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Bora K, Kanaujia SP, Dubey VK. Targeting antioxidant defense system enzymes for Leishmaniasis treatment. Int J Biol Macromol 2025; 316:144650. [PMID: 40425118 DOI: 10.1016/j.ijbiomac.2025.144650] [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: 03/20/2025] [Revised: 05/07/2025] [Accepted: 05/23/2025] [Indexed: 05/29/2025]
Abstract
Leishmaniasis, caused by the genus Leishmania remains a significant global health challenge. Current chemotherapeutics have limitations in terms of drug resistance, toxicity, and limited efficacy. As most of the currently used chemotherapeutics are single-target drugs, the chances of drug resistance development are very high. To overcome this challenge, the polypharmacology approach to designing multiple molecular target drugs is becoming a promising approach against leishmaniasis. Parasite Leishmania has a unique redox defense system to maintain cellular oxidative stress that helps it survive inside the host oxidative environment generated by the host immune response. This evolutionary divergence of redox systems of Leishmania from the human host is ideal for therapeutic interventions. This review focuses on the currently used anti-leishmanial therapeutics limitations and considers antioxidant defense system as a potential drug target pathway. By focusing on these phylogenetically distinct and parasite-specific enzymes, polypharmacological drugs can be developed to inhibit multiple molecular targets, simultaneously increasing efficacy and reducing the potential for resistance while minimizing adverse effects on the human host. This paradigm, which moves from single target to multi-target shift, holds promise for more effective treatments.
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Affiliation(s)
- Kushal Bora
- School of Biochemical Engineering, Indian Institute of Technology (BHU), Varanasi 221005, Uttar Pradesh, India; Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Shankar Prasad Kanaujia
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Vikash Kumar Dubey
- School of Biochemical Engineering, Indian Institute of Technology (BHU), Varanasi 221005, Uttar Pradesh, India.
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Wu X, Chen X, Liu X, Jin B, Zhang Y, Wang Y, Xu H, Wan X, Zheng Y, Xu L, Xiao Y, Chen Z, Wang H, Mao Y, Lu X, Sang X, Zhao L, Du S. LINC02257 regulates colorectal cancer liver metastases through JNK pathway. Heliyon 2024; 10:e30841. [PMID: 38826728 PMCID: PMC11141284 DOI: 10.1016/j.heliyon.2024.e30841] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 05/06/2024] [Accepted: 05/06/2024] [Indexed: 06/04/2024] Open
Abstract
Background Long noncoding RNAs (lncRNAs) have emerged as critical regulators of colorectal cancer (CRC) progression, but their roles and underlying mechanisms in colorectal cancer liver metastases (CRLMs) remain poorly understood. Methods To explore the expression patterns and functions of lncRNAs in CRLMs, we analyzed the expression profiles of lncRNAs in CRC tissues using the TCGA database and examined the expression patterns of lncRNAs in matched normal, CRC, and CRLM tissues using clinical samples. We further investigated the biological roles of LINC02257 in CRLM using in vitro and in vivo assays, and verified its therapeutic potential in a mouse model of CRLM. Results Our findings showed that LINC02257 was highly expressed in metastatic CRC tissues and its expression was negatively associated with overall survival. Functionally, LINC02257 promoted CRC cell growth, migration, metastasis, and inhibited cell apoptosis in vitro, and enhanced liver metastasis in vivo. Mechanistically, LINC02257 up-regulated phosphorylated c-Jun N-terminal kinase (JNK) to promote CRLM. Conclusions Our study revealed that LINC02257 played a key role in the proliferation and metastasis of CRC cells through the LINC02257/JNK axis. Targeting this axis may represent a promising therapeutic strategy for the treatment of liver metastases in patients with CRC.
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Affiliation(s)
- Xiangan Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaokun Chen
- Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao Liu
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Bao Jin
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yuke Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yuxin Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Haifeng Xu
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xueshuai Wan
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yongchang Zheng
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Lai Xu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yi Xiao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Zhengju Chen
- Pooling Medical Research Institutes, Beijing, China
| | - Haiwen Wang
- Pooling Medical Research Institutes, Beijing, China
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xin Lu
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Lin Zhao
- Department of Medical Oncology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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Di Donato M, Di Zazzo E, Salvati A, Sorrentino C, Giurato G, Fiore D, Proto MC, Rienzo M, Casamassimi A, Gazzerro P, Bifulco M, Castoria G, Weisz A, Nassa G, Abbondanza C. RIZ2 at the crossroad of the EGF/EGFR signaling in colorectal cancer. J Transl Med 2023; 21:736. [PMID: 37853459 PMCID: PMC10585774 DOI: 10.1186/s12967-023-04621-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 10/11/2023] [Indexed: 10/20/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the third most deadly and fourth most diagnosed cancer worldwide. Despite the progress in early diagnosis and advanced therapeutic options, CRC shows a poor prognosis with a 5 year survival rate of ~ 45%. PRDM2/RIZ, a member of PR/SET domain family (PRDM), expresses two main molecular variants, the PR-plus isoform (RIZ1) and the PR-minus (RIZ2). The imbalance in their expression levels in favor of RIZ2 is observed in many cancer types. The full length RIZ1 has been extensively investigated in several cancers where it acts as a tumor suppressor, whereas few studies have explored the RIZ2 oncogenic properties. PRDM2 is often target of frameshift mutations and aberrant DNA methylation in CRC. However, little is known about its role in CRC. METHODS We combined in-silico investigation of The Cancer Genome Atlas (TCGA) CRC datasets, cellular and molecular assays, transcriptome sequencing and functional annotation analysis to assess the role of RIZ2 in human CRC. RESULTS Our in-silico analysis on TCGA datasets confirmed that PRDM2 gene is frequently mutated and transcriptionally deregulated in CRC and revealed that a RIZ2 increase is highly correlated with a significant RIZ1 downregulation. Then, we assayed several CRC cell lines by qRT-PCR analysis for the main PRDM2 transcripts and selected DLD1 cell line, which showed the lowest RIZ2 levels. Therefore, we overexpressed RIZ2 in these cells to mimic TCGA datasets analysis results and consequently to assess the PRDM2/RIZ2 role in CRC. Data from RNA-seq disclosed that RIZ2 overexpression induced profound changes in CRC cell transcriptome via EGF pathway deregulation, suggesting that RIZ2 is involved in the EGF autocrine regulation of DLD1 cell behavior. Noteworthy, the forced RIZ2 expression increased cell viability, growth, colony formation, migration and organoid formation. These effects could be mediated by the release of high EGF levels by RIZ2 overexpressing DLD1 cells. CONCLUSIONS Our findings add novel insights on the putative RIZ2 tumor-promoting functions in CRC, although additional efforts are warranted to define the underlying molecular mechanism.
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Affiliation(s)
- Marzia Di Donato
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Erika Di Zazzo
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Annamaria Salvati
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, 84081, Baronissi, Italy
| | - Carmela Sorrentino
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giorgio Giurato
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, 84081, Baronissi, Italy
- CRGS-Genome Research Center for Health, University of Salerno Campus of Medicine, 84081, Baronissi, Italy
| | - Donatella Fiore
- Department of Pharmacy, University of Salerno, Fisciano, Italy
| | | | - Monica Rienzo
- Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Amelia Casamassimi
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
| | | | - Maurizio Bifulco
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Naples, Italy
| | - Gabriella Castoria
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Alessandro Weisz
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, 84081, Baronissi, Italy
- CRGS-Genome Research Center for Health, University of Salerno Campus of Medicine, 84081, Baronissi, Italy
| | - Giovanni Nassa
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, 84081, Baronissi, Italy
- CRGS-Genome Research Center for Health, University of Salerno Campus of Medicine, 84081, Baronissi, Italy
| | - Ciro Abbondanza
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
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Mesleh A, Ehtewish H, de la Fuente A, Al-shamari H, Ghazal I, Al-Faraj F, Al-Shaban F, Abdesselem HB, Emara M, Alajez NM, Arredouani A, Decock J, Albagha O, Stanton LW, Abdulla SA, El-Agnaf OMA. Blood Proteomics Analysis Reveals Potential Biomarkers and Convergent Dysregulated Pathways in Autism Spectrum Disorder: A Pilot Study. Int J Mol Sci 2023; 24:7443. [PMID: 37108604 PMCID: PMC10138652 DOI: 10.3390/ijms24087443] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/16/2023] [Accepted: 03/18/2023] [Indexed: 04/29/2023] Open
Abstract
Autism spectrum disorder (ASD) is an umbrella term that encompasses several disabling neurodevelopmental conditions. These conditions are characterized by impaired manifestation in social and communication skills with repetitive and restrictive behaviors or interests. Thus far, there are no approved biomarkers for ASD screening and diagnosis; also, the current diagnosis depends heavily on a physician's assessment and family's awareness of ASD symptoms. Identifying blood proteomic biomarkers and performing deep blood proteome profiling could highlight common underlying dysfunctions between cases of ASD, given its heterogeneous nature, thus laying the foundation for large-scale blood-based biomarker discovery studies. This study measured the expression of 1196 serum proteins using proximity extension assay (PEA) technology. The screened serum samples included ASD cases (n = 91) and healthy controls (n = 30) between 6 and 15 years of age. Our findings revealed 251 differentially expressed proteins between ASD and healthy controls, of which 237 proteins were significantly upregulated and 14 proteins were significantly downregulated. Machine learning analysis identified 15 proteins that could be biomarkers for ASD with an area under the curve (AUC) = 0.876 using support vector machine (SVM). Gene Ontology (GO) analysis of the top differentially expressed proteins (TopDE) and weighted gene co-expression analysis (WGCNA) revealed dysregulation of SNARE vesicular transport and ErbB pathways in ASD cases. Furthermore, correlation analysis showed that proteins from those pathways correlate with ASD severity. Further validation and verification of the identified biomarkers and pathways are warranted.
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Affiliation(s)
- Areej Mesleh
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
- Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Hanan Ehtewish
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
- Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Alberto de la Fuente
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Doha P.O. Box 34110, Qatar
| | - Hawra Al-shamari
- Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Iman Ghazal
- Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Fatema Al-Faraj
- Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Fouad Al-Shaban
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
- Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Houari B. Abdesselem
- Proteomics Core Facility, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Mohamed Emara
- Basic Medical Sciences Department, College of Medicine, QU Health, Qatar University (QU), Doha P.O. Box 2713, Qatar
| | - Nehad M. Alajez
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
- Translational Cancer and Immunity Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Abdelilah Arredouani
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Doha P.O. Box 34110, Qatar
| | - Julie Decock
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
- Translational Cancer and Immunity Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Omar Albagha
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Lawrence W. Stanton
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
- Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Sara A. Abdulla
- Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Omar M. A. El-Agnaf
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
- Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
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Basu D, Pal R, Sarkar M, Barma S, Halder S, Roy H, Nandi S, Samadder A. To Investigate Growth Factor Receptor Targets and Generate Cancer Targeting Inhibitors. Curr Top Med Chem 2023; 23:2877-2972. [PMID: 38164722 DOI: 10.2174/0115680266261150231110053650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 09/20/2023] [Accepted: 10/02/2023] [Indexed: 01/03/2024]
Abstract
Receptor tyrosine kinase (RTK) regulates multiple pathways, including Mitogenactivated protein kinases (MAPKs), PI3/AKT, JAK/STAT pathway, etc. which has a significant role in the progression and metastasis of tumor. As RTK activation regulates numerous essential bodily processes, including cell proliferation and division, RTK dysregulation has been identified in many types of cancers. Targeting RTK is a significant challenge in cancer due to the abnormal upregulation and downregulation of RTK receptors subfamily EGFR, FGFR, PDGFR, VEGFR, and HGFR in the progression of cancer, which is governed by multiple RTK receptor signalling pathways and impacts treatment response and disease progression. In this review, an extensive focus has been carried out on the normal and abnormal signalling pathways of EGFR, FGFR, PDGFR, VEGFR, and HGFR and their association with cancer initiation and progression. These are explored as potential therapeutic cancer targets and therefore, the inhibitors were evaluated alone and merged with additional therapies in clinical trials aimed at combating global cancer.
