|
1
|
Khan MN, Farooq U, Khushal A, Wani TA, Zargar S, Khan S. Unraveling potential EGFR kinase inhibitors: Computational screening, molecular dynamics insights, and MMPBSA analysis for targeted cancer therapy development. PLoS One 2025; 20:e0321500. [PMID: 40344575 PMCID: PMC12064201 DOI: 10.1371/journal.pone.0321500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 03/06/2025] [Indexed: 05/11/2025] Open
Abstract
EGFR is critical for tumor angiogenesis and cancer progression, but existing treatments like erlotinib face limitations such as acquired resistance and side effects. To address these issues, this study employs structure-based drug design techniques including virtual screening, molecular docking, and molecular dynamics simulations to identify new small molecule inhibitors targeting the EGFR kinase domain. From an initial selection of 633,000 compounds from diverse databases, top candidates were identified based on their binding affinity and stability. The virtual screening and docking analyses revealed compounds with higher binding scores than erlotinib. Molecular dynamics simulations and Anisotropic Network Model (ANM) analysis uniquely report that EGFR undergoes significant conformational shifts: inward flap movements in the bound state stabilize a closed conformation, while outward movements in the free state result in a more open conformation. Among the identified inhibitors, compounds such as JFD00243, NPA015124, and others exhibited strong binding affinities and stable interactions with both active and inactive forms of EGFR. Notably, JFD00243 was effective in targeting EGFR in both active and inactive conformations. These findings suggest that the identified inhibitors could potentially overcome current treatment limitations and improve targeted cancer therapies by effectively inhibiting EGFR-mediated tumor angiogenesis.
Collapse
Affiliation(s)
- Muhammad Naseem Khan
- Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, Pakistan
| | - Umar Farooq
- Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, Pakistan
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Molecular Reaction dynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Aneela Khushal
- Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, Pakistan
| | - Tanveer A. Wani
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Seema Zargar
- Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Sara Khan
- Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, Pakistan
- Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania, United States of America
| |
Collapse
|
|
2
|
Srinivasarao DA, Shah S, Famta P, Vambhurkar G, Jain N, Pindiprolu SKSS, Sharma A, Kumar R, Padhy HP, Kumari M, Madan J, Srivastava S. Unravelling the role of tumor microenvironment responsive nanobiomaterials in spatiotemporal controlled drug delivery for lung cancer therapy. Drug Deliv Transl Res 2025; 15:407-435. [PMID: 39037533 DOI: 10.1007/s13346-024-01673-z] [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] [Accepted: 07/08/2024] [Indexed: 07/23/2024]
Abstract
Design and development of efficient drug delivery technologies that impart site-specificity is the need of the hour for the effective treatment of lung cancer. The emergence of materials science and nanotechnology partially helped drug delivery scientists to achieve this objective. Various stimuli-responsive materials that undergo degradation at the pathological tumor microenvironment (TME) have been developed and explored for drug delivery applications using nanotechnological approaches. Nanoparticles (NPs), owing to their small size and high surface area to volume ratio, demonstrated enhanced cellular internalization, permeation, and retention at the tumor site. Such passive accumulation of stimuli-responsive materials helped to achieve spatiotemporally controlled and targeted drug delivery within the tumors. In this review, we discussed various stimuli-physical (interstitial pressure, temperature, and stiffness), chemical (pH, hypoxia, oxidative stress, and redox state), and biological (receptor expression, efflux transporters, immune cells, and their receptors or ligands)-that are characteristic to the TME. We mentioned an array of biomaterials-based nanoparticulate delivery systems that respond to these stimuli and control drug release at the TME. Further, we discussed nanoparticle-based combinatorial drug delivery strategies. Finally, we presented our perspectives on challenges related to scale-up, clinical translation, and regulatory approvals.
Collapse
Affiliation(s)
- Dadi A Srinivasarao
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India.
| | - Saurabh Shah
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India
| | - Paras Famta
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India
| | - Ganesh Vambhurkar
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India
| | - Naitik Jain
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India
| | - Sai Kiran S S Pindiprolu
- Aditya Pharmacy College, Surampalem, 533 437, Andhra Pradesh, India
- Jawaharlal Nehru Technological University, Kakinada, 533 003, Andhra Pradesh, India
| | - Anamika Sharma
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), 500037, Telangana, Hyderabad, India
| | - Rahul Kumar
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), 500037, Telangana, Hyderabad, India
| | - Hara Prasad Padhy
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), 500037, Telangana, Hyderabad, India
| | - Meenu Kumari
- Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER), 500037, Telangana, Hyderabad, India
| | - Jitender Madan
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India
| | - Saurabh Srivastava
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India.
| |
Collapse
|
|
3
|
Chen Y, Xiong T, Peng Q, Du J, Sun W, Fan J, Peng X. Self-reporting photodynamic nanobody conjugate for precise and sustainable large-volume tumor treatment. Nat Commun 2024; 15:6935. [PMID: 39138197 PMCID: PMC11322375 DOI: 10.1038/s41467-024-51253-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 08/02/2024] [Indexed: 08/15/2024] Open
Abstract
Nanobodies (Nbs), the smallest antigen-binding fragments with high stability and affinity derived from the variable domain of naturally occurring heavy-chain-only antibodies in camelids, have been shown as an efficient way to improve the specificity to tumors for photodynamic therapy (PDT). Nonetheless, the rapid clearance of Nbs in vivo restricts the accumulation and retention of the photosensitizer at the tumor site causing insufficient therapeutic outcome, especially in large-volume tumors. Herein, we develop photodynamic conjugates, MNB-Pyra Nbs, through site-specific conjugation between 7D12 Nbs and type I photosensitizer MNB-Pyra (morpholine-modified nile blue structure connected to pyrazolinone) in a 1:2 ratio. The photosensitizers with long-term retention can be released at the tumor site by reactive oxygen species cleavage after illumination, accompanied with fluorescence recovery for self-reporting the occurrence of PDT. Ultimately, a single dose of MNB-Pyra Nbs demonstrate highly effective tumor suppression with high biosafety in the large-volume tumor models after three rounds of PDT. This nanobody conjugate provides a paradigm for the design of precise long-time retention photosensitizers and is expected to promote the development of PDT.
Collapse
Affiliation(s)
- Yingchao Chen
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, No. 2 Linggong Road, Dalian, 116024, China
- Liaoning Binhai Laboratory, Dalian, 116023, China
| | - Tao Xiong
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, No. 2 Linggong Road, Dalian, 116024, China
- Liaoning Binhai Laboratory, Dalian, 116023, China
| | - Qiang Peng
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, No. 2 Linggong Road, Dalian, 116024, China
- Liaoning Binhai Laboratory, Dalian, 116023, China
| | - Jianjun Du
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, No. 2 Linggong Road, Dalian, 116024, China
- Liaoning Binhai Laboratory, Dalian, 116023, China
| | - Wen Sun
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, No. 2 Linggong Road, Dalian, 116024, China
- Liaoning Binhai Laboratory, Dalian, 116023, China
| | - Jiangli Fan
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, No. 2 Linggong Road, Dalian, 116024, China.
- Liaoning Binhai Laboratory, Dalian, 116023, China.
| | - Xiaojun Peng
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, No. 2 Linggong Road, Dalian, 116024, China
- Liaoning Binhai Laboratory, Dalian, 116023, China
| |
Collapse
|
|
4
|
Wanika L, Evans ND, Johnson M, Tomkinson H, Chappell MJ. In vitro PK/PD modeling of tyrosine kinase inhibitors in non-small cell lung cancer cell lines. Clin Transl Sci 2024; 17:e13714. [PMID: 38477045 PMCID: PMC10933606 DOI: 10.1111/cts.13714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 11/22/2023] [Accepted: 12/14/2023] [Indexed: 03/14/2024] Open
Abstract
Tyrosine kinase inhibitors (TKIs) are routinely prescribed for the treatment of non-small cell lung cancer (NSCLC). As with all medications, patients can experience adverse events due to TKIs. Unfortunately, the relationship between many TKIs and the occurrence of certain adverse events remains unclear. There are limited in vivo studies which focus on TKIs and their effects on different regulation pathways. Many in vitro studies, however, that investigate the effects of TKIs observe additional changes, such as changes in gene activations or protein expressions. These studies could potentially help to gain greater understanding of the mechanisms for TKI induced adverse events. However, in order to utilize these pathways in a pharmacokinetic/pharmacodynamic (PK/PD) framework, an in vitro PK/PD model needs to be developed, in order to characterize the effects of TKIs in NSCLC cell lines. Through the use of ordinary differential equations, cell viability data and nonlinear mixed effects modeling, an in vitro TKI PK/PD model was developed with estimated PK and PD parameter values for the TKIs alectinib, crizotinib, erlotinib, and gefitinib. The relative standard errors for the population parameters are all less than 25%. The inclusion of random effects enabled the model to predict individual parameter values which provided a closer fit to the observed response. It is hoped that this model can be extended to include in vitro data of certain pathways that may potentially be linked with adverse events and provide a better understanding of TKI-induced adverse events.
Collapse
Affiliation(s)
- Linda Wanika
- School of EngineeringUniversity of WarwickCoventryUK
| | - Neil D. Evans
- School of EngineeringUniversity of WarwickCoventryUK
| | | | | | | |
Collapse
|
|
5
|
Valle-Mendiola A, Gutiérrez-Hoya A, Soto-Cruz I. JAK/STAT Signaling and Cervical Cancer: From the Cell Surface to the Nucleus. Genes (Basel) 2023; 14:1141. [PMID: 37372319 DOI: 10.3390/genes14061141] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/13/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023] Open
Abstract
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway constitutes a rapid signaling module from the cell surface to the nucleus, and activates different cellular responses, such as proliferation, survival, migration, invasion, and inflammation. When the JAK/STAT pathway is altered, it contributes to cancer progression and metastasis. STAT proteins play a central role in developing cervical cancer, and inhibiting the JAK/STAT signaling may be necessary to induce tumor cell death. Several cancers show continuous activation of different STATs, including cervical cancer. The constitutive activation of STAT proteins is associated with a poor prognosis and overall survival. The human papillomavirus (HPV) oncoproteins E6 and E7 play an essential role in cervical cancer progression, and they activate the JAK/STAT pathway and other signals that induce proliferation, survival, and migration of cancer cells. Moreover, there is a crosstalk between the JAK/STAT signaling cascade with other signaling pathways, where a plethora of different proteins activate to induce gene transcription and cell responses that contribute to tumor growth. Therefore, inhibition of the JAK/STAT pathway shows promise as a new target in cancer treatment. In this review, we discuss the role of the JAK/STAT pathway components and the role of the HPV oncoproteins associated with cellular malignancy through the JAK/STAT proteins and other signaling pathways to induce tumor growth.
Collapse
Affiliation(s)
- Arturo Valle-Mendiola
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, FES Zaragoza, National University of Mexico, Batalla 5 de Mayo s/n, Colonia Ejército de Oriente, Mexico City 09230, Mexico
| | - Adriana Gutiérrez-Hoya
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, FES Zaragoza, National University of Mexico, Batalla 5 de Mayo s/n, Colonia Ejército de Oriente, Mexico City 09230, Mexico
- Cátedra CONACYT, FES Zaragoza, National University of Mexico, Mexico City 09230, Mexico
| | - Isabel Soto-Cruz
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, FES Zaragoza, National University of Mexico, Batalla 5 de Mayo s/n, Colonia Ejército de Oriente, Mexico City 09230, Mexico
| |
Collapse
|
|
6
|
Islam R, Zhao L, Zhang X, Liu LZ. MiR-218-5p/EGFR Signaling in Arsenic-Induced Carcinogenesis. Cancers (Basel) 2023; 15:1204. [PMID: 36831545 PMCID: PMC9954652 DOI: 10.3390/cancers15041204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 02/11/2023] [Indexed: 02/17/2023] Open
Abstract
BACKGROUND Arsenic is a well-known carcinogen inducing lung, skin, bladder, and liver cancer. Abnormal epidermal growth factor receptor (EGFR) expression is common in lung cancer; it is involved in cancer initiation, development, metastasis, and treatment resistance. However, the underlying mechanism for arsenic-inducing EGFR upregulation remains unclear. METHODS RT-PCR and immunoblotting assays were used to detect the levels of miR-218-5p and EGFR expression. The Luciferase assay was used to test the transcriptional activity of EGFR mediated by miR-218-5p. Cell proliferation, colony formation, wound healing, migration assays, tube formation assays, and tumor growth assays were used to study the function of miR-218-5p/EGFR signaling. RESULTS EGFR and miR-218-5p were dramatically upregulated and downregulated in arsenic-induced transformed (As-T) cells, respectively. MiR-218-5p acted as a tumor suppressor to inhibit cell proliferation, migration, colony formation, tube formation, tumor growth, and angiogenesis. Furthermore, miR-218-5p directly targeted EGFR by binding to its 3'-untranslated region (UTR). Finally, miR-218-5p exerted its antitumor effect by inhibiting its direct target, EGFR. CONCLUSION Our study highlights the vital role of the miR-218-5p/EGFR signaling pathway in arsenic-induced carcinogenesis and angiogenesis, which may be helpful for the treatment of lung cancer induced by chronic arsenic exposure in the future.
