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Qian X, Jin M, Bei Y, Zhou C, Fang S, Liu K. SLC20A1 is a prospective prognostic and therapy response predictive biomarker in head and neck squamous cell carcinoma. Aging (Albany NY) 2024; 16:4423-4444. [PMID: 38412319 PMCID: PMC10968711 DOI: 10.18632/aging.205597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 01/11/2024] [Indexed: 02/29/2024]
Abstract
BACKGROUND SLC20A1, a prominent biomarker in several cancers, has been understudied in its predictive role in head and neck squamous cell carcinoma (HNSCC). METHODS The Cancer Genome Atlas (TCGA) database was used to analyze HNSCC prognosis, SLC20A1 overexpression, and clinical characteristics. Quantitative real-time PCR and Western blot analysis confirmed SLC20A1 expression in HNSCC tissues. Cellular behaviors such as invasion, migration and proliferation were assessed using Transwell, wound healing and colony formation assays. Immune system data were obtained from the Tumor Immune Estimation Resource (TIMER) and CIBERSORT databases. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were used to explore biological parameters and pathways associated with SLC20A1 overexpression in HNSCC. RESULTS In 499 HNSCC samples, SLC20A1 mRNA and protein expression were significantly higher than in 44 normal counterparts, confirmed by 24 paired samples. Patients were categorized based on SLC20A1 levels, survival status and overall survival. High SLC20A1 expression correlated with advanced T stage, increased risk scores and decreased survival. Stage, age and SLC20A1 expression emerged as independent predictive factors for HNSCC in univariate and multivariate analyses. SLC20A1 overexpression, which is associated with poor prognosis, may influence cell proliferation, migration, invasion, chemotherapy response, and the immune milieu. CONCLUSIONS SLC20A1 overexpression in HNSCC, characterized by increased cellular invasion, migration and proliferation, is a potential prognostic biomarker and therapeutic response indicator.
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Affiliation(s)
- Xiajing Qian
- Department of Radiation Oncology, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Ming Jin
- Department of Radiation Oncology, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Yanping Bei
- Department of Radiation Oncology, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Chongchang Zhou
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Shuai Fang
- Department of Thoracic Surgery, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Kaitai Liu
- Department of Radiation Oncology, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
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Huo RX, Jin YY, Zhuo YX, Ji XT, Cui Y, Wu XJ, Wang YJ, Zhang L, Zhang WH, Cai YM, Zheng CC, Cui RX, Wang QY, Sun Z, Wang FW. Concurrent chemoradiotherapy using gemcitabine and nedaplatin in recurrent or locally advanced head and neck squamous cell carcinoma. World J Clin Cases 2022; 10:3414-3425. [PMID: 35611190 PMCID: PMC9048568 DOI: 10.12998/wjcc.v10.i11.3414] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 01/14/2022] [Accepted: 03/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Patients with recurrent or locally advanced head and neck squamous cell carcinoma (HNSCC) typically have limited treatment options and poor prognosis.
AIM To evaluate the efficacy and safety of two drugs with potent radio-sensitization properties including gemcitabine and nedaplatin as concurrent chemoradiotherapy regimens in treating HNSCC.
METHODS This single-arm prospective study enrolled patients with HNSCC to receive gemcitabine on days 1 and 8 and nedaplatin on days 1 to 3 for 21 days. Intensity-modulated radiation therapy with a conventional fraction was delivered 5 days per week. Objective response rate (ORR), disease control rate, and toxicity were observed as primary endpoints. Overall survival (OS) and progression free survival were recorded and analyzed as secondary endpoints.
RESULTS A total of 24 patients with HNSCC were enrolled. During the median 22.4-mo follow-up, both ORR and disease control rate were 100%. The one-year OS was 75%, and one-year progression-free survival (PFS) was 66.7% (median PFS was 15.1 mo). Recurrent HNSCC patients had a poorer prognosis than the treatment-naïve patients, and patients who achieved complete response had better survival than those in the PR group (all P < 0.05). The most common grade 1-4 (100%) or grade 3-4 toxicities (75%) were hematological, and the most common grade 3-4 non-hematological toxicity was mucositis in 17 (71%) patients.
CONCLUSION Gemcitabine plus nedaplatin with concurrent chemoradiotherapy is a therapeutic option for HNSCC with predictable tolerability. Considering the high adverse event rate, the optimized dose and schedule must be further explored.
