established PDOX models by direct intrafemoral injection of bone marrow and peripheral blood cells from AML and ALL patients, characterized their pathology, cytology, and genetics, and compared the model's characteristics and drug responsiveness with those of the corresponding patients.
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Affiliation(s)
- Jun Li
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, No. 126 XianTai Street, Changchun, Jilin, 130033, China
| | - Hongkui Chen
- Shanghai LIDE Biotech, Co. Ltd, No. 77-78, Lane 887, Zuchongzhi Road, Pudong, Shanghai, China
| | - ShiZhu Zhao
- Shanghai LIDE Biotech, Co. Ltd, No. 77-78, Lane 887, Zuchongzhi Road, Pudong, Shanghai, China
| | - Danyi Wen
- Shanghai LIDE Biotech, Co. Ltd, No. 77-78, Lane 887, Zuchongzhi Road, Pudong, Shanghai, China
| | - Lintao Bi
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, No. 126 XianTai Street, Changchun, Jilin, 130033, China.
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Pion E, Karnosky J, Boscheck S, Wagner BJ, Schmidt KM, Brunner SM, Schlitt HJ, Aung T, Hackl C, Haerteis S. 3D In Vivo Models for Translational Research on Pancreatic Cancer: The Chorioallantoic Membrane (CAM) Model. Cancers (Basel) 2022; 14:cancers14153733. [PMID: 35954398 PMCID: PMC9367548 DOI: 10.3390/cancers14153733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/21/2022] [Accepted: 07/28/2022] [Indexed: 11/25/2022] Open
Abstract
Simple Summary The 5-year overall survival rate for all stages of pancreatic cancer is relatively low at about only 6%. As a result of this exceedingly poor prognosis, new research models are necessary to investigate this highly malignant cancer. One model that has been used extensively for a vast variety of different cancers is the chorioallantoic membrane (CAM) model. It is based on an exceptionally vascularized membrane that develops within fertilized chicken eggs and can be used for the grafting and analysis of tumor tissue. The aim of the study was to summarize already existing works on pancreatic ductal adenocarcinoma (PDAC) and the CAM model. The results were subdivided into different categories that include drug testing, angiogenesis, personalized medicine, modifications of the model, and further developments to help improve the unfavorable prognosis of this disease. Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with adverse outcomes that have barely improved over the last decade. About half of all patients present with metastasis at the time of diagnosis, and the 5-year overall survival rate across all stages is only 6%. Innovative in vivo research models are necessary to combat this cancer and to discover novel treatment strategies. The chorioallantoic membrane (CAM) model represents one 3D in vivo methodology that has been used in a large number of studies on different cancer types for over a century. This model is based on a membrane formed within fertilized chicken eggs that contain a dense network of blood vessels. Because of its high cost-efficiency, simplicity, and versatility, the CAM model appears to be a highly valuable research tool in the pursuit of gaining more in-depth insights into PDAC. A summary of the current literature on the usage of the CAM model for the investigation of PDAC was conducted and subdivided into angiogenesis, drug testing, modifications, personalized medicine, and further developments. On this comprehensive basis, further research should be conducted on PDAC in order to improve the abysmal prognosis of this malignant disease.
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Affiliation(s)
- Eric Pion
- Institute for Molecular and Cellular Anatomy, University of Regensburg, 93053 Regensburg, Germany; (E.P.); (S.B.); (T.A.)
| | - Julia Karnosky
- Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany; (J.K.); (B.J.W.); (K.M.S.); (S.M.B.); (H.J.S.); (C.H.)
| | - Sofie Boscheck
- Institute for Molecular and Cellular Anatomy, University of Regensburg, 93053 Regensburg, Germany; (E.P.); (S.B.); (T.A.)
| | - Benedikt J. Wagner
- Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany; (J.K.); (B.J.W.); (K.M.S.); (S.M.B.); (H.J.S.); (C.H.)