Collapse
Affiliation(s)
| | | | | | - Ling-Zhi Liu
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| |
Collapse
|
|
7
|
Matada GSP, Dhiwar PS, Abbas N, Singh E, Ghara A, Patil R, Raghavendra NM. Pharmacophore modeling, virtual screening, molecular docking and dynamics studies for the discovery of HER2-tyrosine kinase inhibitors: An in-silico approach. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.132531] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
|
|
8
|
Sharma B, Singh VJ, Chawla PA. Epidermal growth factor receptor inhibitors as potential anticancer agents: An update of recent progress. Bioorg Chem 2021; 116:105393. [PMID: 34628226 DOI: 10.1016/j.bioorg.2021.105393] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/16/2021] [Accepted: 09/28/2021] [Indexed: 12/20/2022]
Abstract
Epidermal growth factor receptor (EGFR) is a vital intermediate in cell signaling pathway including cell proliferation, angiogenesis, apoptosis, and metastatic spread and also having four divergent members with similar structural features, such as EGFR (HER1/ErbB1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). Despite this, clinically exploited inhibitors of EGFR (including erlotinib, lapatinib, gefitinib, selumetinib, etc.) are not specific thus provoking unenviable adverse effects. Some of the paramount obstacles to generate and develop new lead molecules of EGFR inhibitors are drug resistance, mutation, and also selectivity which inspire medicinal chemists to generate novel chemotypes. The discovery of therapeutic agents that inhibit the precise stage in tumorous cells such as EGFR is one of the chief successful targets in many cancer therapies, including lung and breast cancers. This review aims to compile the various recent progressions (2016-2021) in the discovery and development of diverse epidermal growth factor receptor (EGFR) inhibitors belonging to distinct structural classes like pyrazoline, pyrazole, imidazole, pyrimidine, coumarin, benzothiazole, etc. We have summarized preclinical and clinical data, structure-activity relationships (SAR) containing mechanistic and in silico studies to provide proposals for the design and invention of new EGFR inhibitors with therapeutic significance. The detailed progress of the work in the field will provide inexorable scope for the development of novel drug candidates with greater selectivity and efficacy.
Collapse
Affiliation(s)
- Bharti Sharma
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, India
| | - Vikram Jeet Singh
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, India
| | - Pooja A Chawla
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, India.
| |
Collapse
|
|
9
|
Das M, Singh KK, Khan E, Sinha RK, Singh RK, Tandon P, Gangopadhyay D. N-Acetylcysteine versus arsenic poisoning: A mechanistic study of complexation by molecular spectroscopy and density functional theory. J Mol Liq 2021. [DOI: 10.1016/j.molliq.2021.117168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
|
|
10
|
Medda A, Duca D, Chiocca S. Human Papillomavirus and Cellular Pathways: Hits and Targets. Pathogens 2021; 10:262. [PMID: 33668730 PMCID: PMC7996217 DOI: 10.3390/pathogens10030262] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/08/2021] [Accepted: 02/19/2021] [Indexed: 12/18/2022] Open
Abstract
The Human Papillomavirus (HPV) is the causative agent of different kinds of tumors, including cervical cancers, non-melanoma skin cancers, anogenital cancers, and head and neck cancers. Despite the vaccination campaigns implemented over the last decades, we are far from eradicating HPV-driven malignancies. Moreover, the lack of targeted therapies to tackle HPV-related tumors exacerbates this problem. Biomarkers for early detection of the pathology and more tailored therapeutic approaches are needed, and a complete understanding of HPV-driven tumorigenesis is essential to reach this goal. In this review, we overview the molecular pathways implicated in HPV infection and carcinogenesis, emphasizing the potential targets for new therapeutic strategies as well as new biomarkers.
Collapse
Affiliation(s)
| | | | - Susanna Chiocca
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; (A.M.); (D.D.)
| |
Collapse
|
|
11
|
Samatiwat P, Tabtimmai L, Suphakun P, Jiwacharoenchai N, Toviwek B, Kukongviriyapan V, Gleeson MP, Choowongkomon K. The Effect of the EGFR - Targeting Compound 3-[(4-Phenylpyrimidin-2-yl) Amino] Benzene-1-Sulfonamide (13f) against Cholangiocarcinoma Cell Lines. Asian Pac J Cancer Prev 2021; 22:381-390. [PMID: 33639651 PMCID: PMC8190356 DOI: 10.31557/apjcp.2021.22.2.381] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 02/05/2021] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE Cholangiocarcinoma (CCA) is a noxious malignancy of epithelium of the bile duct with a low response rate to chemotherapy. The epidermal growth factor receptor (EGFR) signaling pathway is implicated in the development of cancerous cells, especially CCA. In this study, we report detailed biological profiling of 13f identified from our earlier hit expansion studies. The aim of this work was to expand our understanding of 13f via more detailed investigations of its mechanism of action against KKU-100, KKU-452 and KKU-M156 CCA cells, as well as in comparison to the EGFR inhibitor Gefitinib and non-specific chemotherapeutic agents such as Cisplatin. METHODS Inhibiting EGFR-Kinase, cytotoxicity, clonogenic assay, wound healing and apoptosis were performed. Levels of total expression of EGFR and EGFR phosphorylation proteins were detected. RESULTS 13f was confirmed as an inhibitor of EGFR with an IC50 value against the tyrosine kinase of EGFR of 22 nM and IC50 values for 48 h incubation period were 1.3 ± 1.9, 1.5 ± 0.4 and 1.7 ± 1.1 µM of KKU-100, KKU-452 and KKU-M156, respectively through dose- and time-dependent induction of early apoptosis of CCA cells. The compound also suppressed the clonogenic ability of KKU-100 and KKU-M156 cells stronger than Gefitinib, while potently inhibiting EGF-stimulated CCA cell migratory activity in KKU-452 cells. It was observed that under normal conditions EGFR was activated in CCA cells. EGF-stimulated basal expression of EGFR in KKU-452 cells was suppressed following 13f treatment, which was significantly greater than that of the marketed EGFR inhibitor Gefitinib. CONCLUSION In summary, our study showed that 13f has potent anti-cancer activities including antiproliferation, clonogenic ability and migration through the modulation of EGFR signaling pathway in CCA for the first time. The compound represents an interesting starting point as a potential chemotherapeutic agent in ongoing efforts to improve response rate in CCA patients.
.
Collapse
Affiliation(s)
- Papavee Samatiwat
- Department of Pharmacology, Faculty of Medicine, Srinakharinwirot University, Bangkok, 10110, Thailand.
| | - Lueacha Tabtimmai
- Department of Biochemistry, Kasetsart University, Bangkok, 10900, Thailand.
| | - Prapasri Suphakun
- Department of Biochemistry, Kasetsart University, Bangkok, 10900, Thailand.
| | - Nattanan Jiwacharoenchai
- Genetic Engineering Interdisciplinary Program, Graduate School, Kasetsart University, 10900, Thailand.
| | | | - Veerapol Kukongviriyapan
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.
| | - M. Paul Gleeson
- Department of Biomedical Engineering, Faculty of Engineering, King Mongkut’s Institute of Technology Ladkrabang, Bangkok. Thailand.
| | - Kiattawee Choowongkomon
- Department of Biochemistry, Kasetsart University, Bangkok, 10900, Thailand.
- Center for Advanced Studies in Nanotechnology for Chemical, Food and Agricultural Industries, KU Institute for Advanced Studies, Kasetsart University, Bangkok 10900, Thailand.
| |
Collapse
|
|
12
|
Sabbah DA, Hajjo R, Sweidan K. Review on Epidermal Growth Factor Receptor (EGFR) Structure, Signaling Pathways, Interactions, and Recent Updates of EGFR Inhibitors. Curr Top Med Chem 2021; 20:815-834. [PMID: 32124699 DOI: 10.2174/1568026620666200303123102] [Citation(s) in RCA: 295] [Impact Index Per Article: 73.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 11/21/2019] [Accepted: 12/10/2019] [Indexed: 12/13/2022]
Abstract
The epidermal growth factor receptor (EGFR) belongs to the ERBB family of tyrosine kinase receptors. EGFR signaling cascade is a key regulator in cell proliferation, differentiation, division, survival, and cancer development. In this review, the EGFR structure and its mutations, signaling pathway, ligand binding and EGFR dimerization, EGF/EGFR interaction, and the progress in the development of EGFR inhibitors have been explored.
Collapse
Affiliation(s)
- Dima A Sabbah
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
| | - Rima Hajjo
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
| | - Kamal Sweidan
- Department of Chemistry, The University of Jordan, Amman 11942, Jordan
| |
Collapse
|
|
13
|
Milian L, Mata M, Alcacer J, Oliver M, Sancho-Tello M, Martín de Llano JJ, Camps C, Galbis J, Carretero J, Carda C. Cannabinoid receptor expression in non-small cell lung cancer. Effectiveness of tetrahydrocannabinol and cannabidiol inhibiting cell proliferation and epithelial-mesenchymal transition in vitro. PLoS One 2020; 15:e0228909. [PMID: 32049991 PMCID: PMC7015420 DOI: 10.1371/journal.pone.0228909] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 01/27/2020] [Indexed: 12/31/2022] Open
Abstract
Background/Objective Patients with non-small cell lung cancer (NSCLC) develop resistance to antitumor agents by mechanisms that involve the epithelial-to-mesenchymal transition (EMT). This necessitates the development of new complementary drugs, e.g., cannabinoid receptors (CB1 and CB2) agonists including tetrahydrocannabinol (THC) and cannabidiol (CBD). The combined use of THC and CBD confers greater benefits, as CBD enhances the effects of THC and reduces its psychotropic activity. We assessed the relationship between the expression levels of CB1 and CB2 to the clinical features of a cohort of patients with NSCLC, and the effect of THC and CBD (individually and in combination) on proliferation, EMT and migration in vitro in A549, H460 and H1792 lung cancer cell lines. Methods Expression levels of CB1, CB2, EGFR, CDH1, CDH2 and VIM were evaluated by quantitative reverse transcription-polymerase chain reaction. THC and CBD (10–100 μM), individually or in combination (1:1 ratio), were used for in vitro assays. Cell proliferation was determined by BrdU incorporation assay. Morphological changes in the cells were visualized by phase-contrast and fluorescence microscopy. Migration was studied by scratch recolonization induced by 20 ng/ml epidermal growth factor (EGF). Results The tumor samples were classified according to the level of expression of CB1, CB2, or both. Patients with high expression levels of CB1, CB2, and CB1/CB2 showed increased survival reaching significance for CB1 and CB1/CB2 (p = 0.035 and 0.025, respectively). Both cannabinoid agonists inhibited the proliferation and expression of EGFR in lung cancer cells, and CBD potentiated the effect of THC. THC and CBD alone or in combination restored the epithelial phenotype, as evidenced by increased expression of CDH1 and reduced expression of CDH2 and VIM, as well as by fluorescence analysis of cellular cytoskeleton. Finally, both cannabinoids reduced the in vitro migration of the three lung cancer cells lines used. Conclusions The expression levels of CB1 and CB2 have a potential use as markers of survival in patients with NSCLC. THC and CBD inhibited the proliferation and expression of EGFR in the lung cancer cells studied. Finally, the THC/CBD combination restored the epithelial phenotype in vitro.