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Affiliation(s)
- Debroop Basu
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Riya Pal
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, IndiaIndia
| | - Maitrayee Sarkar
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Soubhik Barma
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Sumit Halder
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Harekrishna Roy
- Nirmala College of Pharmacy, Vijayawada, Guntur, Andhra Pradesh, India
| | - Sisir Nandi
- Global Institute of Pharmaceutical Education and Research (Affiliated to Uttarakhand Technical University), Kashipur, 244713, India
| | - Asmita Samadder
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
- Cytogenetics and Molecular Biology Lab., Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
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Ali DS, Othman HO, Anwer ET. The Advances in Chitosan-based Drug Delivery Systems for Colorectal Cancer: A Narrative Review. Curr Pharm Biotechnol 2023; 24:1554-1559. [PMID: 36733239 DOI: 10.2174/1389201024666230202160504] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 11/13/2022] [Accepted: 11/22/2022] [Indexed: 02/04/2023]
Abstract
Colorectal cancer (CRC) is considered a lethal cancer all around the world, and its incidence has been reported to be increasing. Chemotherapeutic drugs commonly used for treating this cancer have shown some drawbacks, including toxicity to healthy cells and non-precise delivery. Thus, there is a necessity for discovering novel diagnostic and therapeutic options to increase the survival rate of CRC patients. Chitosan, as a natural polymer, has attracted a lot attention during the past years in different fields, including cancer. Studies have indicated that chitosan-based materials play various roles in prevention, diagnosis, and treatment of cancers. Chitosan nanoparticles (NPs) have been shown to serve as anti-cancer agents, which provide sustained drug release and targeted delivery of drugs to the tumor site. In this paper, we review available literature on the roles of chitosan in CRC. We discuss the applications of chitosan in designing drug delivery systems as well as anti-cancer activities of chitosan and involved signaling pathways.
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Affiliation(s)
- Diyar Salahuddin Ali
- Department of Chemistry, College of Science, Salahaddin University-Erbil, Erbil, Iraq
| | - Hazha Omar Othman
- Department of Chemistry, College of Science, Salahaddin University-Erbil, Erbil, Iraq
- Department of Pharmaceutics, Faculty of Pharmacy, Tishk International University, Erbil, Iraq
| | - Esra Tariq Anwer
- Department of Pharmaceutics, Faculty of Pharmacy, Tishk International University, Erbil, Iraq
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Kciuk M, Gielecińska A, Budzinska A, Mojzych M, Kontek R. Metastasis and MAPK Pathways. Int J Mol Sci 2022; 23:ijms23073847. [PMID: 35409206 PMCID: PMC8998814 DOI: 10.3390/ijms23073847] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/18/2022] [Accepted: 03/29/2022] [Indexed: 02/07/2023] Open
Abstract
Cancer is a leading cause of death worldwide. In many cases, the treatment of the disease is limited due to the metastasis of cells to distant locations of the body through the blood and lymphatic drainage. Most of the anticancer therapeutic options focus mainly on the inhibition of tumor cell growth or the induction of cell death, and do not consider the molecular basis of metastasis. The aim of this work is to provide a comprehensive review focusing on cancer metastasis and the mitogen-activated protein kinase (MAPK) pathway (ERK/JNK/P38 signaling) as a crucial modulator of this process.
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Affiliation(s)
- Mateusz Kciuk
- Doctoral School of Exact and Natural Sciences, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland
- Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 12/16 Banacha St., 90-237 Lodz, Poland; (A.G.); (R.K.)
- Correspondence:
| | - Adrianna Gielecińska
- Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 12/16 Banacha St., 90-237 Lodz, Poland; (A.G.); (R.K.)
| | - Adrianna Budzinska
- Laboratory of Mitochondrial Biochemistry, Department of Bioenergetics, Faculty of Biology, Adam Mickiewicz University, 61-614 Poznan, Poland;
| | - Mariusz Mojzych
- Department of Chemistry, Siedlce University of Natural Sciences and Humanities, 3 Maja 54, 08-110 Siedlce, Poland;
| | - Renata Kontek
- Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 12/16 Banacha St., 90-237 Lodz, Poland; (A.G.); (R.K.)
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Chen WT, Lin YH, Changchien CY, Chen Y, Chang HH, Tsai WC, Tsai HC, Wang CY, Shen MS, Cheng LT, Tsai CL. Concurrent Blockade of Endothelial EGFR and VEGF Signaling on Malignant Associated Pleural Fluid Induced Angiogenesis: From Clinic to Bench. Biomedicines 2021; 9:biomedicines9101327. [PMID: 34680445 PMCID: PMC8533568 DOI: 10.3390/biomedicines9101327] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/20/2021] [Accepted: 09/23/2021] [Indexed: 12/04/2022] Open
Abstract
Malignant-associated pleural fluid (MAPF) represented an unsolved problem in advanced lung cancer. Our previous work characterized increased pleural angiogenesis in lung adenocarcinoma and the propensity of MAPF on endothelial angiogenesis. This study investigated the combined efficacy of the tyrosine kinase inhibitor (gefitinib) and bevacizumab in opposing MAPF-induced angiogenesis. In lung adenocarcinoma patients with malignant pleural effusion (MPE), Kaplan–Meier analysis revealed the benefit of cotreatment with target therapy and bevacizumab. Increased EGFR expression was observed in the pleural microvessels of patients with lung adenocarcinoma both with and without mutations in EGFR. MAPF was obtained from lung adenocarcinoma patients both wild-type and mutant EGFRs. Total and phosphorylated EGFR were upregulated in HUVEC cultured with MAPF. Treatment with gefitinib as an EGFR inhibitor suppressed MAPF-induced endothelial migration and partially attenuated endothelial proliferation in both wild-type and mutant EGFR lung adenocarcinoma. Cotreatment with gefitinib and bevacizumab produced better inhibition of MAPF-induced endothelial angiogenesis than gefitinib alone in the mutant EGFR subgroup. Protein analysis of MAPF-derived exosomes revealed abundant EGFR and p-EGFR components that implied possible transfer to endothelial cells. Concluding Kaplan–Meier analysis and in vitro studies, the results indicated that the addition of bevacizumab on gefitinib treatment could suppress MAPF-induced angiogenesis in lung adenocarcinoma patients.
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Affiliation(s)
- Wei-Teing Chen
- Division of Chest Medicine, Department of Medicine, Cheng-Hsin General Hospital, Taipei 112, Taiwan;
- Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan;
| | - Yu-Huei Lin
- Post-Baccalaureate Program in Nursing, College of Nursing, Taipei Medical University, Taipei 110, Taiwan;
| | - Chih-Ying Changchien
- Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan;
- Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, Taiwan; (Y.C.); (H.-H.C.)
| | - Ying Chen
- Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, Taiwan; (Y.C.); (H.-H.C.)
| | - Hsin-Han Chang
- Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, Taiwan; (Y.C.); (H.-H.C.)
| | - Wen-Chiuan Tsai
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan;
| | - Hao-Chung Tsai
- Division of Chest Medicine, Department of Internal Medicine, Tri-Service General Hospital Songshan Branch, Taipei 105, Taiwan;
| | - Chieh-Yung Wang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan; (C.-Y.W.); (L.-T.C.)
| | - Ming-Sheng Shen
- Department of Internal Medicine, Taichung Armed Force General Hospital, Taichung 411, Taiwan;
| | - Li-Ting Cheng
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan; (C.-Y.W.); (L.-T.C.)
| | - Chen-Liang Tsai
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan; (C.-Y.W.); (L.-T.C.)
- Correspondence:
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Bhaskaran NA, Kumar L. Treating colon cancers with a non-conventional yet strategic approach: An overview of various nanoparticulate systems. J Control Release 2021; 336:16-39. [PMID: 34118336 DOI: 10.1016/j.jconrel.2021.06.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/06/2021] [Accepted: 06/07/2021] [Indexed: 12/18/2022]
Abstract
Regardless of progress in therapy management which are developed for colon cancer (CC), it remains the third most common cause of mortality due to cancers around the world. Conventional medicines pose side effects due to untoward action on non-target cells. Their inability to deliver drugs to the affected regions of the colon locally, in a reproducible manner raises a concern towards the efficacy of therapy. In this regard, nanoparticles emerged as a promising drug delivery system due to their flexibility in designing, drug release modulation and cancer cell targeting. Not only are nanoparticles making their way into colon cancer research in the revolution of conventional onco-therapeutics, but they also offer promising scope in the development of colon cancer vaccines and theranostic tools. However, there are challenges with respect to drug delivery using nanoparticles, which may hamper the delivery of these novel carriers to the colon. The present review addresses recent advents in nanotechnology for colon-specific drug delivery (CDDS) which may help to overcome the existing challenges and intends to recognize futuristic potentials in the treatment of CC with CDDS.
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Affiliation(s)
- N A Bhaskaran
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Udupi, Karnataka, India
| | - L Kumar
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Udupi, Karnataka, India.
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10
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Lei X, Deng L, Liu D, Liao S, Dai H, Li J, Rong J, Wang Z, Huang G, Tang C, Xu C, Xiao B, Li T. ARHGEF7 promotes metastasis of colorectal adenocarcinoma by regulating the motility of cancer cells. Int J Oncol 2018; 53:1980-1996. [PMID: 30132516 PMCID: PMC6192735 DOI: 10.3892/ijo.2018.4535] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 06/12/2018] [Indexed: 12/12/2022] Open
Abstract
Previous studies have shown that Rho guanine nucleotide exchange factor 7 (ARHGEF7) is implicated in cytoskeleton remodelling, which is important for cell motility and invasiveness, and exhibits frequent high-level genetic amplification in metastatic lesions of colorectal adenocarcinoma. Therefore, it was hypothesized that ARHGEF7 may be involved in the metastasis of colorectal adenocarcinoma. In the present study, it was demonstrated that the expression level of ARHGEF7 was significantly upregulated in colorectal adenocarcinoma tumor tissues compared with matched nontumorous tissues, and its expression level correlated with colorectal adenocarcinoma metastasis. In vitro assays showed that the overexpression of ARHGEF7 in CRC cells significantly enhanced cell migration and invasion, whereas the knockdown of ARHGEF7 in colorectal adenocarcinoma cells significantly decreased cell migration and invasion. In vivo assays showed that the overexpression of ARHGEF7 in CRC cells facilitated tumor metastasis, whereas the knockdown of ARHGEF7 in CRC cells significantly inhibited tumor metastasis. Furthermore, it was demonstrated that ARHGEF7 promoted cell motility by regulating the actin cytoskeleton. Finally, according to ReMARK guidelines for reporting prognostic biomarkers in cancer, it was found that a high expression of ARHGEF7 was significantly correlated with lymph node, mesenteric and distant metastasis. Patients with colorectal adenocarcinoma with a high expression of ARHGEF7 had shorter disease-free survival (DFS) and shorter overall survival (OS) rates, compared with those with a low expression of ARHGEF7, as determined by the Kaplan-Meier method with a log-rank test. Cox regression analysis showed that a high expression of ARHGEF7 was an independent risk factor for DFS and OS rates in colorectal adenocarcinoma.