| | - Katharina M. Schmidt
- Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany; (J.K.); (B.J.W.); (K.M.S.); (S.M.B.); (H.J.S.); (C.H.)
| | - Stefan M. Brunner
- Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany; (J.K.); (B.J.W.); (K.M.S.); (S.M.B.); (H.J.S.); (C.H.)
| | - Hans J. Schlitt
- Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany; (J.K.); (B.J.W.); (K.M.S.); (S.M.B.); (H.J.S.); (C.H.)
| | - Thiha Aung
- Institute for Molecular and Cellular Anatomy, University of Regensburg, 93053 Regensburg, Germany; (E.P.); (S.B.); (T.A.)
- Faculty of Applied Healthcare Science, Deggendorf Institute of Technology, 94469 Deggendorf, Germany
| | - Christina Hackl
- Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany; (J.K.); (B.J.W.); (K.M.S.); (S.M.B.); (H.J.S.); (C.H.)
| | - Silke Haerteis
- Institute for Molecular and Cellular Anatomy, University of Regensburg, 93053 Regensburg, Germany; (E.P.); (S.B.); (T.A.)
- Correspondence:
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Probing Vasoreactivity and Hypoxic Phenotype in Different Tumor Grafts Grown on the Chorioallantoic Membrane of the Chicken Embryo In Ovo Using MRI. Cancers (Basel) 2022; 14:cancers14133114. [PMID: 35804886 PMCID: PMC9265041 DOI: 10.3390/cancers14133114] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 06/20/2022] [Accepted: 06/20/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Fertilized chicken eggs can be used to study tumors. During their development, chicken eggshells are fenestrated, and the chicken embryo that is enwrapped by a highly vascularized membrane becomes accessible. Tumor cells are then planted onto this membrane, which supports tumor growth and, after one week, the tumor graft is studied using magnetic resonance imaging. To characterize the tumor in living chicken embryos, a gas tube can be fixed into the eggshell window and the chicken embryo and hence, the tumor graft is exposed to air, carbon dioxide-enriched air, or oxygen enriched with carbon dioxide. Different tumor types react differently to such gas challenges, which can be quantitatively measured and related to the tumor grafts’ vascular functioning and oxygenation. Abstract Tumor grafts grown on the chorioallantoic membrane (CAM) of chicken embryos represent a transition between cell culture and mammalian in vivo models. Magnetic resonance imaging (MRI) started to harness this potential. Functional gas challenge is feasible on the CAM. Using quantitative T1 and T2* mapping, we characterized the response of MC-38 colon, A549, and H460 adeno-carcinoma cell grafts to hypercapnic (HC) and hypercapnic-hyperoxic (HCHO) gas challenges, pertaining to the grafts’ vascular and oxygenation phenotypes. MR imaging revealed that larger T1 and T2* were located in the center of H460 and MC-38 tumors. Quantitative analysis showed a significant reduction in T1 and a significant increase in T2* in response to HCHO for A549 grafts, while H460 and MC-38 tumors did not respond to either gas challenge. Different tumor grafts respond differentially to HC and HCHO conditions. A549 tumor grafts, with higher vessel density and smaller tumor diameter compared with H460 and MC-38 grafts, had a significant response in T1 for HCHO and T2* increased slightly during HC and significantly under HCHO, consistent with a normoxic phenotype and functional vasoreactivity. Therefore, gas challenges enable differential characterization of tumor grafts with respect to their vascular and oxygenation status.