Collapse
Affiliation(s)
- Lara Milian
- Department of Pathology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain.,Research Institute of the University Clinical Hospital of Valencia (INCLIVA), Valencia, Spain
| | - Manuel Mata
- Department of Pathology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain.,Research Institute of the University Clinical Hospital of Valencia (INCLIVA), Valencia, Spain.,Networking Research Center on Respiratory Diseases (CIBERER), ISCIII, Carretera Soller Bunyola, Mallorca, Illes Balears, Spain
| | | | - María Oliver
- Department of Pathology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain
| | - María Sancho-Tello
- Department of Pathology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain.,Research Institute of the University Clinical Hospital of Valencia (INCLIVA), Valencia, Spain
| | - José Javier Martín de Llano
- Department of Pathology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain.,Research Institute of the University Clinical Hospital of Valencia (INCLIVA), Valencia, Spain
| | - Carlos Camps
- University General Hospital of Valencia, Valencia, Spain
| | - José Galbis
- Alzira Hospital, Carretera de Corbera, Alzira, Valencia, Spain
| | - Julian Carretero
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain
| | - Carmen Carda
- Department of Pathology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain.,Research Institute of the University Clinical Hospital of Valencia (INCLIVA), Valencia, Spain
| |
Collapse
|
|
14
|
Wu J, Qu J, Cao H, Jing C, Wang Z, Xu H, Ma R. Monoclonal antibody AC10364 inhibits cell proliferation in 5-fluorouracil resistant hepatocellular carcinoma via apoptotic pathways. Onco Targets Ther 2019; 12:5053-5067. [PMID: 31303763 PMCID: PMC6610299 DOI: 10.2147/ott.s206517] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Accepted: 05/16/2019] [Indexed: 01/18/2023] Open
Abstract
Background This study was designed to investigate the antitumor activity of the mAb (AC10364) in vitro and elucidate the related mechanisms of inhibition to cell growth using bel/fu cells treated with AC10364. Methods The inhibitory effects of AC10364 on the proliferation of Bel/fu cells were examined using a cytotoxicity assay. Apoptosis of Bel/fu cells was detected using FITC annexin V and PI staining following treatment with AC10364 for 24 h. The factors regulating apoptosis were identified by Western blot using lysates of Bel/fu cells treated with AC10364 for 0, 12, 24, or 36 h. Genes associated with tumorigenesis or growth were analyzed by reverse transcription–quantitative polymerase chain reaction using Bel/fu cells treated for 12, 24, or 36 h with AC10364. Results The early apoptotic ratios of Bel/fu cells treated with AC10364 increased in a dose-dependent manner. The levels of caspases, including cleaved caspase-3, caspase-3 and caspase-9, were significantly high in Bel/fu cells treated with AC10364 (P<0.001). Compared with untreated cells, those exposed to AC10364 had showed significant downregulation of the expression of binding protein gene (G protein subunit α 15, GNA15) and other protein-coding genes, including fms-related tyrosine kinase 1(FLT1), nicotinamide phosphoribosyltransferase (NAMPT), netrin 4 (NTN4), platelet-derived growth factor subunit A (PDGFA), S100 calcium binding protein A11 (S100A11), tubulin β 3 class III (TUBB3), aldo-keto reductase family 1 member C3 (AKR1C3), endothelial PAS domain protein 1 (EPAS1), and interferon α-inducible protein 27 (IFI27) (P<0.001). Two other genes, AXL receptor tyrosine kinase (AXL) and carboxypeptidase A4 (CPA4), were significantly upregulated (P<0.001). Conclusion AC10364 inhibited cell viability and proliferation through aberrant expression of multiple genes associated with tumorigenesis or growth, which suggests that these genes may be promising therapeutic candidates for cancer therapy.
Collapse
Affiliation(s)
- Jianzhong Wu
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210000, People's Republic of China
| | - Junwei Qu
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210000, People's Republic of China
| | - Haixia Cao
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210000, People's Republic of China
| | - Changwen Jing
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210000, People's Republic of China
| | - Zhuo Wang
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210000, People's Republic of China
| | - Heng Xu
- Laboratory of Pharmaceutical Chemistry, Jiangsu Province Institute of Materia Medica, Nanjing Tech University, Nanjing, Jiangsu 211816, People's Republic of China
| | - Rong Ma
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210000, People's Republic of China
| |
Collapse
|
|
15
|
Gorgoulis VG, Pefani D, Pateras IS, Trougakos IP. Integrating the DNA damage and protein stress responses during cancer development and treatment. J Pathol 2018; 246:12-40. [PMID: 29756349 PMCID: PMC6120562 DOI: 10.1002/path.5097] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 04/16/2018] [Accepted: 05/08/2018] [Indexed: 12/11/2022]
Abstract
During evolution, cells have developed a wide spectrum of stress response modules to ensure homeostasis. The genome and proteome damage response pathways constitute the pillars of this interwoven 'defensive' network. Consequently, the deregulation of these pathways correlates with ageing and various pathophysiological states, including cancer. In the present review, we highlight: (1) the structure of the genome and proteome damage response pathways; (2) their functional crosstalk; and (3) the conditions under which they predispose to cancer. Within this context, we emphasize the role of oncogene-induced DNA damage as a driving force that shapes the cellular landscape for the emergence of the various hallmarks of cancer. We also discuss potential means to exploit key cancer-related alterations of the genome and proteome damage response pathways in order to develop novel efficient therapeutic modalities. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Collapse
Affiliation(s)
- Vassilis G Gorgoulis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of MedicineNational and Kapodistrian University of AthensAthensGreece
- Biomedical Research Foundation of the Academy of AthensAthensGreece
- Faculty of Biology, Medicine and HealthUniversity of Manchester, Manchester Academic Health Science CentreManchesterUK
| | - Dafni‐Eleftheria Pefani
- CRUK/MRC Institute for Radiation Oncology, Department of OncologyUniversity of OxfordOxfordUK
| | - Ioannis S Pateras
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of MedicineNational and Kapodistrian University of AthensAthensGreece
| | - Ioannis P Trougakos
- Department of Cell Biology and Biophysics, Faculty of BiologyNational and Kapodistrian University of AthensAthensGreece
| |
Collapse
|
|
16
|
Arthur DE, Uzairu A, Mamza P, Abechi SE, Shallangwa GA. Structure-based optimization of tyrosine kinase inhibitors: a molecular docking study. ACTA ACUST UNITED AC 2018. [DOI: 10.1007/s13721-018-0170-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
|
|
17
|
Abstract
Over 90% of head and neck cancers overexpress the epidermal growth factor receptor (EGFR). In diverse tumor types, EGFR overexpression has been associated with poorer prognosis and outcomes. Therapies targeting EGFR include monoclonal antibodies, tyrosine kinase inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and antisense gene therapy. Few EGFR-targeted therapeutics are approved for clinical use. The monoclonal antibody cetuximab is a Food and Drug Administration (FDA)-approved EGFR-targeted therapy, yet has exhibited modest benefit in clinical trials. The humanized monoclonal antibody nimotuzumab is also approved for head and neck cancers in Cuba, Argentina, Colombia, Peru, India, Ukraine, Ivory Coast, and Gabon in addition to nasopharyngeal cancers in China. Few other EGFR-targeted therapeutics for head and neck cancers have led to as significant responses as seen in lung carcinomas, for instance. Recent genome sequencing of head and neck tumors has helped identify patient subgroups with improved response to EGFR inhibitors, for example, cetuximab in patients with the KRAS-variant and the tyrosine kinase inhibitor erlotinib for tumors harboring MAPK1E322K mutations. Genome sequencing has furthermore broadened our understanding of dysregulated pathways, holding the potential to enhance the benefit derived from therapies targeting EGFR.
Collapse
|
|
18
|
Improved detection of EGFR mutations in the tumor cells enriched from the malignant pleural effusion of non-small cell lung cancer patient. Gene 2018; 644:87-92. [DOI: 10.1016/j.gene.2017.10.073] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 10/23/2017] [Accepted: 10/26/2017] [Indexed: 01/16/2023]
|
|
19
|
Li X, Zhou C. Comparison of cross-platform technologies for EGFR T790M testing in patients with non-small cell lung cancer. Oncotarget 2017; 8:100801-100818. [PMID: 29246024 PMCID: PMC5725066 DOI: 10.18632/oncotarget.19007] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 06/19/2017] [Indexed: 12/14/2022] Open
Abstract
Somatic mutations in the gene encoding epidermal growth factor receptor (EGFR) play an important role in determining targeted treatment modalities in non-small cell lung cancer (NSCLC). The EGFR T790M mutation emerges in approximately 50% of cases who acquire resistance to tyrosine kinase inhibitors. Detecting EGFR T790M mutation in tumor tissue is challenging due to heterogeneity of the tumor, low abundance of the mutation and difficulty for re-biopsy in patients with advanced disease. Alternatively, circulating tumor DNA (ctDNA) has been proposed as a non-invasive method for mutational analysis. The presence of EGFR mutations in ctDNA predicts response to the EGFR TKIs in the first-line setting. Molecular testing is now considered a standard care for NSCLC. The advent of standard commercially available kits and targeted mutational analysis has revolutionized the accuracy of mutation detection platforms for detection of EGFR mutations. Our review provides an overview of various commonly used platforms for detecting EGFR T790M mutation in tumor tissue and plasma.
Collapse
Affiliation(s)
- Xuefei Li
- Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Pulmonary Cancer institute, Tongji University School of Medicine, Shanghai, P. R. China
| | - Caicun Zhou
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China
| |
Collapse
|
|
20
|
Simon GR, Ruckdeschel JC, Williams C, Cantor A, Chiappori A, Rocha Lima CM, Antonia S, Haura E, Wagner H, Robinson L, Sommers E, Alberts M, Bepler G. Gefitinib (ZD1839) in Previously Treated Advanced Non-Small-Cell Lung Cancer: Experience from a Single Institution. Cancer Control 2017; 10:388-95. [PMID: 14581894 DOI: 10.1177/107327480301000506] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND We conducted an analysis of gefitinib in patients with advanced non-small-cell lung cancer (NSCLC) to assess the antitumor efficacy of this epidermal growth factor receptor tyrosine kinase inhibitor. METHODS Our single-center, prospective landmark analysis included 183 patients with advanced NSCLC who received 250 mg of gefitinib orally once daily in an expanded-use program at our institution. Thirty-three of the 183 patients were previously untreated. The patients included in this analysis had all received at least 12 weeks of gefitinib. RESULTS The objective tumor response rate was 3.8%, but an additional 53.5% of patients experienced clinically meaningful disease stabilization. Median progression-free survival time was 3.6 months, and median overall survival time was 8.8 months. The 1-year survival rate for the entire cohort was 35%. Predictors of longer survival included female gender, adenocarcinoma or bronchoalveolar carcinoma histology, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. CONCLUSIONS In this single-center experience, gefitinib demonstrated clinically significant antitumor activity and provided good palliation in a predominantly pretreated group of patients. Our results, which are likely to be reproducible in a community setting, demonstrated a 1-year survival rate of 35% in a cohort of patients who were able to take the drug for at least 12 weeks.