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Affiliation(s)
- Xiong Lei
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Li Deng
- Department of General Surgery, Jiangxi Pingxiang People's Hospital, Pingxiang, Jiangxi 337000, P.R. China
| | - Dongning Liu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Shijun Liao
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Hua Dai
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jiaxi Li
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jun Rong
- Department of General Surgery, Jiangxi Pingxiang People's Hospital, Pingxiang, Jiangxi 337000, P.R. China
| | - Zhiwen Wang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Guodong Huang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Cheng Tang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Chen Xu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Benping Xiao
- Department of General Surgery, Jiangxi Pingxiang People's Hospital, Pingxiang, Jiangxi 337000, P.R. China
| | - Taiyuan Li
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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11
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Niazi S, Purohit M, Sonawani A, Niazi JH. Revealing the molecular interactions of aptamers that specifically bind to the extracellular domain of HER2 cancer biomarker protein: An in silico assessment. J Mol Graph Model 2018; 83:112-121. [DOI: 10.1016/j.jmgm.2018.06.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 06/03/2018] [Accepted: 06/04/2018] [Indexed: 12/16/2022]
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12
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Mésange P, Bouygues A, Ferrand N, Sabbah M, Escargueil AE, Savina A, Chibaudel B, Tournigand C, André T, de Gramont A, Larsen AK. Combinations of Bevacizumab and Erlotinib Show Activity in Colorectal Cancer Independent of RAS Status. Clin Cancer Res 2018; 24:2548-2558. [PMID: 29490990 DOI: 10.1158/1078-0432.ccr-17-3187] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 01/09/2018] [Accepted: 02/20/2018] [Indexed: 11/16/2022]
Abstract
Purpose: There is extensive cross-talk between VEGF- and EGFR-pathway signaling in colorectal cancer. However, combinations of VEGF- and EGFR-targeted monoclonal antibodies (mAb) show disappointing activity, in particular for patients with mutant RAS Previous results show that tyrosine kinase inhibitors (TKI) can be active in colorectal cancer models resistant to mAbs. This prompted us to examine whether the activity of bevacizumab can be increased by combination with erlotinib.Experimental Design: The antitumor activity of bevacizumab, erlotinib, and their combination was determined in colorectal cancer models with different RAS status and bevacizumab sensitivity. EGFR/VEGF pathway activation was characterized by immunohistochemistry, Western blot, and ELISA assays. The influence of cetuximab and erlotinib on EGF-mediated migration and the EGFR-EGF ligand feedback loop was established in colorectal cancer cell lines with different RAS status.Results: The addition of erlotinib increased bevacizumab activity in all models independent of RAS status. Bevacizumab exposure was accompanied by marked EGFR activation in tumor cells as well as in tumor-associated endothelial cells (TECs) and resulted in strong accumulation of intracellular EGFR, which could be attenuated by erlotinib. In cellular models, erlotinib was able to attenuate EGF-mediated functions in all cell lines independent of RAS status while cetuximab only showed activity in RAS wild-type cells.Conclusions: These results should provide a molecular framework to better understand the increased activity of the bevacizumab-erlotinib combination, compared with bevacizumab alone, in the GERCOR DREAM phase III clinical trial. Differential activity of mAbs and TKIs targeting the same signaling pathway is likely applicable for other tumor types. Clin Cancer Res; 24(11); 2548-58. ©2018 AACR.
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Affiliation(s)
- Paul Mésange
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, Paris, France
| | - Anaïs Bouygues
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, Paris, France
| | - Nathalie Ferrand
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, Paris, France
| | - Michèle Sabbah
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, Paris, France.,Centre National de la Recherche Scientifique (CNRS), Paris, France
| | - Alexandre E Escargueil
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, Paris, France
| | - Ariel Savina
- Roche Scientific Partnerships, Boulogne-Billancourt, France
| | - Benoist Chibaudel
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Department of Medical Oncology, Institut Hospitalier Franco-Britannique, Levallois-Perret, France
| | - Christophe Tournigand
- Department of Medical Oncology, Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Créteil, France.,Université Paris Est, Créteil, France
| | - Thierry André
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, Paris, France.,Department of Medical Oncology, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France
| | - Aimery de Gramont
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Department of Medical Oncology, Institut Hospitalier Franco-Britannique, Levallois-Perret, France
| | - Annette K Larsen
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France. .,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, Paris, France.,Centre National de la Recherche Scientifique (CNRS), Paris, France
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13
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Toffoli G, De Mattia E, Cecchin E, Biason P, Masier S, Corona G. Pharmacology of Epidermal Growth Factor Inhibitors. Int J Biol Markers 2018; 22:24-39. [DOI: 10.1177/17246008070221s404] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Research into the molecular bases of malignant diseases has yielded the development of many novel agents with potential antitumor activity. Evidence for a causative role for the epidermal growth factor receptor (EGFR), which is now regarded as an excellent target for cancer chemotherapy in human cancer, leads to the development of EGFR inhibitors. Two classes of anti-EGFR agents are currently in clinical use: monoclonal antibodies directed at the extracellular domain of the receptor, and the low-molecular-weight receptor tyrosine kinase inhibitors acting intracellularly by competing with adenosine triphosphate for binding to the tyrosine kinase portion of the EGFR. The effect on the receptor interferes with key biological functions including cell cycle arrest, potentiation of apoptosis, inhibition of angiogenesis and cell invasion and metastasis. Cetuximab, a monoclonal antibody, and the receptor tyrosine kinase inhibitors gefitinib and erlotinib are currently approved for the treatment of patients with cancer. New agents with clinical activity are entering the clinic, and new combinatorial approaches are being explored with the aim of improving the potency and pharmacokinetics of EGFR inhibition, to increase the synergistic activity in combination with chemotherapy and overcome resistance to the EGFR inhibitors.
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Affiliation(s)
- G. Toffoli
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico, Aviano, Pordenone - Italy
| | - E. De Mattia
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico, Aviano, Pordenone - Italy
| | - E. Cecchin
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico, Aviano, Pordenone - Italy
| | - P. Biason
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico, Aviano, Pordenone - Italy
| | - S. Masier
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico, Aviano, Pordenone - Italy
| | - G. Corona
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico, Aviano, Pordenone - Italy
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14
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Cai F, Chen M, Zha D, Zhang P, Zhang X, Cao N, Wang J, He Y, Fan X, Zhang W, Fu Z, Lai Y, Hua ZC, Zhuang H. Curcumol potentiates celecoxib-induced growth inhibition and apoptosis in human non-small cell lung cancer. Oncotarget 2017; 8:115526-115545. [PMID: 29383179 PMCID: PMC5777791 DOI: 10.18632/oncotarget.23308] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 12/05/2017] [Indexed: 01/01/2023] Open
Abstract
Combinatorial therapies that target multiple signaling pathways may provide improved therapeutic responses over monotherapies. Celecoxib and curcumol are two highly hydrophobic drugs which show bioavailability problems due to their poor aqueous solubility. In the present study, we evaluated the effects of celecoxib and curcumol alone and in combination on cell proliferation, invasion, migration, cell cycle and apoptosis induction in non-small cell lung cancer (NSCLC) cells using in vitro and in vivo experiments. Our data showed that the sensitivity of a combined therapy using low concentration of celecoxib and curcumol was higher than that of celecoxib or curcumol alone. Suppression of NF-κB transcriptional activity, activation of caspase-9/caspase-3, cell cycle G1 arrest, and inhibition of survival MAPK and PI3K/AKT signaling pathway contributed to the synergistic effects of this combination therapy for induction of apoptosis. Additionally, either celecoxib alone or in combination with curcumol inhibited NSCLC cell migration and invasion by suppressing FAK and matrix metalloproteinase-9 activities. Furthermore, the combined treatment reduced tumor volume and weight in xenograft mouse model, and significantly decreased tumor metastasis nodules in lung tissues by tail vein injection. Our results confirm and provide mechanistic insights into the prominent anti-proliferative activities of celecoxib and/or curcumol on NSCLC cells, which provide a rationale for further detailed preclinical and potentially clinical studies of this combination for the therapy of lung cancer.
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Affiliation(s)
- Fangfang Cai
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Minghui Chen
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.,State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Daolong Zha
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Peng Zhang
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Xiangyu Zhang
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Nini Cao
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Jishuang Wang
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Yan He
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Xinxin Fan
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Wenjing Zhang
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Zhongping Fu
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Yueyang Lai
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.,Nanjing Industrial Innovation Center for Pharmaceutical Biotechnology, Nanjing, China
| | - Zi-Chun Hua
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.,State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Hongqin Zhuang
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
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15
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Alsaid MS, Al-Mishari AA, Soliman AM, Ragab FA, Ghorab MM. Discovery of Benzo[g]quinazolin benzenesulfonamide derivatives as dual EGFR/HER2 inhibitors. Eur J Med Chem 2017; 141:84-91. [PMID: 29028534 DOI: 10.1016/j.ejmech.2017.09.061] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 09/25/2017] [Accepted: 09/27/2017] [Indexed: 12/27/2022]
Abstract
An array of some new N-(substituted)-2-((4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-yl)thio)acetamide 5-19 were synthesized from the starting compound 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl)benzenesulfonamide 4, to be assessed for their cytotoxic activity against A549 lung cancer cell line and to determine their inhibitory effect on EGFR tyrosine kinase enzyme. Compounds 5-19 showed high activity towards A549 cell line with IC50 values of 0.12-8.70 μM. Compounds 6, 12 and 18 were the most potent in this series. These compounds were further screened as dual inhibitors for EGFR/HER2 enzymes in comparison with erlotinib and were found to possess very potent activity. Compound 12 showed the highest activity with IC50 values of 0.06 μM and 0.30 μM towards EGFR and HER2, respectively. Accordingly, the apoptotic effect of the most potent compounds 6, 12 and 18 was investigated and showed a marked increase in the level of caspases-3 by 6, 9 and 8 folds, respectively, compared to the control cells. Moreover, Molecular modeling was performed inside the active site of EGFR, keeping in mind their binding possibilities, bond lengths, angles and energy scores. It was found that the most active compounds demonstrated the best binding scores in the active site of EGFR, which may clarify their high inhibition profile.