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Xing F, Ai N, Huang S, Jiang C, Mughal MJ, Ge W, Wang G, Deng CX. An In Vivo Fluorescence Resonance Energy Transfer-Based Imaging Platform for Targeted Drug Discovery and Cancer Therapy. Front Bioeng Biotechnol 2022; 10:839078. [PMID: 35237583 PMCID: PMC8884137 DOI: 10.3389/fbioe.2022.839078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 01/21/2022] [Indexed: 01/28/2023] Open
Abstract
In the present study, an efficient in vivo drug screening platform is established based on FRET technique. We transfected cancer cells with FRET-based caspase-3 (C3) sensor and validated the cell lines by detecting the change in FRET signal caused by the in vitro drug-induced cell apoptosis. Furthermore, the C3 expressing cancer cells were then injected into zebrafish embryos and nude mice to establish the corresponding in vivo xenograft models. We found that cancer cell lines expressing C3 were effective in detecting cell death following drug treatment, including the detection of the tipping point of apoptosis. The drug-induced cell apoptosis was also observed in both zebrafish embryos and nude mice xenograft models. Overall, the FRET-based platform, through in vivo imaging, is potentially useful to improve drug screening efficiency.
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Affiliation(s)
- Fuqiang Xing
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China,Department of Biology, School of Life Sciences, Guangdong Provincial Key Laboratory of Computational Science and Material Design, Southern University of Science and Technology, Shenzhen, China,Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Nana Ai
- Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macau SAR, China
| | - Shigao Huang
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China
| | - Cheng Jiang
- School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, China
| | | | - Wei Ge
- Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macau SAR, China
| | - Guanyu Wang
- Department of Biology, School of Life Sciences, Guangdong Provincial Key Laboratory of Computational Science and Material Design, Southern University of Science and Technology, Shenzhen, China,School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, China,*Correspondence: Guanyu Wang, ; Chu-Xia Deng,
| | - Chu-Xia Deng
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China,*Correspondence: Guanyu Wang, ; Chu-Xia Deng,
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Kalthoff H. How open is the therapeutic horizon for pancreatic cancer patients? Hepatobiliary Pancreat Dis Int 2022; 21:1-3. [PMID: 34789410 DOI: 10.1016/j.hbpd.2021.11.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 10/26/2021] [Indexed: 02/05/2023]
Affiliation(s)
- Holger Kalthoff
- Institute for Experimental Cancer Research, Christian-Albrechts-University, Kiel, Germany.
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10
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Efficient nano-enabled therapy for gastrointestinal cancer using silicasome delivery technology. Sci China Chem 2021. [DOI: 10.1007/s11426-021-1126-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Heinrich MA, Mostafa AMRH, Morton JP, Hawinkels LJAC, Prakash J. Translating complexity and heterogeneity of pancreatic tumor: 3D in vitro to in vivo models. Adv Drug Deliv Rev 2021; 174:265-293. [PMID: 33895214 DOI: 10.1016/j.addr.2021.04.018] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/16/2021] [Accepted: 04/19/2021] [Indexed: 02/08/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive type of cancer with an overall survival rate of less than 7-8%, emphasizing the need for novel effective therapeutics against PDAC. However only a fraction of therapeutics which seemed promising in the laboratory environment will eventually reach the clinic. One of the main reasons behind this low success rate is the complex tumor microenvironment (TME) of PDAC, a highly fibrotic and dense stroma surrounding tumor cells, which supports tumor progression as well as increases the resistance against the treatment. In particular, the growing understanding of the PDAC TME points out a different challenge in the development of efficient therapeutics - a lack of biologically relevant in vitro and in vivo models that resemble the complexity and heterogeneity of PDAC observed in patients. The purpose and scope of this review is to provide an overview of the recent developments in different in vitro and in vivo models, which aim to recapitulate the complexity of PDAC in a laboratory environment, as well to describe how 3D in vitro models can be integrated into drug development pipelines that are already including sophisticated in vivo models. Hereby a special focus will be given on the complexity of in vivo models and the challenges in vitro models face to reach the same levels of complexity in a controllable manner. First, a brief introduction of novel developments in two dimensional (2D) models and ex vivo models is provided. Next, recent developments in three dimensional (3D) in vitro models are described ranging from spheroids, organoids, scaffold models, bioprinted models to organ-on-chip models including a discussion on advantages and limitations for each model. Furthermore, we will provide a detailed overview on the current PDAC in vivo models including chemically-induced models, syngeneic and xenogeneic models, highlighting hetero- and orthotopic, patient-derived tissues (PDX) models, and genetically engineered mouse models. Finally, we will provide a discussion on overall limitations of both, in vitro and in vivo models, and discuss necessary steps to overcome these limitations to reach an efficient drug development pipeline, as well as discuss possibilities to include novel in silico models in the process.