Collapse
Affiliation(s)
- George R Simon
- Thoracic Oncology Program, H. Lee Moffitt Cancer Center Research Institute, Tampa, FL 33612, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Feng Q, Yang ZY, Zhang JT, Tang JL. Comparison of direct sequencing and amplification refractory mutation system for detecting epidermal growth factor receptor mutation in non-small-cell lung cancer patients: a systematic review and meta-analysis. Oncotarget 2017; 8:59552-59562. [PMID: 28938658 PMCID: PMC5601754 DOI: 10.18632/oncotarget.19110] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 06/27/2017] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Direct sequencing and amplification refractory mutation system (ARMS) are commonly used to detect epidermal growth factor receptor (EGFR) mutation status in patients with non-small-cell lung cancer to inform the decision-making on tyrosine kinase inhibitors treatment. This study aimed to systematically compare the two methods in terms of the rate of detected mutations and the association of detected mutations with clinical outcomes. MATERIAL AND METHODS PubMed, EMBASE, China National Knowledge Infrastructure (in Chinese) and Wanfang database (in Chinese) were searched to identify relevant studies. Meta-analyses of EGFR mutation rates, rate differences, and the associations of EGFR mutations with clinical outcomes of tyrosine kinase inhibitors treatment were conducted. RESULTS Eight hundred and sixty-six records were retrieved and 26 studies with 3282 patients were included. The pooled rate of mutations detected by ARMS (41%, 95% confidence interval (CI) 35% to 47%) was significantly higher than that by direct sequencing (28%, 95%CI 22% to 34%), with a weighted rate difference of 11% (95%CI 8% to 13%). There was a consistent trend that the associations between ARMS-detected mutations and clinical outcomes were stronger than those between direct-sequencing-detected mutations and clinical outcomes (pooled risk ratio for objective response: 5.18 vs. 2.25; hazard ratio for progression-free survival: 0.30 vs. 0.42; hazard ratio for overall survival: 0.46 vs. 0.54). CONCLUSIONS More patients with EGFR mutations can be identified by ARMS than by direct sequencing, and those identified by ARMS seems to be able to benefit more from tyrosine kinase inhibitors than those identified by direct sequencing.
Collapse
Affiliation(s)
- Qi Feng
- Division of Epidemiology, JC School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Zu-Yao Yang
- Division of Epidemiology, JC School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Jia-Tong Zhang
- Division of Epidemiology, JC School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Jin-Ling Tang
- Division of Epidemiology, JC School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| |
Collapse
|
|
22
|
Abstract
PIWI-interacting RNA Likes (piR-Ls) were recently reported to regulate functions of their target phospho-Proteins (p-Proteins) in somatic lung cells. However, the mechanism underlying this functionality remains unclear. piR-Ls interact with their targets through direct binding but do not follow base-pairing rules, known to have important roles at levels of transcription, RNA processing and translation for small non-coding RNA (sncRNA). These observations imply a fundamentally different type of sncRNA with behavior that causes a molecular response in their target p-Proteins. Furthermore, the interaction of piR-Ls with their targets regulates the functional efficacy of target p-Proteins. In addition, except for writers (kinase) and erasers (phosphatase), the functional efficacy of p-Proteins on their readers still remains unknown. It is reasonable to consider the existence of protein functional effector sncRNAs (pfeRNAs), which were identified by deep sequencing the immunoprecipitation products of antibodies targeting phosphorylated residues in proteins, as well as by functional analysis. pfeRNAs harbor unique features in size distribution, 3' terminal modification, shared core sequences, and functional manner, and could be new players in lung physiological and pathological conditions.
Collapse
Affiliation(s)
- Malcolm Brock
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, 1650 Orleans Street, Baltimore, MD 21287, USA.
| | - Yuping Mei
- Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, 650 W Baltimore St, Baltimore, MD 21201, USA.
| |
Collapse
|
|
23
|
Rezaei M, Khodayar MJ, Seydi E, Soheila A, Parsi IK. Acute, but not Chronic, Exposure to Arsenic Provokes Glucose Intolerance in Rats: Possible Roles for Oxidative Stress and the Adrenergic Pathway. Can J Diabetes 2017; 41:273-280. [DOI: 10.1016/j.jcjd.2016.10.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Revised: 09/06/2016] [Accepted: 10/17/2016] [Indexed: 12/12/2022]
|
|
24
|
Miao F, Zhang M, Zhao Y, Li X, Yao R, Wu F, Huang R, Li K, Miao S, Ma C, Ju H, Song W, Wang L. RHBDD1 upregulates EGFR via the AP-1 pathway in colorectal cancer. Oncotarget 2017; 8:25251-25260. [PMID: 28445956 PMCID: PMC5421926 DOI: 10.18632/oncotarget.15694] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 01/24/2017] [Indexed: 01/08/2023] Open
Abstract
Our previous study showed that RHBDD1 can activate the EGFR signaling pathway to promote colorectal cancer growth. In the present study, EGFR was decreased when RHBDD1 was knocked down or inactivated. Further analysis found that c-Jun and EGFR protein expression was decreased in RHBDD1 knockdown and inactivated cells. c-Jun overexpression in RHBDD1-inactivated cells rescued EGFR expression in a dose-dependent manner. RHBDD1 overexpression in RHBDD1-inactivated cells restored EGFR expression, but this effect was counteracted by c-Jun knockdown. Furthermore, EGFR and c-Jun were attenuated in the RHBDD1 knockdown and inactivated groups in animal tumor models. Tissue microarray assays demonstrated a correlation between RHBDD1 and EGFR in colorectal cancer patients. Therefore, our findings indicate that RHBDD1 stimulates EGFR expression by promoting the AP-1 pathway.
Collapse
Affiliation(s)
- Fei Miao
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Mengmeng Zhang
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Yuechao Zhao
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Xiaolu Li
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Rongyan Yao
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Fan Wu
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Rong Huang
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Kai Li
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Shiying Miao
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Changwu Ma
- Department of Medical Oncology, Chifeng Municipal Hospital, Chifeng 024000, China
| | - Hongge Ju
- Department of Pathology, Baotou Medical College, Baotou 014040, China.,Department of Pathology, The First Affiliated Hospital of Baotou Medical College, Baotou 014010, China
| | - Wei Song
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Linfang Wang
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| |
Collapse
|
|
25
|
Gable T, Wang Y, Clark D, Kumari P, Shetty AC, Li M, Mei Y. A phosphorylation-wide sncRNA screen reveals Protein Functional Effector sncRNAs (pfeRNAs) in human lung somatic cells. Cancer Lett 2017; 396:85-93. [PMID: 28323037 DOI: 10.1016/j.canlet.2017.03.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 03/08/2017] [Accepted: 03/09/2017] [Indexed: 12/11/2022]
Abstract
We recently reported that PIWI-interacting RNAs likes (piR-Ls) could regulate functions of the interacting phosphorylated proteins (p-Proteins). In addition, except for writers and erasers, functional efficacy of p-Proteins on their readers still remains unknown. We, therefore, reasoned there was a type of sncRNAs which could regulate functional efficacy of p-Proteins. Here, we profiled sncRNAs interacting with phosphorylated -Ser, -Thr and -Tyr residues in 3 HBE and 4 lung SCC cell lines, investigated effects and mechanisms of phosphorylated-residue-interacting sncRNAs. Our results demonstrated sncRNAs regulating functional efficacy of p-Proteins and we thus referred them as Protein Functional Effector sncRNAs (pfeRNAs). pfeRNAs were distributed among 26 to 50 nucleotides, shared some core sequences and showed distinctive expression patterns between HBE and SCC cells. Core sequences 417 (CS417), showing consistent upregulation in all 4 SCC cells, bound directly to p-Nucleolin (NCL), which was dependent on the key elements CGCG of CS417 and p-Ser619 of NCL. The CS417/p-NCL interaction was critical for functional efficacy of p-NCL in basic activities of lung normal and cancer cells. Thus, we revealed a novel type of pfeRNAs controlling functional efficacy of p-Proteins in lung somatic cells.
Collapse
Affiliation(s)
- Tyler Gable
- Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, University of Maryland, 650 W Baltimore St, Baltimore, MD, 21201, USA
| | - Yuyan Wang
- Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, University of Maryland, 650 W Baltimore St, Baltimore, MD, 21201, USA; Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Beijing Institute for Cancer Research, Beijing, 100142, China
| | - David Clark
- Department of Pathology, Johns Hopkins University, Baltimore, MD, 21287, USA
| | - Priti Kumari
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Amol Carl Shetty
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Mao Li
- Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, University of Maryland, 650 W Baltimore St, Baltimore, MD, 21201, USA
| | - Yuping Mei
- Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, University of Maryland, 650 W Baltimore St, Baltimore, MD, 21201, USA.
| |
Collapse
|
|
26
|
Narita Y, Muro K. Challenges in molecular targeted therapy for gastric cancer: considerations for efficacy and safety. Expert Opin Drug Saf 2017; 16:319-327. [PMID: 27976952 DOI: 10.1080/14740338.2017.1273348] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION The Cancer Genome Atlas Research Network recently proposed a molecular classification for gastric cancer (GC) into four subtypes based on comprehensive evaluation. While the mechanisms of molecular targeted therapies in GC were confirmed by multiple clinical studies, only a limited number of therapeutics for GC have been approved to date. Areas covered: In this systematic review of the available literature, we discuss the completed and ongoing clinical trials of molecular targeted therapies in patients with GC, with a focus on their efficacy and safety profiles. Expert opinion: Results of recent studies clearly demonstrated that trastuzumab and ramucirumab, monoclonal antibodies (mAbs) against human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF), respectively, improved overall survival (OS) in GC with manageable safety profiles. Careful surveillance of ongoing clinical trials and timely profiling and monitoring of genetic signatures are imperative to establish a strong foundation for precision medicine in GC.
Collapse
Affiliation(s)
- Yukiya Narita
- a Department of Clinical Oncology , Aichi Cancer Center Hospital , Nagoya , Japan
| | - Kei Muro
- a Department of Clinical Oncology , Aichi Cancer Center Hospital , Nagoya , Japan
| |
Collapse
|
|
27
|
Nand M, Maiti P, Pant R, Kumari M, Chandra S, Pande V. Virtual screening of natural compounds as inhibitors of EGFR 696-1022 T790M associated with non-small cell lung cancer. Bioinformation 2016; 12:311-317. [PMID: 28293073 PMCID: PMC5320927 DOI: 10.6026/97320630012311] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 07/08/2016] [Accepted: 07/09/2016] [Indexed: 11/23/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most dominating and lethal type of lung cancer triggering more than 1.3 million deaths per year. The most effective line of treatment against NSCLC is to target epidermal growth factor receptor (EGFR) activating mutation. The present study aims to identify the novel anti-lung cancer compounds form nature against EGFR 696-1022 T790M by using in silico approaches. A library of 419 compounds from several natural resources was subjected to pre-screen through machine learning model using Random Forest classifier resulting 63 screened molecules with active potential. These molecules were further screened by molecular docking against the active site of EGFR 696-1022 T790M protein using AutoDock Vina followed by rescoring using X-Score. As a result 4 compounds were finally screened namely Granulatimide, Danorubicin, Penicinoline and Austocystin D with lowest binding energy which were -6.5 kcal/mol, -6.1 kcal/mol, -6.3 kcal/mol and -7.1 kcal/mol respectively. The drug likeness of the screened compounds was evaluated using FaF-Drug3 server. Finally toxicity of the hit compounds was predicted in cell line using the CLC-Pred server where their cytotoxic ability against various lung cancer cell lines was confirmed. We have shown 4 potential compounds, which could be further exploited as efficient drug candidates against lung cancer.