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Affiliation(s)
- Mansour S Alsaid
- Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Abdullah A Al-Mishari
- Medicinal, Aromatic and Poisonous Plants Research Center (MAPPRC), College of Pharmacy, King Saud University, Saudi Arabia
| | - Aiten M Soliman
- Department of Drug Radiation Research, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo 113701, Egypt
| | - Fatma A Ragab
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Egypt
| | - Mostafa M Ghorab
- Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Department of Drug Radiation Research, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo 113701, Egypt.
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16
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Chaurasia S, Patel RR, Vure P, Mishra B. Potential of Cationic-Polymeric Nanoparticles for Oral Delivery of Naringenin: In Vitro and In Vivo Investigations. J Pharm Sci 2017; 107:706-716. [PMID: 29031951 DOI: 10.1016/j.xphs.2017.10.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 09/26/2017] [Accepted: 10/02/2017] [Indexed: 02/02/2023]
Abstract
The objective of the study was to improve the bioavailability and anticancer potential of naringenin (NRG) by developing a drug-loaded polymeric nanodelivery system. NRG-loaded eudragit E100 nanoparticle (NRG-EE100-NPs) system was developed and physicochemically characterized. In vivo pharmacokinetic and in vitro cytotoxicity abilities of the NRG-EE100-NPs were investigated. In vivo anticancer activity was evaluated in murine BALB/c mice-bearing colorectal tumor. The NRG-EE100-NPs had an optimum mean particle size (430.42 ± 5.78 nm), polydispersity index (0.283 ± 0.089) with percent entrapment efficiency (68.83 ± 3.45%). The NRG-EE100-NPs demonstrated significant higher bioavailability (∼96-fold; p <0.05) as well as cytotoxicity (∼16-fold; p <0.001) as compared to free NRG. Furthermore, NRG-EE100-NPs indicated significant tumor suppression (p <0.01) subsequently improvement in survival rate compared to free NRG in vivo. Thus, the physicochemical properties and colorectal cancer efficacy of NRG were improved by successful encapsulating in cationic-polymeric nanoparticle system.
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Affiliation(s)
- Sundeep Chaurasia
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221 005, Uttar Pradesh, India; Formulation Research and Development, Complex Generics Division, Virchow Biotech Pvt. Ltd., Survey No. 172 Part, Gagillapur (V), Quthbullapur (M), Ranga Reddy (Dist.), Hyderabad 500 043, Telangana, India
| | - Ravi R Patel
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221 005, Uttar Pradesh, India
| | - Prasad Vure
- Formulation Research and Development, Complex Generics Division, Virchow Biotech Pvt. Ltd., Survey No. 172 Part, Gagillapur (V), Quthbullapur (M), Ranga Reddy (Dist.), Hyderabad 500 043, Telangana, India
| | - Brahmeshwar Mishra
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221 005, Uttar Pradesh, India.
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17
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Zhou X, Geng L, Wang D, Yi H, Talmon G, Wang J. R-Spondin1/LGR5 Activates TGFβ Signaling and Suppresses Colon Cancer Metastasis. Cancer Res 2017; 77:6589-6602. [PMID: 28939678 DOI: 10.1158/0008-5472.can-17-0219] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 06/16/2017] [Accepted: 09/19/2017] [Indexed: 01/10/2023]
Abstract
Leucine-rich repeat containing G-protein-coupled receptor 5 (LGR5), an intestinal stem cell marker, is known to exhibit tumor suppressor activity in colon cancer, the mechanism of which is not understood. Here we show that R-spondin 1 (RSPO1)/LGR5 directly activates TGFβ signaling cooperatively with TGFβ type II receptor in colon cancer cells, enhancing TGFβ-mediated growth inhibition and stress-induced apoptosis. Knockdown of LGR5 attenuated downstream TGFβ signaling and increased cell proliferation, survival, and metastasis in an orthotopic model of colon cancer in vivo Upon RSPO1 stimulation, LGR5 formed complexes with TGFβ receptors. Studies of patient specimens indicate that LGR5 expression was reduced in advanced stages and positively correlated with markers of TGFβ activation in colon cancer. Our study uncovers a novel cross-talk between LGR5 and TGFβ signaling in colon cancer and identifies LGR5 as a new modulator of TGFβ signaling able to suppress colon cancer metastasis. Cancer Res; 77(23); 6589-602. ©2017 AACR.
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Affiliation(s)
- Xiaolin Zhou
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, Omaha, Nebraska
| | - Liying Geng
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, Omaha, Nebraska
| | - Degeng Wang
- Department of Environmental Toxicology, The Institute of Environmental and Human Health, Texas Tech University, Lubbock, Texas
| | - Haowei Yi
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, Omaha, Nebraska
| | - Geoffrey Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, Nebraska
| | - Jing Wang
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, Omaha, Nebraska. .,Department of Genetics, Cell Biology and Anatomy, Fred & Pamela Buffett Cancer Center, Omaha, Nebraska.,Department of Biochemistry and Molecular Biology, Fred & Pamela Buffett Cancer Center, Omaha, Nebraska
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18
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Carrasco P, Zuazo-Gaztelu I, Casanovas O. Sprouting strategies and dead ends in anti-angiogenic targeting of NETs. J Mol Endocrinol 2017; 59:R77-R91. [PMID: 28469004 DOI: 10.1530/jme-17-0029] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 05/03/2017] [Indexed: 01/13/2023]
Abstract
Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that arise from cells of the neuroendocrine system. NETs are characterized by being highly vascularized tumors that produce large amounts of proangiogenic factors. Due to their complexity and heterogeneity, progress in the development of successful therapeutic approaches has been limited. For instance, standard chemotherapy-based therapies have proven to be poorly selective for tumor cells and toxic for normal tissues. Considering the urge to develop an efficient therapy to treat NET patients, vascular targeting has been proposed as a new approach to block tumor growth. This review provides an update of the mechanisms regulating different components of vessels and their contribution to tumor progression in order to develop new therapeutic drugs. Following the description of classical anti-angiogenic therapies that target VEGF pathway, new angiogenic targets such as PDGFs, EGFs, FGFs and semaphorins are further explored. Based on recent research in the field, the combination of therapies that target multiple and different components of vessel formation would be the best approach to specifically target NETs and inhibit tumor growth.
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Affiliation(s)
- Patricia Carrasco
- Tumor Angiogenesis GroupProCURE, Catalan Institute of Oncology - IDIBELL, Barcelona, Spain
| | - Iratxe Zuazo-Gaztelu
- Tumor Angiogenesis GroupProCURE, Catalan Institute of Oncology - IDIBELL, Barcelona, Spain
| | - Oriol Casanovas
- Tumor Angiogenesis GroupProCURE, Catalan Institute of Oncology - IDIBELL, Barcelona, Spain
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19
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Katsiampoura A, Raghav K, Jiang ZQ, Menter DG, Varkaris A, Morelli MP, Manuel S, Wu J, Sorokin AV, Rizi BS, Bristow C, Tian F, Airhart S, Cheng M, Broom BM, Morris J, Overman MJ, Powis G, Kopetz S. Modeling of Patient-Derived Xenografts in Colorectal Cancer. Mol Cancer Ther 2017; 16:1435-1442. [PMID: 28468778 DOI: 10.1158/1535-7163.mct-16-0721] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 03/13/2017] [Accepted: 04/19/2017] [Indexed: 12/16/2022]
Abstract
Developing realistic preclinical models using clinical samples that mirror complex tumor biology and behavior are vital to advancing cancer research. While cell line cultures have been helpful in generating preclinical data, the genetic divergence between these and corresponding primary tumors has limited clinical translation. Conversely, patient-derived xenografts (PDX) in colorectal cancer are highly representative of the genetic and phenotypic heterogeneity in the original tumor. Coupled with high-throughput analyses and bioinformatics, these PDXs represent robust preclinical tools for biomarkers, therapeutic target, and drug discovery. Successful PDX engraftment is hypothesized to be related to a series of anecdotal variables namely, tissue source, cancer stage, tumor grade, acquisition strategy, time to implantation, exposure to prior systemic therapy, and genomic heterogeneity of tumors. Although these factors at large can influence practices and patterns related to xenotransplantation, their relative significance in determining the success of establishing PDXs is uncertain. Accordingly, we systematically examined the predictive ability of these factors in establishing PDXs using 90 colorectal cancer patient specimens that were subcutaneously implanted into immunodeficient mice. Fifty (56%) PDXs were successfully established. Multivariate analyses showed tissue acquisition strategy [surgery 72.0% (95% confidence interval (CI): 58.2-82.6) vs. biopsy 35% (95% CI: 22.1%-50.6%)] to be the key determinant for successful PDX engraftment. These findings contrast with current empiricism in generating PDXs and can serve to simplify or liberalize PDX modeling protocols. Better understanding the relative impact of these factors on efficiency of PDX formation will allow for pervasive integration of these models in care of colorectal cancer patients. Mol Cancer Ther; 16(7); 1435-42. ©2017 AACR.
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Affiliation(s)
- Anastasia Katsiampoura
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kanwal Raghav
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Zhi-Qin Jiang
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David G Menter
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Andreas Varkaris
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Maria P Morelli
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shanequa Manuel
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ji Wu
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alexey V Sorokin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Bahar Salimian Rizi
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Christopher Bristow
- Department of Applied Cancer Science Institute, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Feng Tian
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Susan Airhart
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Bradley M Broom
- Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jeffrey Morris
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael J Overman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Garth Powis
- Sanford Burnham Prebys Discovery Institute, La Jolla, California
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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20
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Farey JE, Fisher OM, Levert-Mignon AJ, Forner PM, Lord RV. Decreased Levels of Circulating Cancer-Associated Protein Biomarkers Following Bariatric Surgery. Obes Surg 2017; 27:578-585. [PMID: 27525640 PMCID: PMC5306243 DOI: 10.1007/s11695-016-2321-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Epidemiological studies have identified obesity as a major risk factor for cancer in humans, and trials have demonstrated a significant reduction in the incidence of cancer after bariatric surgery. The rapidity of weight loss after bariatric surgery provides an opportunity to identify the molecular changes associated with effective obesity treatment. Indirectly, this may provide some insights into the mechanisms that drive the association between obesity and cancer. We sought to measure circulating cancer-associated proteins before and after laparoscopic sleeve gastrectomy (LSG). METHODS We prospectively enrolled 15 patients undergoing LSG. Thirty-four plasma protein biomarkers thought to be associated with cancer processes were analyzed at baseline and following successful weight loss at 12 weeks using a multiplex bead-based assay. RESULTS Mean excess body weight loss was 44 % at 12-week follow-up. After LSG, a significant reduction in circulating plasma levels was observed for half (17/34) of the proteins assessed: VEGF-A, VEGF-C, VEGF-D, endoglin, PLGF, sFASL, IGFBP-1, IL-18, prolactin, EGF, TGFα, sCD40L, IL-18, TNFα, IL-6, HB-EGF, and PAI-1. Nonsignificant decreases were found for the remaining proteins. CONCLUSIONS Circulating cancer-related biomarker levels were reduced by surgical weight loss, and this benefit was achieved as early as 3 months after operation. The observed reduction in cancer biomarkers may be related to the reported decrease in cancer incidence following bariatric surgery.