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Affiliation(s)
- Marcel A Heinrich
- Department of Biomaterials Science and Technology, Section Targeted Therapeutics, Technical Medical Centre, University of Twente, 7500AE Enschede, the Netherlands
| | - Ahmed M R H Mostafa
- Department of Biomaterials Science and Technology, Section Targeted Therapeutics, Technical Medical Centre, University of Twente, 7500AE Enschede, the Netherlands
| | - Jennifer P Morton
- Cancer Research UK, Beatson Institute, Garscube Estate, Switchback Rd, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Rd, Glasgow G61 1QH, UK
| | - Lukas J A C Hawinkels
- Department of Gastroenterology-Hepatology, Leiden University Medical Centre, PO-box 9600, 2300 RC Leiden, the Netherlands
| | - Jai Prakash
- Department of Biomaterials Science and Technology, Section Targeted Therapeutics, Technical Medical Centre, University of Twente, 7500AE Enschede, the Netherlands.
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12
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Mallya K, Gautam SK, Aithal A, Batra SK, Jain M. Modeling pancreatic cancer in mice for experimental therapeutics. Biochim Biophys Acta Rev Cancer 2021; 1876:188554. [PMID: 33945847 DOI: 10.1016/j.bbcan.2021.188554] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/19/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy that is characterized by early metastasis, low resectability, high recurrence, and therapy resistance. The experimental mouse models have played a central role in understanding the pathobiology of PDAC and in the preclinical evaluation of various therapeutic modalities. Different mouse models with targetable pathological hallmarks have been developed and employed to address the unique challenges associated with PDAC progression, metastasis, and stromal heterogeneity. Over the years, mouse models have evolved from simple cell line-based heterotopic and orthotopic xenografts in immunocompromised mice to more complex and realistic genetically engineered mouse models (GEMMs) involving multi-gene manipulations. The GEMMs, mostly driven by KRAS mutation(s), have been widely accepted for therapeutic optimization due to their high penetrance and ability to recapitulate the histological, molecular, and pathological hallmarks of human PDAC, including comparable precursor lesions, extensive metastasis, desmoplasia, perineural invasion, and immunosuppressive tumor microenvironment. Advanced GEMMs modified to express fluorescent proteins have allowed cell lineage tracing to provide novel insights and a new understanding about the origin and contribution of various cell types in PDAC pathobiology. The syngeneic mouse models, GEMMs, and target-specific transgenic mice have been extensively used to evaluate immunotherapies and study therapy-induced immune modulation in PDAC yielding meaningful results to guide various clinical trials. The emerging mouse models for parabiosis, hepatic metastasis, cachexia, and image-guided implantation, are increasingly appreciated for their high translational significance. In this article, we describe the contribution of various experimental mouse models to the current understanding of PDAC pathobiology and their utility in evaluating and optimizing therapeutic modalities for this lethal malignancy.