Collapse
Affiliation(s)
- Mahesha Nand
- Department of Biotechnology, Kumaun University, Bhimtal Campus Bhimtal, Uttarakhand, India
| | - Priyanka Maiti
- Department of Botany, Kumaun University, S.S.J Campus, Almora, Uttarakhand, India
| | - Ragini Pant
- Department of Biotechnology, Kumaun University, Bhimtal Campus Bhimtal, Uttarakhand, India
| | - Madhulata Kumari
- Department of Information Technology, Kumaun University, SSJ Campus, Almora, Uttarakhand 263601, India
| | - Subhash Chandra
- Department of Botany, Kumaun University, S.S.J Campus, Almora, Uttarakhand, India
| | - Veena Pande
- Department of Biotechnology, Kumaun University, Bhimtal Campus Bhimtal, Uttarakhand, India
| |
Collapse
|
|
28
|
Guo H, Xing Y, Mu A, Li X, Li T, Bian X, Yang C, Zhang X, Liu Y, Wang X. Correlations between EGFR gene polymorphisms and pleural metastasis of lung adenocarcinoma. Onco Targets Ther 2016; 9:5257-70. [PMID: 27601918 PMCID: PMC5004999 DOI: 10.2147/ott.s97907] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Proliferation, growth, and differentiation of cells are strictly controlled by the signal system of epidermal growth factor receptor (EGFR). If any link of the EGFR signals system is interfered with or damaged, the proliferation, growth, and differentiation of cells would become uncontrolled. EGFR is overexpressed in a variety of malignant tumors, such as non-small-cell lung cancer, colorectal cancer and breast cancer. Results of the study have proved that EGFR overexpression is closely associated with mutations and variants of the EGFR genes, whose mutations and variants are associated with occurrence, metastasis, and prognosis of different types of tumors, including lung cancer. This study is aimed at investigating whether the polymorphisms of CA simple sequence repeat in intron 1 (CA-SSR1), -216G/T, and R497K in the EGFR are able to induce EGFR activation and whether overexpression is associated with pleural metastasis of lung adenocarcinoma. A total of 432 lung adenocarcinoma patients with pleural metastasis (metastasis group) and 424 patients with lung adenocarcinoma but without pleural metastasis (nonmetastasis group) were enrolled in this study. For all patients, the CA-SSR1 genotypes were determined by capillary electrophoresis, polymerase chain reaction amplification, and direct DNA sequencing, and the R497K and -216G/T genotypes were determined by polymerase chain reaction amplification and direct DNA sequencing. EGFR expression was evaluated by immunohistochemical staining in primary tumor tissues with different -216G/T, R497K, and CA-SSR1 genotypes. Our results showed significant differences between pleural metastasis and nonmetastasis groups in the genotype and allele distribution of -216G/T, R497K, and CA-SSR1 polymorphisms of the EGFR gene. The -216T allele, Arg allele, and shorter CA-SSR1 (<17) had significantly increased risks of pleural metastasis compared with the -216G allele, Lys allele, and longer CA-SSR1 (≥17), respectively. The expression of EGFR was higher in patients with genotypes of -216T/T or -216G/T, Arg/Arg or Arg/Lys, and shorter CA-SSR1 (<17) than that in patients with genotypes of -216G/G, Lys/Lys, and longer CA-SSR1 (≥17), respectively. These results indicate that -216G/T, R497K, and CA-SSR1 polymorphisms are associated with the risk of pleural metastasis of lung adenocarcinoma, which may be related to the overexpression of EGFR protein induced by -216G/T, R497K, and CA-SSR1 polymorphisms.
Collapse
Affiliation(s)
- Haisheng Guo
- Department of Oncology, Dongying People's Hospital
| | - Yunhui Xing
- Department of Tuberculosis, Shengli Hospital of Shengli Oil Field
| | - Ailan Mu
- Department of Oncology, Dongying People's Hospital
| | | | - Tingshan Li
- Personnel Department, Dongying People's Hospital, Dongying, Shandong, People's Republic of China
| | - Xia Bian
- Department of Oncology, Dongying People's Hospital
| | - Chunmei Yang
- Department of Oncology, Dongying People's Hospital
| | | | - Yuefen Liu
- Department of Oncology, Dongying People's Hospital
| | - Xunguo Wang
- Department of Oncology, Dongying People's Hospital
| |
Collapse
|
|
29
|
Differences among lesions with exon 19, exon 21 EGFR mutations and wild types in surgically resected non-small cell lung cancer. Sci Rep 2016; 6:31636. [PMID: 27527915 PMCID: PMC4985828 DOI: 10.1038/srep31636] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 07/22/2016] [Indexed: 02/07/2023] Open
Abstract
The clinical behavior of patients with advanced non-small cell lung cancer (NSCLC) differ between epidermal growth factor receptor (EGFR) exon 19 deletion (Ex19) and EGFR exon 21 L858R mutation (Ex21). This study aimed to evaluate whether these differences exist in surgically resected NSCLC. A total of 198 patients with surgically resected NSCLC harbouring Ex19 (n = 53), Ex21 (n = 51), and EGFR wild-type (Wt) (n = 94) were analyzed. The clinicopathological features, laboratory parameters, recurrent sites and disease-free survival (DFS) were compared according to mutational EGFR status. Ex21 occurred more frequently in female (p < 0.001), never-smokers (p < 0.001), adenocarcinoma (p < 0.001), low grade (p = 0.013) than Wt lesions. Ex19 occurred more frequently in female (p = 0.016), never-smokers (p = 0.008), adenocarcinoma (p < 0.001), low grade (p = 0.025) than Wt lesions. Ex 21 lesions (p = 0.026) had larger lepidic components than Wt lesions. Wt lesions had larger mucinous variant components than Ex21 lesions (p = 0.045) and Ex19 lesions (p = 0.015). Ex21 lesions were associated with lower pretreatment neutrophil: lymphocyte ratio (NLR) than Wt lesions (p = 0.017). The recurrent sites and DFS were similar among patients with Wt, Ex19 and Ex21.
Collapse
|
|
30
|
Shepherd FA, Bunn PA, Paz-Ares L. Lung cancer in 2013: state of the art therapy for metastatic disease. Am Soc Clin Oncol Educ Book 2016:339-46. [PMID: 23714542 DOI: 10.14694/edbook_am.2013.33.339] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Lung cancer is the leading worldwide cause of cancer death and the majority of patients present with metastatic stage IV disease. At diagnosis, clinical, histologic, and molecular features must be considered in therapeutic decision-making for systemic therapy. Molecular testing for at least epidermal growth factor receptor (EGFR) and ALK should be performed in all patients before therapy. Platinum doublet chemotherapy may be considered for "fit" patients who do not have a molecular driver genetic abnormality. Bevacizumab can be considered for addition to the doublet in patients with nonsquamous cancers who have no contraindications. A pemetrexed combination is considered only in nonsquamous histology. Patients with EGFR mutations or ALK fusions should be treated with erlotinib or crizotinib, respectively, even in patients with tumor-related poor performance. The tyrosine-kinase inhibitors (TKIs) may be continued until multisite, symptomatic progression. For patients initially treated with a platinum doublet, maintenance chemotherapy with pemetrexed, erlotinib, gemcitabine, or possibly docetaxel is an option with selection based on clinical features, histology, type of initial therapy, and response to first-line therapy.
Collapse
Affiliation(s)
- Frances A Shepherd
- From the Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada; University of Colorado Denver, Aurora, CO; Medical Oncology Department, Instituto de Biomedicina de Sevilla and Hospital Universitario Virgen del Rocío, Seville, Spain
| | | | | |
Collapse
|
|
31
|
Morales-Espinosa D, García-Román S, Karachaliou N, Rosell R. Pharmacogenomics in the treatment of lung cancer: an update. Pharmacogenomics 2015; 16:1751-60. [DOI: 10.2217/pgs.15.99] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Significant advances have been made in the analysis of the human genome in the first decades of the 21st century and understanding of tumor biology has matured greatly. The identification of tumor-associated mutations and the pathways involved has led to the development of targeted anticancer therapies. However, the challenge now in using chemotherapy to treat nonsmall-cell lung cancer is to identify more molecular markers predictive of drug sensitivity and determine the optimal drug sequences in order to tailor treatment to each patient. This approach could permit selection of patients who could benefit most from a specific type of chemotherapy by matching their tumor and individual genetic profile. Nevertheless, this potential has been limited so far by reliance on the single biomarker approach, though this is now on the way to being overcome through whole genome studies.
Collapse
Affiliation(s)
- Daniela Morales-Espinosa
- Translational Research Laboratory, Catalan Institute of Oncology, Hospital Universitari Germans Trias I Pujol, Ctra Canyet s/n, Badalona, 08916 Barcelona, Spain
- Fundación Clínica, Médica Sur, Mexico City, Mexico
- Carcinogenesis Laboratory, National Cancer Institute, Mexico City, México
- Dr Rosell Oncology Institute, Quirón Dexeus University Hospital, Barcelona, Spain
| | | | - Niki Karachaliou
- Dr Rosell Oncology Institute, Quirón Dexeus University Hospital, Barcelona, Spain
| | - Rafael Rosell
- Translational Research Laboratory, Catalan Institute of Oncology, Hospital Universitari Germans Trias I Pujol, Ctra Canyet s/n, Badalona, 08916 Barcelona, Spain
- Dr Rosell Oncology Institute, Quirón Dexeus University Hospital, Barcelona, Spain
- Pangaea Biotech S.L., Barcelona, Spain
- Molecular Oncology Research (MORe) Foundation, Barcelona, Spain
| |
Collapse
|
|
32
|
Frederick JW, Sweeny L, Hartman Y, Zhou T, Rosenthal EL. Epidermal growth factor receptor inhibition by anti-CD147 therapy in cutaneous squamous cell carcinoma. Head Neck 2015; 38:247-52. [PMID: 25270595 DOI: 10.1002/hed.23885] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2014] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND Advanced cutaneous squamous cell carcinoma (SCC) is an uncommon and aggressive malignancy. As a result, there is limited understanding of its biology and pathogenesis. CD147 and epidermal growth factor receptor (EGFR) have been identified as oncologically important targets, but their relationship remains undefined in cutaneous SCC. METHODS Multiple cutaneous SCC cell lines (Colo-16, SRB-1, and SRB-12), were treated in vitro with a range of chimeric anti-CD147 monoclonal antibody (mAb) (0, 50, 100, and 200 µg/mL) or transfected with a small interfering RNA against CD147 (SiCD147). Cell proliferation, migration (scratch wound healing assay), and protein expression was then assessed. In vivo, Colo-16 flank xenografts were treated anti-CD147 mAb (150 µg i.p. triweekly). RESULTS After treatment with anti-CD147 (200 µg/mL), there was a significant decrease in proliferation for all cell lines relative to controls (p < .005). In addition, treatment with anti-CD147 (200 µg/mL) resulted in decreased cell migration for all cell lines, with an average of 43% reduction in closure compared to controls (p < .001). Colo-16 SiCD147 expression demonstrated similar reduction in proliferation and wound closure. Anti-CD147 antibody therapy and siRNA mediated reduction in CD147 expression were both found to decrease protein expression of EGFR, which correlated with a reduction in downstream total and phosphorylated protein kinase B (pAKT). Tumor growth in vivo was reduced for both the anti-CD147 treatment group and the SiCD147 group relative to controls. CONCLUSION Inhibition and downregulation of CD147 in cutaneous SCC resulted in suppression of the malignant phenotype in vitro and in vivo, which may be mediated in part by an alteration in EGFR expression. As a result, CD147 may serve as a potential therapeutic target for advanced cutaneous SCC.
Collapse
Affiliation(s)
- John W Frederick
- Department of Surgery, Division of Otolaryngology - Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Larissa Sweeny
- Department of Surgery, Division of Otolaryngology - Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Yolanda Hartman
- Department of Surgery, Division of Otolaryngology - Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Tong Zhou
- Department of Medicine, Division of Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Eben L Rosenthal
- Department of Surgery, Division of Otolaryngology - Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama
| |
Collapse
|
|
33
|
Hong HHL, Hoenerhoff MJ, Ton TV, Herbert RA, Kissling GE, Hooth MJ, Behl M, Witt KL, Smith-Roe SL, Sills RC, Pandiri AR. Kras, Egfr, and Tp53 Mutations in B6C3F1/N Mouse and F344/NTac Rat Alveolar/Bronchiolar Carcinomas Resulting from Chronic Inhalation Exposure to Cobalt Metal. Toxicol Pathol 2015; 43:872-82. [PMID: 26059825 DOI: 10.1177/0192623315581192] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Rodent lung tumors are morphologically similar to a subtype of human lung adenocarcinomas. The objective of this study was to evaluate Kirsten rat sarcoma oncogene homolog (Kras), epidermal growth factor receptor (Egfr), and tumor protein 53 (Tp53) mutations, which are relevant to human lung cancer, in cobalt metal dust (CMD)-induced alveolar/bronchiolar tumors of B6C3F1/N mice and F344/NTac rats. Kras mutations were detected in 67% (mice) and 31% (rats) of CMD-induced lung tumors and were predominantly exon 1 codon 12 G to T transversions (80% in mice and 57% in rats). Egfr mutations were detected in 17% (both mice and rats) of CMD-induced lung tumors and were predominantly in exon 20 with 50% G to A transitions (mice and rats). Tp53 mutations were detected in 19% (mice) and 23% (rats) of CMD-induced lung tumors and were predominant in exon 5 (mice, 69% transversions) and exon 6 (rats, all transitions). No mutations were observed for these genes in spontaneous lung tumors or normal lungs from untreated controls. Ames assay indicated that CMD is mutagenic in the absence but not in the presence of S9 mix. Thus, the mutation data (G to T transversions) and Ames assay results suggest that oxidative damage to DNA may be a contributing factor in CMD-induced pulmonary carcinogenesis in rodents.