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Affiliation(s)
- John Edward Farey
- Department of Surgery, University of Notre Dame Australia, School of Medicine, Sydney, Darlinghurst, NSW Australia
- Gastro-Oesophageal Cancer Research Program, St Vincent’s Centre for Applied Medical Research, Darlinghurst, NSW Australia
| | - Oliver M. Fisher
- Department of Surgery, University of Notre Dame Australia, School of Medicine, Sydney, Darlinghurst, NSW Australia
- Gastro-Oesophageal Cancer Research Program, St Vincent’s Centre for Applied Medical Research, Darlinghurst, NSW Australia
| | - Angelique J. Levert-Mignon
- Department of Surgery, University of Notre Dame Australia, School of Medicine, Sydney, Darlinghurst, NSW Australia
- Gastro-Oesophageal Cancer Research Program, St Vincent’s Centre for Applied Medical Research, Darlinghurst, NSW Australia
| | - Patrice M. Forner
- Department of Surgery, University of Notre Dame Australia, School of Medicine, Sydney, Darlinghurst, NSW Australia
- Gastro-Oesophageal Cancer Research Program, St Vincent’s Centre for Applied Medical Research, Darlinghurst, NSW Australia
| | - Reginald V. Lord
- Department of Surgery, University of Notre Dame Australia, School of Medicine, Sydney, Darlinghurst, NSW Australia
- Gastro-Oesophageal Cancer Research Program, St Vincent’s Centre for Applied Medical Research, Darlinghurst, NSW Australia
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21
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Tommelein J, Gremonprez F, Verset L, De Vlieghere E, Wagemans G, Gespach C, Boterberg T, Demetter P, Ceelen W, Bracke M, De Wever O. Age and cellular context influence rectal prolapse formation in mice with caecal wall colorectal cancer xenografts. Oncotarget 2016; 7:75603-75615. [PMID: 27689329 PMCID: PMC5342764 DOI: 10.18632/oncotarget.12312] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 09/14/2016] [Indexed: 12/24/2022] Open
Abstract
In patients with rectal prolapse is the prevalence of colorectal cancer increased, suggesting that a colorectal tumor may induce rectal prolapse. Establishment of tumor xenografts in immunodeficient mice after orthotopic inoculations of human colorectal cancer cells into the caecal wall is a widely used approach for the study of human colorectal cancer progression and preclinical evaluation of therapeutics. Remarkably, 70% of young mice carrying a COLO320DM caecal tumor showed symptoms of intussusception of the large bowel associated with intestinal lumen obstruction and rectal prolapse. The quantity of the COLO320DM bioluminescent signal of the first three weeks post-inoculation predicts prolapse in young mice. Rectal prolapse was not observed in adult mice carrying a COLO320DM caecal tumor or young mice carrying a HT29 caecal tumor. In contrast to HT29 tumors, which showed local invasion and metastasis, COLO320DM tumors demonstrated a non-invasive tumor with pushing borders without presence of metastasis. In conclusion, rectal prolapse can be linked to a non-invasive, space-occupying COLO320DM tumor in the gastrointestinal tract of young immunodeficient mice. These data reveal a model that can clarify the association of patients showing rectal prolapse with colorectal cancer.
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Affiliation(s)
- Joke Tommelein
- Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Félix Gremonprez
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium.,Department of Surgery, Ghent University Hospital, Ghent, Belgium
| | - Laurine Verset
- Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Elly De Vlieghere
- Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Glenn Wagemans
- Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Christian Gespach
- Institut National de la Santé et de la Recherche Médicale, INSERM, Department of Molecular and Clinical Oncology, Université Paris VI Pierre et Marie Curie, Paris, France
| | - Tom Boterberg
- Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Pieter Demetter
- Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Wim Ceelen
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium.,Department of Surgery, Ghent University Hospital, Ghent, Belgium
| | - Marc Bracke
- Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Olivier De Wever
- Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
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22
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Lim Y, Yoo J, Kim MS, Hur M, Lee EH, Hur HS, Lee JC, Lee SN, Park TW, Lee K, Chang KH, Kim K, Kang Y, Hong KW, Kim SH, Kim YG, Yoon Y, Nam DH, Yang H, Kim DG, Cho HS, Won J. GC1118, an Anti-EGFR Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity against High-Affinity EGFR Ligands. Mol Cancer Ther 2015; 15:251-63. [PMID: 26586721 DOI: 10.1158/1535-7163.mct-15-0679] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 11/12/2015] [Indexed: 11/16/2022]
Abstract
The EGFR-targeted monoclonal antibodies are a valid therapeutic strategy for patients with metastatic colorectal cancer (mCRC). However, only a small subset of mCRC patients has therapeutic benefits and there are high demands for EGFR therapeutics with a broader patient pool and more potent efficacy. In this study, we report GC1118 exhibiting a different character in terms of binding epitope, affinity, mode of action, and efficacy from other anti-EGFR antibodies. Structural analysis of the EGFR-GC1118 crystal complex revealed that GC1118 recognizes linear, discrete N-terminal epitopes of domain III of EGFR, critical for EGF binding but not overlapping with those of other EGFR-targeted antibodies. GC1118 exhibited superior inhibitory activity against high-affinity EGFR ligands in terms of EGFR binding, triggering EGFR signaling, and proliferation compared with cetuximab and panitumumab. EGFR signaling driven by low-affinity ligands, on the contrary, was well inhibited by all the antibodies tested. GC1118 demonstrated robust antitumor activity in tumor xenografts with elevated expression of high-affinity ligands in vivo, whereas cetuximab did not. Considering the significant role of high-affinity EGFR ligands in modulating tumor microenvironment and inducing resistance to various cancer therapeutics, our study suggests a potential therapeutic advantage of GC1118 in terms of efficacy and a range of benefited patient pool. Mol Cancer Ther; 15(2); 251-63. ©2015 AACR.
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Affiliation(s)
- Yangmi Lim
- MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea
| | - Jiho Yoo
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Min-Soo Kim
- MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea
| | - Minkyu Hur
- MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea. Graduate School of Medicine, Korea University College of Medicine, Korea University, Seoul, Republic of Korea
| | - Eun Hee Lee
- MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea
| | - Hyung-Suk Hur
- MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea
| | - Jae-Chul Lee
- MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea
| | - Shi-Nai Lee
- MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea
| | - Tae Wook Park
- MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea
| | - Kyuhyun Lee
- MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea
| | - Ki Hwan Chang
- MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea
| | - Kuglae Kim
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - YingJin Kang
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Kwang-Won Hong
- MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea
| | - Se-Ho Kim
- University-Industry Cooperation Foundation, and Department of Systems Immunology, College of Biomedical Science, Kangwon National University, Chuncheon, Kangwon-Do, Republic of Korea
| | - Yeon-Gil Kim
- Pohang Accelerator Laboratory, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea
| | - Yeup Yoon
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea. Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea
| | - Do-Hyun Nam
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea. Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea. Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea
| | - Heekyoung Yang
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea. Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea. Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea
| | - Dong Geon Kim
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea
| | - Hyun-Soo Cho
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
| | - Jonghwa Won
- MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea.
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23
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Zhu Y, Choi SH, Shah K. Multifunctional receptor-targeting antibodies for cancer therapy. Lancet Oncol 2015; 16:e543-e554. [DOI: 10.1016/s1470-2045(15)00039-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 05/28/2015] [Accepted: 06/01/2015] [Indexed: 12/29/2022]
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24
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Computer-aided identification of novel anticancer compounds with a possible dual HER1/HER2 inhibition mechanism. Bioorg Med Chem Lett 2015; 25:758-62. [DOI: 10.1016/j.bmcl.2014.12.095] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Revised: 12/23/2014] [Accepted: 12/31/2014] [Indexed: 11/24/2022]
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25
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Abstract
The combination of chemotherapy and targeted therapies is rapidly becoming the standard of care in the treatment of metastatic colorectal cancer. Panitumumab (formerly ABX-EGF) is a fully human antibody developed to target the human epidermal growth factor receptor (EGFR/HER-1), which is expressed in up to 75% of patients with colorectal cancer. As a fully human antibody, panitumumab can be administered without any premedication and few infusion reactions have been reported. It has recently been approved in the USA for the treatment of colorectal cancer as a single agent in the salvage setting. Ongoing studies are being performed to determine whether the addition of panitumumab to standard treatment for metastatic colorectal cancer will improve the survival of these patients.
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26
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MicroRNA-192 suppresses liver metastasis of colon cancer. Oncogene 2013; 33:5332-40. [PMID: 24213572 PMCID: PMC4016997 DOI: 10.1038/onc.2013.478] [Citation(s) in RCA: 113] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Revised: 09/05/2013] [Accepted: 09/20/2013] [Indexed: 02/06/2023]
Abstract
Metastasis causes most deaths from colon cancer yet mechanistic understanding and therapeutic options remain limited. Here we show that expression of microRNA (miR)-192 is inversely correlated with metastatic potential of colon cancer cells. Ectopic expression of miR-192 sensitizes colon cancer cells to growth factor deprivation stress (GFDS)-induced apoptosis whereas inhibition of miR-192 confers resistance. Overexpression of miR-192 inhibits metastatic colonization to the liver in an orthotopic mouse model of colon cancer. Alterations associated with the metastatic phenotype in the primary tumors include increased apoptosis, decreased proliferation and angiogenesis. Further studies indicate that miR-192 down-regulates expression of Bcl-2, Zeb2 and VEGFA in vitro and in vivo, which is responsible for enhanced apoptosis, increased expression of E-cadherin and decreased angiogenesis in vivo respectively. Finally, studies performed on human colonic adenocarcinoma show that expression of miR-192 is significantly reduced in neoplastic cells as compared to normal colonic epithelium. Importantly, there is a significant decrease of miR-192 expression in stage IV tumors when compared to stage I or II lesions. These findings indicate that miR-192 plays an important role in colon cancer development and progression. Our studies underscore the clinical relevance and prognostic significance of miR-192 expression in colon cancer. Therefore, a major implication of our studies is that restoration of miR-192 expression or antagonism of its target genes (Bcl-2, Zeb2 or VEGFA) may have considerable therapeutic potential for anti-metastatic therapy in patients with colon cancer.
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27
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The role of epidermal growth factor receptor in cancer metastasis and microenvironment. BIOMED RESEARCH INTERNATIONAL 2013; 2013:546318. [PMID: 23986907 PMCID: PMC3748428 DOI: 10.1155/2013/546318] [Citation(s) in RCA: 201] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 06/25/2013] [Indexed: 02/06/2023]
Abstract
Despite significant improvements in diagnosis, surgical techniques, and advancements in general patient care, the majority of deaths from cancer are caused by the metastases. There is an urgent need for an improved understanding of the cellular and molecular factors that promote cancer metastasis. The process of cancer metastasis depends on multiple interactions between cancer cells and host cells. Studies investigating the TGF α-EGFR signaling pathways that promote the growth and spread of cancer cells. Moreover, the signaling activates not only tumor cells, but also tumor-associated endothelial cells. TGF α-EGFR signaling in colon cancer cells creates a microenvironment that is conducive for metastasis, providing a rationale for efforts to inhibit EGFR signaling in TGF α-positive cancers. In this review, we describe the recent advances in our understanding of the molecular basis of cancer metastasis.