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Affiliation(s)
- Kavita Mallya
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Shailendra K Gautam
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
| | - Abhijit Aithal
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
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13
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Ex vivo culture of intact human patient derived pancreatic tumour tissue. Sci Rep 2021; 11:1944. [PMID: 33479301 PMCID: PMC7820421 DOI: 10.1038/s41598-021-81299-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 12/31/2020] [Indexed: 02/07/2023] Open
Abstract
The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is attributed to the highly fibrotic stroma and complex multi-cellular microenvironment that is difficult to fully recapitulate in pre-clinical models. To fast-track translation of therapies and to inform personalised medicine, we aimed to develop a whole-tissue ex vivo explant model that maintains viability, 3D multicellular architecture, and microenvironmental cues of human pancreatic tumours. Patient-derived surgically-resected PDAC tissue was cut into 1-2 mm explants and cultured on gelatin sponges for 12 days. Immunohistochemistry revealed that human PDAC explants were viable for 12 days and maintained their original tumour, stromal and extracellular matrix architecture. As proof-of-principle, human PDAC explants were treated with Abraxane and we observed different levels of response between patients. PDAC explants were also transfected with polymeric nanoparticles + Cy5-siRNA and we observed abundant cytoplasmic distribution of Cy5-siRNA throughout the PDAC explants. Overall, our novel model retains the 3D architecture of human PDAC and has advantages over standard organoids: presence of functional multi-cellular stroma and fibrosis, and no tissue manipulation, digestion, or artificial propagation of organoids. This provides unprecedented opportunity to study PDAC biology including tumour-stromal interactions and rapidly assess therapeutic response to drive personalised treatment.
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14
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Pineda-Farias JB, Saloman JL, Scheff NN. Animal Models of Cancer-Related Pain: Current Perspectives in Translation. Front Pharmacol 2021; 11:610894. [PMID: 33381048 PMCID: PMC7768910 DOI: 10.3389/fphar.2020.610894] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 10/30/2020] [Indexed: 01/15/2023] Open
Abstract
The incidence of pain in cancer patients during diagnosis and treatment is exceedingly high. Although advances in cancer detection and therapy have improved patient prognosis, cancer and its treatment-associated pain have gained clinical prominence. The biological mechanisms involved in cancer-related pain are multifactorial; different processes for pain may be responsible depending on the type and anatomic location of cancer. Animal models of cancer-related pain have provided mechanistic insights into the development and process of pain under a dynamic molecular environment. However, while cancer-evoked nociceptive responses in animals reflect some of the patients’ symptoms, the current models have failed to address the complexity of interactions within the natural disease state. Although there has been a recent convergence of the investigation of carcinogenesis and pain neurobiology, identification of new targets for novel therapies to treat cancer-related pain requires standardization of methodologies within the cancer pain field as well as across disciplines. Limited success of translation from preclinical studies to the clinic may be due to our poor understanding of the crosstalk between cancer cells and their microenvironment (e.g., sensory neurons, infiltrating immune cells, stromal cells etc.). This relatively new line of inquiry also highlights the broader limitations in translatability and interpretation of basic cancer pain research. The goal of this review is to summarize recent findings in cancer pain based on preclinical animal models, discuss the translational benefit of these discoveries, and propose considerations for future translational models of cancer pain.
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Affiliation(s)
- Jorge B Pineda-Farias
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Jami L Saloman
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Nicole N Scheff
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Hillman Cancer Center, University of Pittsburgh Medicine Center, Pittsburgh, PA, United States
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15
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Ahmed A, Angell R, Oxenford S, Worthington J, Williams N, Barton N, Fowler TG, O’Flynn DE, Sunose M, McConville M, Vo T, Wilson WD, Karim SA, Morton JP, Neidle S. Asymmetrically Substituted Quadruplex-Binding Naphthalene Diimide Showing Potent Activity in Pancreatic Cancer Models. ACS Med Chem Lett 2020; 11:1634-1644. [PMID: 32832034 PMCID: PMC7429975 DOI: 10.1021/acsmedchemlett.0c00317] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 07/16/2020] [Indexed: 12/13/2022] Open
Abstract
Targeting of genomic quadruplexes is an approach to treating complex human cancers. We describe a series of tetra-substituted naphthalene diimide (ND) derivatives with a phenyl substituent directly attached to the ND core. The lead compound (SOP1812) has 10 times superior cellular and in vivo activity compared with previous ND compounds and nanomolar binding to human quadruplexes. The pharmacological properties of SOP1812 indicate good bioavailability, which is consistent with the in vivo activity in xenograft and genetic models for pancreatic cancer. Transcriptome analysis shows that it down-regulates several cancer gene pathways, including Wnt/β-catenin signaling.