Collapse
Affiliation(s)
- Hue-Hua L Hong
- Cellular and Molecular Pathology Branch, Division of the National Toxicology Program (NTP), National Institute of Environmental Health Science (NIEHS), Research Triangle Park, North Carolina, USA
| | - Mark J Hoenerhoff
- Cellular and Molecular Pathology Branch, Division of the National Toxicology Program (NTP), National Institute of Environmental Health Science (NIEHS), Research Triangle Park, North Carolina, USA Current address: University of Michigan, Ann Arbor, Michigan, USA
| | - Thai-Vu Ton
- Cellular and Molecular Pathology Branch, Division of the National Toxicology Program (NTP), National Institute of Environmental Health Science (NIEHS), Research Triangle Park, North Carolina, USA
| | - Ronald A Herbert
- Cellular and Molecular Pathology Branch, Division of the National Toxicology Program (NTP), National Institute of Environmental Health Science (NIEHS), Research Triangle Park, North Carolina, USA
| | - Grace E Kissling
- Biostatistics Branch, NTP, NIEHS, Research Triangle Park, North Carolina, USA
| | - Michelle J Hooth
- Program Operations Branch, DNTP, NIEHS, Research Triangle Park, North Carolina, USA
| | - Mamta Behl
- Toxicology Branch, NTP, NIEHS, Research Triangle Park, North Carolina, USA
| | - Kristine L Witt
- Biomolecular Screening Branch, NTP, NIEHS, Research Triangle Park, North Carolina, USA
| | - Stephanie L Smith-Roe
- Biomolecular Screening Branch, NTP, NIEHS, Research Triangle Park, North Carolina, USA
| | - Robert C Sills
- Cellular and Molecular Pathology Branch, Division of the National Toxicology Program (NTP), National Institute of Environmental Health Science (NIEHS), Research Triangle Park, North Carolina, USA
| | - Arun R Pandiri
- Cellular and Molecular Pathology Branch, Division of the National Toxicology Program (NTP), National Institute of Environmental Health Science (NIEHS), Research Triangle Park, North Carolina, USA Experimental Pathology Laboratories, Inc., Durham, North Carolina, USA
| |
Collapse
|
|
34
|
A benzimidazole derivative exhibiting antitumor activity blocks EGFR and HER2 activity and upregulates DR5 in breast cancer cells. Cell Death Dis 2015; 6:e1686. [PMID: 25766325 PMCID: PMC4385914 DOI: 10.1038/cddis.2015.25] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 01/12/2015] [Accepted: 01/12/2015] [Indexed: 12/14/2022]
Abstract
Aberrant expression or function of epidermal growth factor receptor (EGFR) or the closely related human epidermal growth factor receptor 2 (HER2) can promote cell proliferation and survival, thereby contributing to tumorigenesis. Specific antibodies and low-molecular-weight tyrosine kinase inhibitors of both proteins are currently in clinical trials for cancer treatment. Benzimidazole derivatives possess diverse biological activities, including antitumor activity. However, the anticancer mechanism of 5a (a 2-aryl benzimidazole compound; 2-chloro-N-(2-p-tolyl-1H-benzo[d]imidazol-5-yl)acetamide, C16H14ClN3O, MW299), a novel 2-aryl benzimidazole derivative, toward breast cancer is largely unknown. Here, we demonstrate that 5a potently inhibited both EGFR and HER2 activity by reducing EGFR and HER2 tyrosine phosphorylation and preventing downstream activation of PI3K/Akt and MEK/Erk pathways in vitro and in vivo. We also show that 5a inhibited the phosphorylation of FOXO and promoted FOXO translocation from the cytoplasm into the nucleus, resulting in the G1-phase cell cycle arrest and apoptosis. Moreover, 5a potently induced apoptosis via the c-Jun N-terminal kinase (JNK)-mediated death receptor 5 upregulation in breast cancer cells. The antitumor activity of 5a was consistent with additional results demonstrating that 5a significantly reduced tumor volume in nude mice in vivo. Analysis of the primary breast cancer cell lines with HER2 overexpression further confirmed that 5a significantly inhibited Akt Ser473 and Bad Ser136 phosphorylation and reduced cyclin D3 expression. On the basis of our findings, further development of this 2-aryl benzimidazole derivative, a new class of multitarget anticancer agents, is warranted and represents a novel strategy for improving breast cancer treatment.
Collapse
|
|
35
|
Yamashita H, Yano Y, Kawano K, Matsuzaki K. Oligomerization-function relationship of EGFR on living cells detected by the coiled-coil labeling and FRET microscopy. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2015; 1848:1359-66. [PMID: 25771448 DOI: 10.1016/j.bbamem.2015.03.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 02/09/2015] [Accepted: 03/04/2015] [Indexed: 12/20/2022]
Abstract
The epidermal growth factor receptor (EGFR) is a well-studied receptor tyrosine kinase and an important anticancer therapeutic target. The activity of EGFR autophosphorylation and transphosphorylation, which induces several cell signaling pathways, has been suggested to be related to its oligomeric state. However, the oligomeric states of EGFRs induced by EGF binding and the receptor-ligand stoichiometry required for its activation are still controversial. In the present study, we performed Förster resonance energy transfer (FRET) measurements by combining the coiled-coil tag-probe labeling method and spectral imaging to quantitatively analyze EGFR oligomerization on living CHO-K1 cell membranes at physiological expression levels. In the absence of its ligands, EGFRs mainly existed as monomers with a small fraction of predimers (~10%), whereas ~70% of the EGFRs formed dimers after being stimulated with the ligand EGF. Ligand-induced dimerization was not significantly affected by the perturbation of membrane components (cholesterol or monosialoganglioside GM3). We also investigated both dose and time dependences of EGF-dependent EGFR dimerization and autophosphorylation. The formation of dimers occurred within 20s of the ligand stimulation and preceded its autophosphorylation, which reached a plateau 90 s after the stimulation. The EGF concentration needed to evoke half-maximum dimerization (~1 nM) was lower than that for half-maximum autophosphorylation (~8 nM), which suggested the presence of an inactive dimer binding a single EGF molecule.
Collapse
Affiliation(s)
- Hirotaka Yamashita
- Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Yoshiaki Yano
- Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Kenichi Kawano
- Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Katsumi Matsuzaki
- Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
| |
Collapse
|
|
36
|
Belkhiri A, El-Rifai W. Advances in targeted therapies and new promising targets in esophageal cancer. Oncotarget 2015; 6:1348-58. [PMID: 25593196 PMCID: PMC4359299 DOI: 10.18632/oncotarget.2752] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 11/15/2014] [Indexed: 01/29/2023] Open
Abstract
Esophageal cancer, comprising squamous carcinoma and adenocarcinoma, is a leading cause of cancer-related death in the world. Notably, the incidence of esophageal adenocarcinoma has increased at an alarming rate in the Western world. Unfortunately, the standard first-line chemo-radiotherapeutic approaches are toxic and of limited efficacy in the treatment of a significant number of cancer patients. The molecular analysis of cancer cells has uncovered key genetic and epigenetic alterations underlying the development and progression of tumors. These discoveries have paved the way for the emergence of targeted therapy approaches. This review will highlight recent progress in the development of targeted therapies in esophageal cancer. This will include a review of drugs targeting receptor tyrosine kinases and other kinases in esophageal cancer. Additional studies will be required to develop a rational integration of these targeted agents with respect to histologic types of esophageal cancer and the optimal selection of cancer patients who would most likely benefit from targeted therapy. Identification of AURKA and AXL as key molecular players in esophageal tumorigenesis and drug resistance strongly justifies the evaluation of the available drugs against these targets in clinical trials.
Collapse
Affiliation(s)
- Abbes Belkhiri
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
| | - Wael El-Rifai
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee 37212, USA
| |
Collapse
|
|
37
|
Zhang BO, Xu CW, Shao Y, Wang HT, Wu YF, Song YY, Li XB, Zhang Z, Wang WJ, Li LQ, Cai CL. Comparison of droplet digital PCR and conventional quantitative PCR for measuring EGFR gene mutation. Exp Ther Med 2015; 9:1383-1388. [PMID: 25780439 PMCID: PMC4353752 DOI: 10.3892/etm.2015.2221] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 12/19/2014] [Indexed: 02/02/2023] Open
Abstract
Early detection of epidermal growth factor receptor (EGFR) mutation, particularly EGFR T790M mutation, is of clinical significance. The aim of the present study was to compare the performances of amplification refractory mutation system-based quantitative polymerase chain reaction (ARMS-qPCR) and droplet digital polymerase chain reaction (ddPCR) approaches in the detection of EGFR mutation and explore the feasibility of using ddPCR in the detection of samples with low mutation rates. EGFR gene mutations in plasmid samples with different T790M mutation rates (0.1-5%) and 10 clinical samples were detected using the ARMS-qPCR and ddPCR approaches. The results demonstrated that the ARMS-qPCR method stably detected the plasmid samples (6,000 copies) with 5 and 1% mutation rates, while the ddPCR approach reliably detected those with 5% (398 copies), 1% (57 copies), 0.5% (24 copies) and 0.1% (average 6 copies) mutation rates. For the 10 clinical samples, the results for nine samples by the ARMS-qPCR and ddPCR methods were consistent; however, the sample N006, indicated to be EGFR wild-type by ARMS-qPCR, was revealed to have a clear EGFR T790M mutation with seven copies of mutant alleles in a background of 6,000 wild-type copies using ddPCR technology. This study demonstrates the feasibility of applying the ddPCR system to detect EGFR mutation and identified the advantage of ddPCR in the detection of samples with a low EGFR mutation abundance, particularly the secondary EGFR T790M resistance mutation, which enables early diagnosis before acquired resistance to tyrosine kinase inhibitors becomes clinically detectable.
Collapse
Affiliation(s)
- B O Zhang
- Department of Pathology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Chun-Wei Xu
- Department of Pathology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Yun Shao
- Department of Pathology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Huai-Tao Wang
- Department of Pathology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Yong-Fang Wu
- Department of Pathology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Ye-Ying Song
- Department of Pathology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Xiao-Bing Li
- Department of Pathology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Zhe Zhang
- Wuhan YZY Medical Science and Technology Co., Ltd., Wuhan, Hubei 430075, P.R. China
| | - Wen-Jing Wang
- Wuhan YZY Medical Science and Technology Co., Ltd., Wuhan, Hubei 430075, P.R. China
| | - Li-Qiong Li
- Wuhan YZY Medical Science and Technology Co., Ltd., Wuhan, Hubei 430075, P.R. China
| | - Cong-Li Cai
- Wuhan YZY Medical Science and Technology Co., Ltd., Wuhan, Hubei 430075, P.R. China
| |
Collapse
|
|
38
|
Goldkorn T, Filosto S, Chung S. Lung injury and lung cancer caused by cigarette smoke-induced oxidative stress: Molecular mechanisms and therapeutic opportunities involving the ceramide-generating machinery and epidermal growth factor receptor. Antioxid Redox Signal 2014; 21:2149-74. [PMID: 24684526 PMCID: PMC4215561 DOI: 10.1089/ars.2013.5469] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Chronic obstructive pulmonary disease (COPD) and lung cancer are frequently caused by tobacco smoking. However, these diseases present opposite phenotypes involving redox signaling at the cellular level. While COPD is characterized by excessive airway epithelial cell death and lung injury, lung cancer is caused by uncontrolled epithelial cell proliferation. Notably, epidemiological studies have demonstrated that lung cancer incidence is significantly higher in patients who have preexisting emphysema/lung injury. However, the molecular link and common cell signaling events underlying lung injury diseases and lung cancer are poorly understood. This review focuses on studies of molecular mechanism(s) underlying smoking-related lung injury (COPD) and lung cancer. Specifically, the role of the ceramide-generating machinery during cigarette smoke-induced oxidative stress leading to both apoptosis and proliferation of lung epithelial cells is emphasized. Over recent years, it has been established that ceramide is a sphingolipid playing a major role in lung epithelia structure/function leading to lung injury in chronic pulmonary diseases. However, new and unexpected findings draw attention to its potential role in lung development, cell proliferation, and tumorigenesis. To address this dichotomy in detail, evidence is presented regarding several protein targets, including Src, p38 mitogen-activated protein kinase, and neutral sphingomyelinase 2, the major sphingomyelinase that controls ceramide generation during oxidative stress. Furthermore, their roles are presented not only in apoptosis and lung injury but also in enhancing cell proliferation, lung cancer development, and resistance to epidermal growth factor receptor-targeted therapy for treating lung cancer.