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28
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Larsen AK, de Gramont A, Poindessous V, Bouygues A, Ayadi M, Mésange P. Functions and Clinical Implications of Autocrine VEGF Signaling in Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2013. [DOI: 10.1007/s11888-013-0177-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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29
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Peng YH, Shiao HY, Tu CH, Liu PM, Hsu JTA, Amancha PK, Wu JS, Coumar MS, Chen CH, Wang SY, Lin WH, Sun HY, Chao YS, Lyu PC, Hsieh HP, Wu SY. Protein Kinase Inhibitor Design by Targeting the Asp-Phe-Gly (DFG) Motif: The Role of the DFG Motif in the Design of Epidermal Growth Factor Receptor Inhibitors. J Med Chem 2013; 56:3889-903. [DOI: 10.1021/jm400072p] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Yi-Hui Peng
- Institute of Biotechnology and
Pharmaceutical Research, National Health Research Institutes, 35 Keyan
Road, Zhunan Town, Miaoli County 350, Taiwan, ROC
| | - Hui-Yi Shiao
- Institute of Biotechnology and
Pharmaceutical Research, National Health Research Institutes, 35 Keyan
Road, Zhunan Town, Miaoli County 350, Taiwan, ROC
| | - Chih-Hsiang Tu
- Institute of Biotechnology and
Pharmaceutical Research, National Health Research Institutes, 35 Keyan
Road, Zhunan Town, Miaoli County 350, Taiwan, ROC
- Institute of Bioinformatics
and Structural Biology, National Tsing Hua University, 101, Sect.
2, Guangfu Road, Hsinchu 300, Taiwan, ROC
| | - Pang-Min Liu
- Institute of Biotechnology and
Pharmaceutical Research, National Health Research Institutes, 35 Keyan
Road, Zhunan Town, Miaoli County 350, Taiwan, ROC
| | - John Tsu-An Hsu
- Institute of Biotechnology and
Pharmaceutical Research, National Health Research Institutes, 35 Keyan
Road, Zhunan Town, Miaoli County 350, Taiwan, ROC
| | - Prashanth Kumar Amancha
- Institute of Biotechnology and
Pharmaceutical Research, National Health Research Institutes, 35 Keyan
Road, Zhunan Town, Miaoli County 350, Taiwan, ROC
| | - Jian-Sung Wu
- Institute of Biotechnology and
Pharmaceutical Research, National Health Research Institutes, 35 Keyan
Road, Zhunan Town, Miaoli County 350, Taiwan, ROC
| | - Mohane Selvaraj Coumar
- Centre for Bioinformatics, School
of Life Sciences, Pondicherry University, Kalapet, Puducherry 605014,
India
| | - Chun-Hwa Chen
- Institute of Biotechnology and
Pharmaceutical Research, National Health Research Institutes, 35 Keyan
Road, Zhunan Town, Miaoli County 350, Taiwan, ROC
| | - Sing-Yi Wang
- Institute of Biotechnology and
Pharmaceutical Research, National Health Research Institutes, 35 Keyan
Road, Zhunan Town, Miaoli County 350, Taiwan, ROC
| | - Wen-Hsing Lin
- Institute of Biotechnology and
Pharmaceutical Research, National Health Research Institutes, 35 Keyan
Road, Zhunan Town, Miaoli County 350, Taiwan, ROC
| | - Hsu-Yi Sun
- Institute of Biotechnology and
Pharmaceutical Research, National Health Research Institutes, 35 Keyan
Road, Zhunan Town, Miaoli County 350, Taiwan, ROC
| | - Yu-Sheng Chao
- Institute of Biotechnology and
Pharmaceutical Research, National Health Research Institutes, 35 Keyan
Road, Zhunan Town, Miaoli County 350, Taiwan, ROC
| | - Ping-Chiang Lyu
- Institute of Bioinformatics
and Structural Biology, National Tsing Hua University, 101, Sect.
2, Guangfu Road, Hsinchu 300, Taiwan, ROC
| | - Hsing-Pang Hsieh
- Institute of Biotechnology and
Pharmaceutical Research, National Health Research Institutes, 35 Keyan
Road, Zhunan Town, Miaoli County 350, Taiwan, ROC
| | - Su-Ying Wu
- Institute of Biotechnology and
Pharmaceutical Research, National Health Research Institutes, 35 Keyan
Road, Zhunan Town, Miaoli County 350, Taiwan, ROC
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Soria JC, Baselga J, Hanna N, Laurie SA, Bahleda R, Felip E, Calvo E, Armand JP, Shepherd FA, Harbison CT, Berman D, Park JS, Zhang S, Vakkalagadda B, Kurland JF, Pathak AK, Herbst RS. Phase I–IIa study of BMS-690514, an EGFR, HER-2 and -4 and VEGFR-1 to -3 oral tyrosine kinase inhibitor, in patients with advanced or metastatic solid tumours. Eur J Cancer 2013; 49:1815-24. [DOI: 10.1016/j.ejca.2013.02.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Accepted: 02/02/2013] [Indexed: 10/27/2022]
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31
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Design and synthesis of novel pyrimido[4,5- b ]azepine derivatives as HER2/EGFR dual inhibitors. Bioorg Med Chem 2013; 21:2250-2261. [DOI: 10.1016/j.bmc.2013.02.014] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2012] [Revised: 02/08/2013] [Accepted: 02/11/2013] [Indexed: 11/20/2022]
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32
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Venkatesan P, Bhutia SK, Singh AK, Das SK, Dash R, Chaudhury K, Sarkar D, Fisher PB, Mandal M. AEE788 potentiates celecoxib-induced growth inhibition and apoptosis in human colon cancer cells. Life Sci 2012; 91:789-99. [DOI: 10.1016/j.lfs.2012.08.024] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Revised: 07/23/2012] [Accepted: 08/14/2012] [Indexed: 10/28/2022]
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33
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Sun NF, Tian AL, Hua YX, Hu SY, Hu AB. Preparation and characterization of nano-liposome-mediated FL gene in the Lovo cells. Cancer Biother Radiopharm 2012; 27:490-4. [PMID: 22988970 DOI: 10.1089/cbr.2012.1189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
AIMS The purpose of the present work was to formulate and evaluate cationic nano-liposomes as novel nonviral gene delivery for colon cancer treatment. METHODS Recombinant pEGFP-c1-Fms-like tyrosine kinase receptor 3 ligand (FL) plasmids containing human FL gene and green fluorescent protein (GFP) reporter genes were constructed. FL and GFP Gene-carrying cationic nano-liposomes were prepared based on the electrostatic adherence principle and then transfected into Lovo cells. The morphology, particle size, and zeta potential of gene-carrying cationic nano-liposomes were observed using an electron microscope. GFP expression was observed by fluorescence microscopy to assay the transfection efficiency. The cytotoxicity of FL/nano-liposomes was evaluated by the MTT method. RESULTS Recombinant plasmids pEGFP-c1-FL are successfully constructed using gene cloning methods and confirmed by restriction enzyme digestion and sequencing. The cationic nano-liposomes carrying pEGFP-cl-FL were observed by an electron micrograph and showed uniform spherical or elliptical shapes and many pores. The fluorescence microscopy images of gene-carrying cationic nano-liposomes showed good expression of GFP in pEGFP and pEGFP-cl-FL groups. The MTT assay of cell death indicated a significantly higher level of cell death between the FL group and the control group at 24, 48, and 96 hours after transplantation. CONCLUSION Cationic nano-liposomes show safe and high-performance transfection as gene carriers. Gene therapy has significant implications for colon cancer treatment in future.
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Affiliation(s)
- Nian-Feng Sun
- Department of General Surgery, Qilu Hospital of Shandong University , Jinan, China
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Reardon DA, Conrad CA, Cloughesy T, Prados MD, Friedman HS, Aldape KD, Mischel P, Xia J, DiLea C, Huang J, Mietlowski W, Dugan M, Chen W, Yung WKA. Phase I study of AEE788, a novel multitarget inhibitor of ErbB- and VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patients. Cancer Chemother Pharmacol 2012; 69:1507-18. [PMID: 22392572 PMCID: PMC4351868 DOI: 10.1007/s00280-012-1854-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Accepted: 02/15/2012] [Indexed: 01/17/2023]
Abstract
PURPOSE Vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) play a significant role in glioblastoma angiogenesis and proliferation, making tyrosine kinase (TK) receptors logical targets for treatment. We evaluated AEE788, a reversible TK inhibitor that inhibits EGFR and VEGFR, in recurrent glioblastoma patients. METHODS In this dose-escalation, phase I study, patients with recurrent glioblastoma received AEE788 once daily in 28-day cycles in stratified subgroups: those receiving (1) non-enzyme-inducing anticonvulsants drugs or no anticonvulsants (Group A) and (2) enzyme-inducing anticonvulsant drugs (Group B). A dose-expansion phase stratified patients by surgical eligibility. Primary objectives were to determine dose-limiting toxicity (DLT) and maximum tolerated dose; secondary objectives included evaluating (1) safety/tolerability, (2) pharmacokinetics, and (3) preliminary antitumor activity. RESULTS Sixty-four glioblastoma patients were enrolled. Two Group A patients experienced DLTs (proteinuria and stomatitis) at 550 mg; 550 mg was, therefore, the highest dose evaluated and dose limiting. One Group B patient receiving 800 mg experienced a DLT (diarrhea). The initially recommended dose for dose-expansion phase for Group A was 400 mg; additional patients received 250 mg to assess the hepatotoxicity. Most frequently reported adverse events (AEs) included diarrhea and rash. Serious AEs, most commonly grade 3/4 liver function test elevations, were responsible for treatment discontinuation in 17% of patients. AEE788 concentrations were reduced by EIACD. The best overall response was stable disease (17%). CONCLUSIONS Continuous, once-daily AEE788 was associated with unacceptable toxicity and minimal activity for the treatment of recurrent glioblastoma. The study was, therefore, discontinued prematurely.
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Affiliation(s)
- David A Reardon
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, SW-460F, Boston, MA 02215, USA.
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Entezari V, Trechsel BL, Dow WA, Stanton SK, Rosso C, Müller A, McKenzie B, Vartanians V, Cereatti A, Della Croce U, Deangelis JP, Ramappa AJ, Nazarian A. Design and manufacture of a novel system to simulate the biomechanics of basic and pitching shoulder motion. Bone Joint Res 2012; 1:78-85. [PMID: 23610675 PMCID: PMC3626244 DOI: 10.1302/2046-3758.15.2000051] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Accepted: 04/11/2012] [Indexed: 11/05/2022] Open
Abstract
Objectives Cadaveric models of the shoulder evaluate discrete motion segments
using the glenohumeral joint in isolation over a defined trajectory.