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Affiliation(s)
- Ahmed
A. Ahmed
- School
of Pharmacy, University College London, London WC1N 1AX, United Kingdom
| | - Richard Angell
- School
of Pharmacy, University College London, London WC1N 1AX, United Kingdom
| | - Sally Oxenford
- School
of Pharmacy, University College London, London WC1N 1AX, United Kingdom
| | - Jenny Worthington
- Axis
Bio Discovery Services, Ltd., Coleraine, Northern Ireland BT51 3RP, United Kingdom
| | - Nicole Williams
- Axis
Bio Discovery Services, Ltd., Coleraine, Northern Ireland BT51 3RP, United Kingdom
| | - Naomi Barton
- Sygnature
Discovery Limited, Nottingham NG1 1GR, United Kingdom
| | | | | | - Mihiro Sunose
- Sygnature
Discovery Limited, Nottingham NG1 1GR, United Kingdom
| | | | - Tam Vo
- Department
of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, Georgia 30303-3083, United States
| | - W. David Wilson
- Department
of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, Georgia 30303-3083, United States
| | - Saadia A. Karim
- Cancer
Research UK Beatson Institute, Glasgow G61 1BD, United
Kingdom
| | - Jennifer P. Morton
- Cancer
Research UK Beatson Institute, Glasgow G61 1BD, United
Kingdom
- Institute
of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom
| | - Stephen Neidle
- School
of Pharmacy, University College London, London WC1N 1AX, United Kingdom
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16
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Meleady P, Abdul Rahman R, Henry M, Moriarty M, Clynes M. Proteomic analysis of pancreatic ductal adenocarcinoma. Expert Rev Proteomics 2020; 17:453-467. [PMID: 32755290 DOI: 10.1080/14789450.2020.1803743] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC), which represents approximately 80% of all pancreatic cancers, is a highly aggressive malignant disease and one of the most lethal among all cancers. Overall, the 5-year survival rate among all pancreatic cancer patients is less than 9%; these rates have shown little change over the past 30 years. A more comprehensive understanding of the molecular mechanisms underlying this complex disease is crucial to the development of new diagnostic tools for early detection and disease monitoring, as well as to identify new and more effective therapeutics to improve patient outcomes. AREA COVERED We summarize recent advances in proteomic strategies and mass spectrometry to identify new biomarkers for early detection and monitoring of disease progression, predict response to therapy, and to identify novel proteins that have the potential to be 'druggable' therapeutic targets. An overview of proteomic studies that have been conducted to further our mechanistic understanding of metastasis and chemotherapy resistance in PDAC disease progression will also be discussed. EXPERT COMMENTARY The results from these PDAC proteomic studies on a variety of PDAC sample types (e.g., blood, tissue, cell lines, exosomes, etc.) provide great promise of having a significant clinical impact and improving patient outcomes.
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Affiliation(s)
- Paula Meleady
- National Institute for Cellular Biotechnology, Dublin City University , Dublin, Ireland
| | - Rozana Abdul Rahman
- St. Vincent's University Hospital , Dublin, Ireland.,St. Luke's Hospital , Dublin, Ireland
| | - Michael Henry
- National Institute for Cellular Biotechnology, Dublin City University , Dublin, Ireland
| | - Michael Moriarty
- National Institute for Cellular Biotechnology, Dublin City University , Dublin, Ireland.,St. Luke's Hospital , Dublin, Ireland
| | - Martin Clynes
- National Institute for Cellular Biotechnology, Dublin City University , Dublin, Ireland
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