Collapse
Affiliation(s)
- Tzipora Goldkorn
- Center for Comparative Respiratory Biology and Medicine, Genome and Biomedical Sciences Facility, University of California School of Medicine , Davis, California
| | | | | |
Collapse
|
|
39
|
Kulshrestha A, Jarouliya U, Prasad GBKS, Flora SJS, Bisen PS. Arsenic-induced abnormalities in glucose metabolism: Biochemical basis and potential therapeutic and nutritional interventions. World J Transl Med 2014; 3:96-111. [DOI: 10.5528/wjtm.v3.i2.96] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 06/21/2014] [Accepted: 07/17/2014] [Indexed: 02/05/2023] Open
Abstract
Health hazards due to the consumption of heavy metals such as arsenic have become a worldwide problem. Metabolism of arsenic produces various intermediates which are more toxic and cause toxicity. Arsenic exposure results in impairment of glucose metabolism, insulin secretion in pancreatic β-cells, altered gene expressions and signal transduction, and affects insulin-stimulated glucose uptake in adipocytes or skeletal muscle cells. Arsenic toxicity causes abnormalities in glucose metabolism through an increase in oxidative stress. Arsenic interferes with the sulfhydryl groups and phosphate groups present in various enzymes involved in glucose metabolism including pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and contributes to their impairment. Arsenic inhibits glucose transporters present in the cell membrane, alters expression of genes involved in glucose metabolism, transcription factors and inflammatory cytokines which stimulate oxidative stress. Some theories suggest that arsenic exposure under diabetic conditions inhibits hyperglycemia. However, the exact mechanism behind the behavior of arsenic as an antagonist or synergist on glucose homeostasis and insulin secretion is not yet fully understood. The present review delineates the relationship between arsenic and the biochemical basis of its relationship to glucose metabolism. This review also addresses potential therapeutic and nutritional interventions for attenuating arsenic toxicity. Several other potential nutritional supplements are highlighted in the review that could be used to combat arsenic toxicity.
Collapse
|
|
40
|
Yang X, Wang W, Wang C, Wang L, Yang M, Qi M, Su H, Sun X, Liu Z, Zhang J, Qin X, Han B. Characterization of EGFR family gene aberrations in cholangiocarcinoma. Oncol Rep 2014; 32:700-8. [PMID: 24927194 DOI: 10.3892/or.2014.3261] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Accepted: 04/07/2014] [Indexed: 12/16/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a highly lethal malignancy of the biliary tract with very few treatment options. Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER2) have been considered as potential therapeutic targets in CCA. In the present study, we attempted to clarify the clinicopathological significance of all EGFR family members, EGFR, HER2, HER3 and HER4, across the full spectrum of CCAs. Immunohistochemistry and FISH were performed to validate expressions and genetic aberrations of these molecules retrospectively in 175 CCA patients. EGFR, HER3 and HER4 were overexpressed in 20 (30.8%), 8 (12.3%) and 41 (63.1%) of the 65 intrahepatic cholangiocarcinomas (IHCCs), and in 23 (20.9%), 13 (11.8%) and 62 (56.4%) of the 110 extrahepatic cholangiocarcinomas (EHCCs), respectively. Overexpression of HER2 was exclusively identified in EHCCs, among which the rate was 4.5% (5/110). A significant association was identified between EGFR amplification and EGFR overexpression (P=0.002). Similarly, HER2 amplification was strongly associated with HER2 overexpression (P<0.001). Multivariate analysis suggested that EGFR overexpression is an independent prognostic factor in IHCC, but not in EHCC cases [HR (95% CI): 3.689 (1.253-10.587), P=0.018]. Notably, for the first time, we demonstrated HER4 expression is a prognostic factor in EGFR-negative IHCC patients. In vitro data further suggested a tumor-suppressor role of HER4 in CCA. siRNA knockdown of HER4 significantly increased RBE cell migration and invasion. By contrast, HER4 overexpression decreased proliferation of HuCCT-1 cells and their migratory and invasive capacity. In summary, our results revealed expression of the EGFR family members in CCA development and progression. CCAs differentially express HER2 protein based on tumor location. HER4 expression status allows stratification of CCA patients into different survival categories.
Collapse
Affiliation(s)
- Xiaoqing Yang
- Department of Pathology, Shandong University Medical School, Jinan, Shandong, P.R. China
| | - Weishan Wang
- Department of General Surgery, Yishui Central Hospital, Linyi, Shandong, P.R. China
| | - Chunni Wang
- Department of Pathology, Shandong University Medical School, Jinan, Shandong, P.R. China
| | - Lin Wang
- Department of Pathology, Shandong University Medical School, Jinan, Shandong, P.R. China
| | - Muyi Yang
- Department of Pathology, Shandong University Medical School, Jinan, Shandong, P.R. China
| | - Mei Qi
- Department of Pathology, Shandong University Medical School, Jinan, Shandong, P.R. China
| | - Hong Su
- Department of Pathology, Shandong University Medical School, Jinan, Shandong, P.R. China
| | - Xiubin Sun
- Department of Statistics, Shandong University School of Public Health, Jinan, Shandong, P.R. China
| | - Zhiyan Liu
- Department of Pathology, Shandong University Medical School, Jinan, Shandong, P.R. China
| | - Juan Zhang
- Department of Pathology, Shandong University Qilu Hospital, Jinan, Shandong, P.R. China
| | - Xiaomin Qin
- Department of Pathology, Shandong University Qilu Hospital, Jinan, Shandong, P.R. China
| | - Bo Han
- Department of Pathology, Shandong University Medical School, Jinan, Shandong, P.R. China
| |
Collapse
|
|
41
|
Lake MC, Aboagye EO. Luciferase fragment complementation imaging in preclinical cancer studies. Oncoscience 2014; 1:310-25. [PMID: 25594026 PMCID: PMC4278313 DOI: 10.18632/oncoscience.45] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 05/31/2014] [Indexed: 12/20/2022] Open
Abstract
The luciferase fragment complementation assay (LFCA) enables molecular events to be non-invasively imaged in live cells in vitro and in vivo in a comparatively cheap and safe manner. It is a development of previous enzyme complementation assays in which reporter genes are split into two, individually enzymatically inactive, fragments that are able to complement one another upon interaction. This complementation can be used to externally visualize cellular activities. In recent years, the number of studies which have used LFCAs to probe questions relevant to cancer have increased, and this review summarizes the most significant and interesting of these. In particular, it focuses on work conducted on the epidermal growth factor, nuclear and chemokine receptor families, and intracellular signaling pathways, including IP3, cAMP, Akt, cMyc, NRF2 and Rho GTPases. LFCAs which have been developed to image DNA methylation and detect RNA transcripts are also discussed.
Collapse
Affiliation(s)
- Madryn C. Lake
- Comprehensive Cancer Imaging Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London
| | - Eric O. Aboagye
- Comprehensive Cancer Imaging Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London
| |
Collapse
|
|
42
|
Gangemi S, Franchina T, Minciullo PL, Profita M, Zanghì M, David A, Kennez I, Adamo V. IL-33/IL-31 axis: a new pathological mechanisms for EGFR tyrosine kinase inhibitors-associated skin toxicity. J Cell Biochem 2014; 114:2673-6. [PMID: 23794184 DOI: 10.1002/jcb.24614] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2013] [Accepted: 06/14/2013] [Indexed: 01/10/2023]
Abstract
The dermatologic side effects are the most common adverse effects associated with Epidermal Growth Factor Receptor tyrosine kinase inhibitors. Although the mechanisms underlying the development of the skin toxicity remain unclear, immunological mechanisms are considered to be involved. A possible correlation between plasma levels of certain cytokines and development of skin toxicity has been reported. The aim of this work was to investigate the possible contribution of IL-31 and IL-33, cytokines involved in disorders associated with itching, in the pathogenesis of pruritus in patients undergoing EGFR-TK inhibitors. We report a significant increase of IL-31 and IL-33 serum levels in a patient with a bronchioalveolar carcinoma, who had showed previous skin rash, xerosis, and pruritus during treatment with different EGFR-TK inhibitors. She developed intense iching during gefitinib therapy. Therefore, we had collected patient blood sample to evaluate IL-31 and IL-33 serum levels compared to controls, reporting a significant increase in serum of patient. In the light of these findings, EGFR-TK inhibitors-related symptoms of dermatologic toxicities might be related to the release of IL-31 and IL-33. In particular, it is supposable that EGFR-TK inhibitors could cause keratinocytes injury, the release of IL-33 and the consequent interaction with its receptor on mast cells, that induces the secretion of several factors capable to cause skin manifestations, included IL-31, a known pruritus-inducing cytokine. This report, to the best of our knowledge, is the first work describing a possible involvement of IL-31/IL-33 axis in the pathogenesis of skin side effects related to EGFR-TK inhibitors treatment.
Collapse
Affiliation(s)
- Sebastiano Gangemi
- School and Division of Allergy and Clinical Immunology, Department of Human Pathology, University Policlinic "G. Martino", via Consolare Valeria 1, Messina, 90125, Italy; Institute of Biomedicine and Molecular Immunology "A. Monroy" (IBIM)-Consiglio Nazionale delle Ricerche (CNR), via Ugo la Malfa 153, Palermo, 90146, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Lozy F, Cai-McRae X, Teplova I, Price S, Reddy A, Bhanot G, Ganesan S, Vazquez A, Karantza V. ERBB2 overexpression suppresses stress-induced autophagy and renders ERBB2-induced mammary tumorigenesis independent of monoallelic Becn1 loss. Autophagy 2014; 10:662-76. [PMID: 24492513 PMCID: PMC4091153 DOI: 10.4161/auto.27867] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Defective autophagy has been implicated in mammary tumorigenesis, as the gene encoding the essential autophagy regulator BECN1 is deleted in human breast cancers and Becn1+/− mice develop mammary hyperplasias. In agreement with a recent study, which reports concurrent allelic BECN1 loss and ERBB2 amplification in a small number of human breast tumors, we found that low BECN1 mRNA correlates with ERBB2-overexpression in breast cancers, suggesting that BECN1 loss and ERBB2 overexpression may functionally interact in mammary tumorigenesis. We now report that ERBB2 overexpression suppressed autophagic response to stress in mouse mammary and human breast cancer cells. ERBB2-overexpressing Becn1+/+ and Becn1+/− immortalized mouse mammary epithelial cells (iMMECs) formed mammary tumors in nude mice with similar kinetics, and monoallelic Becn1 loss did not alter ERBB2- and PyMT-driven mammary tumorigenesis. In human breast cancer databases, ERBB2-expressing tumors exhibit a low autophagy gene signature, independent of BECN1 mRNA expression, and have similar gene expression profiles with non-ERBB2-expressing breast tumors with low BECN1 levels. We also found that ERBB2-expressing BT474 breast cancer cells, despite being partially autophagy-deficient under stress, can be sensitized to the anti-ERBB2 antibody trastuzumab (tzb) by further pharmacological or genetic autophagy inhibition. Our results indicate that ERBB2-driven mammary tumorigenesis is associated with functional autophagy suppression and ERBB2-positive breast cancers are partially autophagy-deficient even in a wild-type BECN1 background. Furthermore and extending earlier findings using tzb-resistant cells, exogenously imposed autophagy inhibition increases the anticancer effect of trastuzumab on tzb-sensitive ERBB2-expressing breast tumor cells, indicating that pharmacological autophagy suppression has a wider role in the treatment of ERBB2-positive breast cancer.