The aim of this study was to design, manufacture and validate a
robotic system to accurately create three-dimensional movement of
the upper body and capture it using high-speed motion cameras. Methods In particular, we intended to use the robotic system to simulate
the normal throwing motion in an intact cadaver. The robotic system
consists of a lower frame (to move the torso) and an upper frame
(to move an arm) using seven actuators. The actuators accurately
reproduced planned trajectories. The marker setup used for motion
capture was able to determine the six degrees of freedom of all
involved joints during the planned motion of the end effector. Results The testing system demonstrated high precision and accuracy based
on the expected versus observed displacements of individual axes.
The maximum coefficient of variation for displacement of unloaded
axes was less than 0.5% for all axes. The expected and observed
actual displacements had a high level of correlation with coefficients
of determination of 1.0 for all axes. Conclusions Given that this system can accurately simulate and track simple
and complex motion, there is a new opportunity to study kinematics
of the shoulder under normal and pathological conditions in a cadaveric
shoulder model.
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Affiliation(s)
- V Entezari
- Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center and Harvard Medical School, USA
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Kawakita Y, Banno H, Ohashi T, Tamura T, Yusa T, Nakayama A, Miki H, Iwata H, Kamiguchi H, Tanaka T, Habuka N, Sogabe S, Ohta Y, Ishikawa T. Design and synthesis of pyrrolo[3,2-d]pyrimidine human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors: exploration of novel back-pocket binders. J Med Chem 2012; 55:3975-91. [PMID: 22439974 DOI: 10.1021/jm300185p] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
To develop novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) kinase inhibitors, we explored pyrrolo[3,2-d]pyrimidine derivatives bearing bicyclic fused rings designed to fit the back pocket of the HER2/EGFR proteins. Among them, the 1,2-benzisothiazole (42m) ring was selected as a suitable back pocket binder because of its potent HER2/EGFR binding and cell growth inhibitory (GI) activities and pseudoirreversibility (PI) profile as well as good bioavailability (BA). Ultimately, we arrived at our preclinical candidate 51m by optimization of the N-5 side chain to improve CYP inhibition and metabolic stability profiles without a loss of potency (HER2/EGFR inhibitory activity, IC(50), 0.98/2.5 nM; and GI activity BT-474 cells, GI(50), 2.0 nM). Reflecting the strong in vitro activities, 51m exhibited potent tumor regressive efficacy against both HER2- and EGFR-overexpressing tumor (4-1ST and CAL27) xenograft models in mice at oral doses of 50 mg/kg and 100 mg/kg.
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Affiliation(s)
- Youichi Kawakita
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited: 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
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Pan Y, Xu Y, Feng S, Luo S, Zheng R, Yang J, Wang L, Zhong L, Yang HY, Wang BL, Yu Y, Liu J, Cao Z, Wang X, Ji P, Wang Z, Chen X, Zhang S, Wei YQ, Yang SY. SKLB1206, a Novel Orally Available Multikinase Inhibitor Targeting EGFR Activating and T790M Mutants, ErbB2, ErbB4, and VEGFR2, Displays Potent Antitumor Activity Both In Vitro and In Vivo. Mol Cancer Ther 2012; 11:952-62. [PMID: 22319204 DOI: 10.1158/1535-7163.mct-11-0679] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Youli Pan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan, China
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Zhang H, Yun S, Batuwangala TD, Steward M, Holmes SD, Pan L, Tighiouart M, Shin HJC, Koenig L, Park W, Rycroft D, Nannapaneni S, Wang Y, Chen ZG, Shin DM. A dual-targeting antibody against EGFR-VEGF for lung and head and neck cancer treatment. Int J Cancer 2011; 131:956-69. [PMID: 21918971 DOI: 10.1002/ijc.26427] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Accepted: 08/03/2011] [Indexed: 12/14/2022]
Abstract
An antibody simultaneously targeting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), two major tumor growth-driving machineries, may provide a novel effective strategy for optimizing tumor targeting and maximizing potential clinical benefits. Human domain antibodies selected against VEGF and EGFR were formatted into a fully human dual-targeting IgG (DT-IgG) to directly target both antigens in a single molecule. We evaluated the efficacy of DT-IgG in comparison with bevacizumab and cetuximab alone and in combination in the lung cancer cell line A549 (low EGFR expression and KRAS mutant) and the head and neck squamous cell carcinoma (HNSCC) cell line Tu212 (high EGFR expression and KRAS wild type) in vitro and in vivo. DT-IgG suppressed Tu212 and A549 cell growth, inhibited EGFR activation and induced apoptosis as effectively as cetuximab, and neutralized VEGF as effectively as bevacizumab. DT-IgG induced EGFR-dependent VEGF internalization, constituting a novel antiangiogenesis mechanism. In xenograft models with lung and head and neck cancer cell lines, DT-IgG displayed efficacy equivalent to bevacizumab in diminishing tumor growth despite its short serum half-life (36 hr in rats) and both agents may constitute preferable alternatives to cetuximab in KRAS-mutant tumors. Immunofluorescence staining revealed that localization of DT-IgG was similar to that of cetuximab, largely associated with EGFR+tumor cells. Our proof of principle study suggests a DT-IgG against EGFR and VEGF as an alternative therapeutic strategy with potentially enhanced clinical benefit.
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Affiliation(s)
- Hongzheng Zhang
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
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Ishikawa T, Seto M, Banno H, Kawakita Y, Oorui M, Taniguchi T, Ohta Y, Tamura T, Nakayama A, Miki H, Kamiguchi H, Tanaka T, Habuka N, Sogabe S, Yano J, Aertgeerts K, Kamiyama K. Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo[3,2-d]pyrimidine scaffold. J Med Chem 2011; 54:8030-50. [PMID: 22003817 DOI: 10.1021/jm2008634] [Citation(s) in RCA: 160] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Dual inhibitors of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors' ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.
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Affiliation(s)
- Tomoyasu Ishikawa
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
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Bruce D, Tan PH. Vascular endothelial growth factor receptors and the therapeutic targeting of angiogenesis in cancer: where do we go from here? ACTA ACUST UNITED AC 2011; 18:85-103. [PMID: 22017472 DOI: 10.3109/15419061.2011.619673] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Abstract Vascular Endothelial Growth Factor receptors (VEGFRs), the interactions with their ligands and the subsequent signalling pathways are known to play a vital role in tumour angiogenesis. Initial clinical trials of VEGFR inhibitors were disappointing but over the past decade some therapies have been successfully brought to market. At present, VEGFR inhibitors appear to be most promising as adjuvants to conventional chemotherapy. However, several interacting signalling molecules and downstream pathways have recently been shown to interact with VEGFR signalling and provide promising novel targets, such as the platelet-derived growth factor (PDGF), epithelial growth factor (EGF), human epithelial receptor-2, (HER-2) Tie-2 and oestrogen receptors. Elucidation of this web of signalling pathways may identify new therapeutic strategies which may be used in combination with VEGFR inhibitors to augment the efficacy of anti-angiogenic cancer treatments. This review assesses the role of modulating VEGFR activity in cancer and systematically examines current evidence and trials in this area.
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Affiliation(s)
- David Bruce
- Nuffield Department of Surgical Science, Oxford University, The John Radcliffe, Headley Way, Oxford, UK
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Poindessous V, Ouaret D, El Ouadrani K, Battistella A, Mégalophonos VF, Kamsu-Kom N, Petitprez A, Escargueil AE, Boudou P, Dumont S, Cervera P, Fléjou JF, André T, Tournigand C, Chibaudel B, de Gramont A, Larsen AK. EGFR- and VEGF(R)-Targeted Small Molecules Show Synergistic Activity in Colorectal Cancer Models Refractory to Combinations of Monoclonal Antibodies. Clin Cancer Res 2011; 17:6522-30. [DOI: 10.1158/1078-0432.ccr-11-1607] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Bruce D, Tan PH. Blocking the interaction of vascular endothelial growth factor receptors with their ligands and their effector signaling as a novel therapeutic target for cancer: time for a new look? Expert Opin Investig Drugs 2011; 20:1413-34. [DOI: 10.1517/13543784.2011.611801] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Targeting EGFR and VEGF(R) pathway cross-talk in tumor survival and angiogenesis. Pharmacol Ther 2011; 131:80-90. [DOI: 10.1016/j.pharmthera.2011.03.012] [Citation(s) in RCA: 190] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2011] [Accepted: 03/07/2011] [Indexed: 01/15/2023]
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Venkatesan P, Puvvada N, Dash R, Prashanth Kumar B, Sarkar D, Azab B, Pathak A, Kundu SC, Fisher PB, Mandal M. The potential of celecoxib-loaded hydroxyapatite-chitosan nanocomposite for the treatment of colon cancer. Biomaterials 2011; 32:3794-806. [DOI: 10.1016/j.biomaterials.2011.01.027] [Citation(s) in RCA: 163] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2010] [Accepted: 01/12/2011] [Indexed: 10/18/2022]
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Dual Inhibitor AEE788 Reduces Tumor Growth in Preclinical Models of Medulloblastoma. Transl Oncol 2010; 3:326-35. [PMID: 20885895 DOI: 10.1593/tlo.10163] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2010] [Revised: 05/25/2010] [Accepted: 06/14/2010] [Indexed: 11/18/2022] Open
Abstract
Medulloblastoma is the most frequent malignant pediatric brain tumor with a dismal prognosis in 30% of cases. We examined the activity of AEE788, a dual inhibitor of human epidermal receptor (HER) 1/2 and vascular endothelial growth factor receptor (VEGFR) 1/2, in medulloblastoma preclinical models. Established lines (Daoy and D283), chemoresistant (Daoy(Pt)), and ectopically HER2-overexpressing (Daoy(HER2)) cells expressed diverse levels of total and activated AEE788 target receptors. In vitro, AEE788 inhibited cell proliferation (IC(50) from 1.7 to 3.8 µM) and prevented epidermal growth factor- and neuregulin-induced HER1, HER2, and HER3 activation. Inhibition of Akt paralleled that of HER receptors. In vivo, AEE788 growth inhibited Daoy, Daoy(Pt), and Daoy(HER2) xenografts by 51%, 45%, and 72%, respectively. Immunohistochemical analysis of mock- and HER2-transfected xenografts revealed that the latter showed, along with high HER2 expression, high VEGFR2 staining in tumor and endothelial cells and increased expression of the endothelial marker CD31. AEE788 reduced the activation of target receptors and angiogenesis. In 21 primary medulloblastoma, HER2 expression significantly correlated (P < .01) with VEGFR2 (r = 0.56) and VEGF (r = 0.61). In conclusion, AEE788 shows similar growth-suppressive activities in chemosensitive and chemoresistant medulloblastoma cells in vitro and in vivo. Ectopic HER2 overexpression sensitizes cells to AEE788 in vivo, but not in vitro, possibly through host-mediated processes. Together with the experimental data, the finding that HER2 positively correlates with VEGFR2 and VEGF in human medulloblastoma specimens indicates HER2-overexpressing medulloblastoma as the subset that most likely might benefit from AEE788 treatment.