Collapse
Affiliation(s)
- Fred Lozy
- Rutgers University; State University of New Jersey; New Brunswick, NJ USA; Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA
| | - Xiaofeng Cai-McRae
- Rutgers University; State University of New Jersey; New Brunswick, NJ USA; Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA
| | - Irina Teplova
- Rutgers University; State University of New Jersey; New Brunswick, NJ USA; Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA
| | - Sandy Price
- Rutgers University; State University of New Jersey; New Brunswick, NJ USA; Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA
| | - Anupama Reddy
- Rutgers University; State University of New Jersey; New Brunswick, NJ USA
| | - Gyan Bhanot
- Rutgers University; State University of New Jersey; New Brunswick, NJ USA; Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA
| | - Shridar Ganesan
- Rutgers University; State University of New Jersey; New Brunswick, NJ USA; Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA; Division of Medical Oncology; Department of Internal Medicine; Rutgers Robert Wood Johnson Medical School; Piscataway, NJ USA
| | - Alexei Vazquez
- Rutgers University; State University of New Jersey; New Brunswick, NJ USA; Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA
| | - Vassiliki Karantza
- Rutgers University; State University of New Jersey; New Brunswick, NJ USA; Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA; Division of Medical Oncology; Department of Internal Medicine; Rutgers Robert Wood Johnson Medical School; Piscataway, NJ USA
| |
Collapse
|
|
44
|
Lung cancer. Mol Oncol 2013. [DOI: 10.1017/cbo9781139046947.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
|
|
45
|
Zhang J, Hochwald SN. Targeting Receptor Tyrosine Kinases in Solid Tumors. Surg Oncol Clin N Am 2013; 22:685-703. [DOI: 10.1016/j.soc.2013.06.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
|
|
46
|
Han Y, Li G, Su C, Ren H, Chu X, Zhao Q, Zhu Y, Wang Z, Hu B, An G, Kang J, Wang W, Yu D, Song X, Xiao N, Li Y, Li X, Yang H, Yu G, Liu Z. Exploratory study on the correlation between 14 lung cancer-related gene expression and specific clinical characteristics of NSCLC patients. Mol Clin Oncol 2013; 1:887-893. [PMID: 24649266 PMCID: PMC3915665 DOI: 10.3892/mco.2013.153] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 05/15/2013] [Indexed: 12/20/2022] Open
Abstract
Personalized medicine has become essential in the treatment of lung cancer. However, the lung cancer-related gene expression profiles in non-small cell lung cancer (NSCLC) patients have not been elucidated. In this study, the correlation between gene expression profiles and clinicopathological characteristics was investigated in NSCLC patients. A total of 95 patients were enrolled in this study. The mRNA expression levels of 14 genes were assessed by multiplex branched DNA liquidchip (MBL) technology and data on 9 clinicopathological characteristics of patients were collected simultaneously. The correlation between gene expression and clinicopathological characteristics was investigated. Out of the 9 clinicopathological parameters, 6 were associated with several of the 14 genes analyzed. Patient gender was associated with TYMS and TOP2A. Clinical stage was associated with VEGFR2, KIT and HER2. There was weak correlation between primary tumor size of ≤3 cm and the expression level of KIT. The mRNA expression levels of VEGFR2 and HER2 correlated with distant metastasis. BRCA1, TYMS, TOP2A and HER2 were associated with histological type. Smoking correlated with higher expression levels of BRCA1, TYMS and TOP2A and lower expression levels of PDGFRβ. The results were suggestive of correlation between the clinicopathological parameters of the NSCLC patients and the mRNA expression levels of certain lung cancer-related genes, including BRCA1, TYMS, TOP2A, PDGFRβ, VEGFR2, KIT and HER2.
Collapse
Affiliation(s)
- Yi Han
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| | - Guo Li
- Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Chongyu Su
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| | - Hua Ren
- General Hospital of the Chinese Armed Police Forces, Beijing 100039, P.R. China
| | - Xiangyang Chu
- Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Qiuyue Zhao
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| | - Yanjun Zhu
- General Hospital of the Air Force, PLA, Beijing 100142, P.R. China
| | - Zitong Wang
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| | - Bin Hu
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Guangyu An
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Jingbo Kang
- Navy General Hospital, Beijing 100048, P.R. China
| | - Wei Wang
- Navy General Hospital, Beijing 100048, P.R. China
| | - Daping Yu
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| | - Xiaoyun Song
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| | - Ning Xiao
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| | - Yunsong Li
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| | - Xia Li
- SurExam Bio-Tech Co. Ltd., Guangzhou Technology Innovation Base, Science City, Guangzhou 510663, P.R. China
| | - Huiyi Yang
- SurExam Bio-Tech Co. Ltd., Guangzhou Technology Innovation Base, Science City, Guangzhou 510663, P.R. China
| | - Gang Yu
- SurExam Bio-Tech Co. Ltd., Guangzhou Technology Innovation Base, Science City, Guangzhou 510663, P.R. China
| | - Zhidong Liu
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| |
Collapse
|
|
47
|
Roengvoraphoj M, Tsongalis GJ, Dragnev KH, Rigas JR. Epidermal growth factor receptor tyrosine kinase inhibitors as initial therapy for non-small cell lung cancer: focus on epidermal growth factor receptor mutation testing and mutation-positive patients. Cancer Treat Rev 2013; 39:839-50. [PMID: 23768755 DOI: 10.1016/j.ctrv.2013.05.001] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Revised: 05/02/2013] [Accepted: 05/04/2013] [Indexed: 01/24/2023]
Abstract
Activation of the epidermal growth factor receptor (EGFR) pathway has been implicated in tumorigenesis in non-small cell lung cancer (NSCLC), the most common type of lung cancer. As a result, EGFR has become a key focus for the development of personalized therapy, with several molecular biomarkers having been investigated as potential predictors of response with EGFR tyrosine kinase inhibitors (TKIs) in NSCLC (e.g., EGFR expression, EGFR gene copy gain, and EGFR mutations). Of these, activating mutations in EGFR have thus far given the most consistent results based on the available evidence from preclinical studies and clinical trials. In an attempt to identify patients who are most likely to benefit from treatment with EGFR TKIs, EGFR mutation testing is being increasingly utilized in clinical practice. Currently in the United States, no EGFR TKI or accompanying mutational test is approved for the identification and first-line treatment of patients with advanced NSCLC. However, the first-generation EGFR TKIs, erlotinib and gefitinib, as well as investigational ErbB family TKIs and EGFR mutation testing methods are being evaluated in this setting. This review will discuss EGFR mutation testing as a biomarker of response to EGFR TKIs and the evolution of EGFR mutational analysis in NSCLC. Completed and ongoing clinical trials evaluating currently available or investigational EGFR TKIs as first-line therapy in molecularly and clinically selected patients with NSCLC, with a focus on trials in patients whose tumors have EGFR mutations, will also be reviewed.
Collapse
Affiliation(s)
- Monic Roengvoraphoj
- Comprehensive Thoracic Oncology Program, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756-0001, USA; The Geisel School of Medicine at Dartmouth, One Rope Ferry Road, Hanover, NH 03755-1404, USA.
| | | | | | | |
Collapse
|
|
48
|
Sathishkumar N, Karpagam V, Sathiyamoorthy S, Woo MJ, Kim YJ, Yang DC. Computer-aided identification of EGFR tyrosine kinase inhibitors using ginsenosides from Panax ginseng. Comput Biol Med 2013; 43:786-97. [PMID: 23668355 DOI: 10.1016/j.compbiomed.2013.02.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Revised: 02/18/2013] [Accepted: 02/20/2013] [Indexed: 10/26/2022]
Abstract
Natural products have served as structural resources in the history of drug discovery for cancer therapy. Among these natural products, Korean Panax ginseng serves as a potential anti-cancer medicinal plant. To determine the anti-cancer activities of Korean P. ginseng active compounds, we performed pharmacophore-based virtual screening and molecular docking studies on EGFR (epidermal growth factor receptor) tyrosine kinase domain. The EGFR family tyrosine kinase receptor is a cell surface receptor that regulates diverse biological processes including cell proliferation, differentiation, survival, and apoptosis. Over expression of EGFR tyrosine kinase domain associated with the development and progression of numerous human cancers. In our study, we developed the best pharmacophore model (Hypo1) using a diverse training set and validated by Fischer's randomization, a test set, and a decoy set. The best validated model was employed in the virtual screening of P. ginseng compound database. Further, chosen molecules were evaluated by applying ADMET screening and molecular docking studies. Finally, 14 compounds were obtained based on binding affinity scores and interactions with protein active site residues. These final lead compounds from P. ginseng can be used in the designing of new EGFR tyrosine kinase inhibitors.
Collapse
Affiliation(s)
- Natarajan Sathishkumar
- Korean Ginseng Center and Ginseng Genetic Resource Bank, Kyung Hee University, Yongin 449-701, Republic of Korea.
| | | | | | | | | | | |
Collapse
|
|
49
|
Gunturu KS, Woo Y, Beaubier N, Remotti HE, Saif MW. Gastric cancer and trastuzumab: first biologic therapy in gastric cancer. Ther Adv Med Oncol 2013; 5:143-51. [PMID: 23450234 DOI: 10.1177/1758834012469429] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer remains difficult to cure and has a poor overall prognosis. Chemotherapy and multimodality therapy has shown some benefit in the treatment of gastric cancer. Current therapies for gastric cancer have their limitations; thus, we are in need of newer treatment options including targeted therapies. Here, we review the biologic therapy with trastuzumab in human epidermal growth factor receptor 2 (HER2)+ gastric cancer.
Collapse
Affiliation(s)
- Krishna S Gunturu
- Division of Hematology/Oncology, Tufts Medical Center, Boston, MA, USA
| | | | | | | | | |
Collapse
|
|
50
|
Lee Y, Lee HJ, Kim YT, Kang CH, Goo JM, Park CM, Paeng JC, Chung DH, Jeon YK. Imaging characteristics of stage I non-small cell lung cancer on CT and FDG-PET: relationship with epidermal growth factor receptor protein expression status and survival. Korean J Radiol 2013; 14:375-83. [PMID: 23483676 PMCID: PMC3590355 DOI: 10.3348/kjr.2013.14.2.375] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Accepted: 09/10/2012] [Indexed: 01/15/2023] Open
Abstract
OBJECTIVE To identify CT and FDG-PET features associated with epidermal growth factor receptor (EGFR) protein overexpression, and to evaluate whether imaging features and EGFR-overexpression can help predict clinical outcome. MATERIALS AND METHODS In 214 patients (M : F = 129 : 85; mean age, 63.2) who underwent curative resection of stage I non-small cell lung cancer, EGFR protein expression status was determined through immunohistochemical analysis. Imaging characteristics on CT and FDG-PET was assessed in relation to EGFR-overexpression. Imaging features and EGFR-overexpression were also evaluated for clinical outcome by using the Cox proportional hazards model. RESULTS EGFR-overexpression was found in 51 patients (23.8%). It was significantly more frequent in tumors with an SUV(max) > 5.0 (p < 0.0001), diameter > 2.43 cm (p < 0.0001), and with ground glass opacity ≤ 50% (p = 0.0073). SUV(max) > 5.0 (OR, 3.113; 95% CI, 1.375-7.049; p = 0.006) and diameter > 2.43 cm (OR, 2.799; 95% CI, 1.285-6.095; p = 0.010) were independent predictors of EGFR overexpression. Multivariate analysis showed that SUV(max) > 4.0 (hazard ratio, 10.660; 95% CI, 1.370-82.966; p = 0.024), and the presence of cavitation within a tumor (hazard ratio, 3.122; 95% CI, 1.143-8.532; p = 0.026) were factors associated with poor prognosis. CONCLUSION EGFR-overexpression is associated with high SUV(max), large tumor diameter, and small GGO proportion. CT and FDG-PET findings, which are closely related to EGFR overexpression, can be valuable in the prediction of clinical outcome.
Collapse
Affiliation(s)
- Youkyung Lee
- Department of Radiology, Seoul National University Hospital, Seoul 110-744, Korea
| | | | | | | | | | | | | | | | | |
Collapse
|