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Dewaele B, Floris G, Finalet-Ferreiro J, Fletcher CD, Coindre JM, Guillou L, Hogendoorn PCW, Wozniak A, Vanspauwen V, Schöffski P, Marynen P, Vandenberghe P, Sciot R, Debiec-Rychter M. Coactivated platelet-derived growth factor receptor {alpha} and epidermal growth factor receptor are potential therapeutic targets in intimal sarcoma. Cancer Res 2010; 70:7304-14. [PMID: 20685895 DOI: 10.1158/0008-5472.can-10-1543] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Intimal sarcoma (IS) is a rare, malignant, and aggressive tumor that shows a relentless course with a concomitant low survival rate and for which no effective treatment is available. In this study, 21 cases of large arterial blood vessel IS were analyzed by immunohistochemistry and fluorescence in situ hybridization and selectively by karyotyping, array comparative genomic hybridization, sequencing, phospho-kinase antibody arrays, and Western immunoblotting in search for novel diagnostic markers and potential molecular therapeutic targets. Ex vivo immunoassays were applied to test the sensitivity of IS primary tumor cells to the receptor tyrosine kinase (RTK) inhibitors imatinib and dasatinib. We showed that amplification of platelet-derived growth factor receptor α (PDGFRA) is a common finding in IS, which should be considered as a molecular hallmark of this entity. This amplification is consistently associated with PDGFRA activation. Furthermore, the tumors reveal persistent activation of the epidermal growth factor receptor (EGFR), concurrent to PDGFRA activation. Activated PDGFRA and EGFR frequently coexist with amplification and overexpression of the MDM2 oncogene. Ex vivo immunoassays on primary IS cells from one case showed the potency of dasatinib to inhibit PDGFRA and downstream signaling pathways. Our findings provide a rationale for investigating therapies that target PDGFRA, EGFR, or MDM2 in IS. Given the clonal heterogeneity of this tumor type and the potential cross-talk between the PDGFRA and EGFR signaling pathways, targeting multiple RTKs and aberrant downstream effectors might be required to improve the therapeutic outcome for patients with this disease.
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Affiliation(s)
- Barbara Dewaele
- Department of Human Genetics, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium
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Diaz R, Nguewa PA, Parrondo R, Perez-Stable C, Manrique I, Redrado M, Catena R, Collantes M, Peñuelas I, Díaz-González JA, Calvo A. Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model. BMC Cancer 2010; 10:188. [PMID: 20459769 PMCID: PMC2883966 DOI: 10.1186/1471-2407-10-188] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2009] [Accepted: 05/11/2010] [Indexed: 11/28/2022] Open
Abstract
Background There is strong evidence demonstrating that activation of epidermal growth factor receptors (EGFRs) leads to tumor growth, progression, invasion and metastasis. Erlotinib and gefitinib, two EGFR-targeted agents, have been shown to be relevant drugs for lung cancer treatment. Recent studies demonstrate that lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER-2 receptors, is clinically effective against HER-2-overexpressing metastatic breast cancer. In this report, we investigated the activity of lapatinib against non-small cell lung cancer (NSCLC). Methods We selected the lung cancer cell line A549, which harbors genomic amplification of EGFR and HER-2. Proliferation, cell cycle analysis, clonogenic assays, and signaling cascade analyses (by western blot) were performed in vitro. In vivo experiments with A549 cells xenotransplanted into nude mice treated with lapatinib (with or without radiotherapy) were also carried out. Results Lapatinib dramatically reduced cell proliferation (P < 0.0001), DNA synthesis (P < 0.006), and colony formation capacity (P < 0.0001) in A549 cells in vitro. Furthermore, lapatinib induced G1 cell cycle arrest (P < 0.0001) and apoptotic cell death (P < 0.0006) and reduced cyclin A and B1 levels, which are regulators of S and G2/M cell cycle stages, respectively. Stimulation of apoptosis in lapatinib-treated A549 cells was correlated with increased cleaved PARP, active caspase-3, and proapoptotic Bak-1 levels, and reduction in the antiapoptic IAP-2 and Bcl-xL protein levels. We also demonstrate that lapatinib altered EGFR/HER-2 signaling pathways reducing p-EGFR, p-HER-2, p-ERK1/2, p-AKT, c-Myc and PCNA levels. In vivo experiments revealed that A549 tumor-bearing mice treated with lapatinib had significantly less active tumors (as assessed by PET analysis) (P < 0.04) and smaller in size than controls. In addition, tumors from lapatinib-treated mice showed a dramatic reduction in angiogenesis (P < 0.0001). Conclusion Overall, these data suggest that lapatinib may be a clinically useful agent for the treatment of lung cancer.
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Affiliation(s)
- Roque Diaz
- Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
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Barbarroja N, Torres LA, Rodriguez-Ariza A, Valverde-Estepa A, Lopez-Sanchez LM, Ruiz-Limon P, Perez-Sanchez C, Carretero RM, Velasco F, López-Pedrera C. AEE788 is a vascular endothelial growth factor receptor tyrosine kinase inhibitor with antiproliferative and proapoptotic effects in acute myeloid leukemia. Exp Hematol 2010; 38:641-52. [PMID: 20380868 DOI: 10.1016/j.exphem.2010.03.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2010] [Revised: 03/26/2010] [Accepted: 03/26/2010] [Indexed: 01/31/2023]
Abstract
OBJECTIVE Aberrant activation of tyrosine kinase receptors is frequently observed in acute myelogenous leukemia (AML). Moreover, activating mutations of the fms-like tyrosine kinase 3 (FLT3) receptor can be found in approximately 30% of patients, thereby representing one of the most frequent single genetic alterations in AML. AEE788, a novel dual receptor tyrosine kinase inhibitor of endothelial growth factor and vascular endothelial growth factor (VEGF), is being studied in several solid tumors with remarkable success. It is not known, however, about the efficacy of this inhibitor in the treatment of AML. Therefore, we investigated the effect of AEE788 in the treatment of three human AML cell lines and seven AML patient samples. MATERIALS AND METHODS Cell survival in THP-1, MOLM-13, and MV4-11 cell lines (the two last harboring the FLT3/internal tandem duplication mutation) and AML blasts incubated with 0.5 to 15 microM AEE788 were quantified. We also studied the activation of VEGF/VEGF receptors loop, FLT3, and their downstream effectors (Akt, extracellular signal-regulated kinase, signal transducers and activators of transcription 5, and nuclear factor-kappaB). RESULTS Our data showed that AEE788 was a tyrosine kinase inhibitor of FLT3 activity and had antiproliferative and proapoptotic activity in AML-derived cell lines and AML blasts that presented phosphorylation of the FLT3 receptor. Consistently, in these cells AEE788 abrogated VEGF/VEGF receptors activation and the survival signaling pathways studied. CONCLUSION Taken together, the activity of AEE788 might represent a promising new option of targeting FLT3 for the treatment of AML.
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Affiliation(s)
- Nuria Barbarroja
- Fundación IMABIS, Hospital Universitario Virgen de la Victoria, Málaga, Spain.
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Minimally invasive colorectal resection is associated with a rapid and sustained decrease in plasma levels of epidermal growth factor (EGF) in the colon cancer setting. Surg Endosc 2010; 24:2617-22. [PMID: 20354877 DOI: 10.1007/s00464-010-1018-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2009] [Accepted: 03/07/2010] [Indexed: 02/08/2023]
Abstract
BACKGROUND Epidermal growth factor (EGF) stimulates tumor growth directly via tumor cell EGF receptors or indirectly via its proangiogenic effects. This study's purpose was to determine the impact of minimally invasive colorectal resection (MICR) on postoperative (postop) plasma EGF levels in the colorectal cancer (CRC) and benign disease settings and to see if preoperative (PreOp) EGF levels are altered in cancer patients. METHODS MICR patients with benign pathology (n = 40) and CRC (n = 48) had blood samples taken PreOp and on postoperative days (POD) 1 and 3. In some patients, late samples were taken between POD7 and POD60; these were bundled into 7-day blocks and considered as single time points. EGF levels were determined by enzyme-linked immunosorbent assay (ELISA) and results were reported as mean ± SD after logarithmic transformation. The Student t test was used (p < 0.008 after Bonferroni correction). RESULTS The cancer and benign groups were comparable except for age. The mean PreOp CRC plasma EGF level (122.9 ± 75.9 pg/ml) was significantly higher than that of the benign group (85.3 ± 38.5 pg/ml) (p = 0.015). The cancer group's EGF levels were significantly decreased on POD1 and POD3 and for the POD31-55 time point (mean EGF level = 63.1 ± 42.2 (n = 10). The benign group's POD3 and POD7-14 EGF levels were significantly lower than the PreOp level; later levels returned toward baseline. Small late sample size limited analysis. CONCLUSION Plasma EGF levels are significantly higher in cancer patients. MICR is associated with a significant decrease in EGF levels early postop in both cancer and benign settings. Unlike the benign group, EGF blood levels in cancer patients remain low during the second postop month. A larger study with more late samples is needed to verify these results. EGF may have value as a tumor marker.
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50
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Deng M, Huang H, Jin H, Dirsch O, Dahmen U. The anti-proliferative side effects of AEE788, a tyrosine kinase inhibitor blocking both EGF- and VEGF-receptor, are liver-size-dependent after partial hepatectomy in rats. Invest New Drugs 2010; 29:593-606. [PMID: 20148349 DOI: 10.1007/s10637-010-9394-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2009] [Accepted: 01/19/2010] [Indexed: 12/16/2022]
Abstract
BACKGROUND Blocking of EGFR signaling by the tyrosine kinase inhibitor AEE788 was well tolerated and did not inhibit liver regeneration after standard 70% partial hepatectomy (PH) in a rat model, as demonstrated previously. However, serum levels of AEE788 at POW1 were 3-fold higher than in the non-resected control group. Therefore, we expanded theses studies to a model of extended 90%PH to investigate the role of liver size for the metabolism of AEE788 and its potential influence on side effects, liver regeneration and liver remodeling. METHOD Rats treated with 50 mg/kg AEE788 or solvent every other day orally were subjected to 90%PH. Animals were sacrificed at 1, 2, 7 and 28 days after PH. We measured plasma and liver levels of AEE788 and assessed anti-proliferative side effects, liver regeneration, and liver architecture. RESULT Liver regeneration and liver architecture were not impaired by AEE788 treatment after 90%PH. 90%PH caused a clinically relevant drug accumulation within 1 week of treatment (AEE788 serum and tissue levels: 90%PH*>70%PH*>normal control, *p < 0.05), suggesting a liver-size-dependent metabolism of the drug. Drug accumulation after 90%PH was associated with severe side effects (delayed body weight recovery, diarrhea, impaired hair growth) within 1 week of treatment. CONCLUSION Treatment with AEE788 could be a potential strategy for adjuvant treatment after oncological liver resection, as liver regeneration was not impaired. Our results suggest a liver-size-dependent metabolism of AEE788 leading to drug accumulation and subsequently to severe side effects. It calls for therapeutic drug monitoring in the early postoperative phase after extended resection.
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Affiliation(s)
- Meihong Deng
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
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