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Affiliation(s)
- Rui-Xue Huo
- Department of Oncology, Tianjin Union Medical Center, Tianjin 300000, China
| | - Ying-Ying Jin
- School of Medicine, Nankai University, Tianjin 300000, China
| | - Yong-Xue Zhuo
- School of Medicine, Nankai University, Tianjin 300000, China
| | - Xiao-Tong Ji
- School of Medicine, Nankai University, Tianjin 300000, China
| | - Yu Cui
- Department of Oncology, Tianjin Union Medical Center, Tianjin 300000, China
| | - Xiao-Jing Wu
- Laboratory of Oncologic Molecular Medicine, Tianjin Union Medical Center, Tianjin 300000, China
| | - Yi-Jia Wang
- Laboratory of Oncologic Molecular Medicine, Tianjin Union Medical Center, Tianjin 300000, China
| | - Long Zhang
- Department of Oncology, Tianjin Union Medical Center, Tianjin 300000, China
| | - Wen-Hua Zhang
- Department of Oncology, Tianjin Union Medical Center, Tianjin 300000, China
| | - Yu-Mei Cai
- Department of Oncology, Tianjin Union Medical Center, Tianjin 300000, China
| | - Cheng-Cheng Zheng
- Department of Oncology, Tianjin Union Medical Center, Tianjin 300000, China
| | - Rui-Xue Cui
- Department of Oncology, Tianjin Union Medical Center, Tianjin 300000, China
| | - Qian-Ye Wang
- Department of Oncology, Tianjin Union Medical Center, Tianjin 300000, China
| | - Zhen Sun
- Department of Oncology, Tianjin Union Medical Center, Tianjin 300000, China
| | - Feng-Wei Wang
- Department of Oncology, Tianjin Union Medical Center, Tianjin 300000, China
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Davoodvandi A, Farshadi M, Zare N, Akhlagh SA, Alipour Nosrani E, Mahjoubin-Tehran M, Kangari P, Sharafi SM, Khan H, Aschner M, Baniebrahimi G, Mirzaei H. Antimetastatic Effects of Curcumin in Oral and Gastrointestinal Cancers. Front Pharmacol 2021; 12:668567. [PMID: 34456716 PMCID: PMC8386020 DOI: 10.3389/fphar.2021.668567] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 07/05/2021] [Indexed: 12/17/2022] Open
Abstract
Gastrointestinal (GI) cancers are known as frequently occurred solid malignant tumors that can cause the high rate mortality in the world. Metastasis is a significant destructive feature of tumoral cells, which directly correlates with decreased prognosis and survival. Curcumin, which is found in turmeric, has been identified as a potent therapeutic natural bioactive compound (Curcuma longa). It has been traditionally applied for centuries to treat different diseases, and it has shown efficacy for its anticancer properties. Numerous studies have revealed that curcumin inhibits migration and metastasis of GI cancer cells by modulating various genes and proteins, i.e., growth factors, inflammatory cytokines and their receptors, different types of enzymes, caspases, cell adhesion molecules, and cell cycle proteins. Herein, we summarized the antimetastatic effects of curcumin in GI cancers, including pancreatic cancer, gastric cancer, colorectal cancer, oral cancer, and esophageal cancer.
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Affiliation(s)
- Amirhossein Davoodvandi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | | | - Noushid Zare
- Faculty of Pharmacy, International Campus, Tehran University of Medical Science, Tehran, Iran
| | | | - Esmail Alipour Nosrani
- Department of Nutrition, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Maryam Mahjoubin-Tehran
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parisa Kangari
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyedeh Maryam Sharafi
- Environment Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Ghazaleh Baniebrahimi
- Department of Pediatric Dentistry, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Kagohara LT, Zamuner F, Davis-Marcisak EF, Sharma G, Considine M, Allen J, Yegnasubramanian S, Gaykalova DA, Fertig EJ. Integrated single-cell and bulk gene expression and ATAC-seq reveals heterogeneity and early changes in pathways associated with resistance to cetuximab in HNSCC-sensitive cell lines. Br J Cancer 2020; 123:101-113. [PMID: 32362655 PMCID: PMC7341752 DOI: 10.1038/s41416-020-0851-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 03/19/2020] [Accepted: 04/01/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Identifying potential resistance mechanisms while tumour cells still respond to therapy is critical to delay acquired resistance. METHODS We generated the first comprehensive multi-omics, bulk and single-cell data in sensitive head and neck squamous cell carcinoma (HNSCC) cells to identify immediate responses to cetuximab. Two pathways potentially associated with resistance were focus of the study: regulation of receptor tyrosine kinases by TFAP2A transcription factor, and epithelial-to-mesenchymal transition (EMT). RESULTS Single-cell RNA-seq demonstrates heterogeneity, with cell-specific TFAP2A and VIM expression profiles in response to treatment and also with global changes to various signalling pathways. RNA-seq and ATAC-seq reveal global changes within 5 days of therapy, suggesting early onset of mechanisms of resistance; and corroborates cell line heterogeneity, with different TFAP2A targets or EMT markers affected by therapy. Lack of TFAP2A expression is associated with HNSCC decreased growth, with cetuximab and JQ1 increasing the inhibitory effect. Regarding the EMT process, short-term cetuximab therapy has the strongest effect on inhibiting migration. TFAP2A silencing does not affect cell migration, supporting an independent role for both mechanisms in resistance. CONCLUSION Overall, we show that immediate adaptive transcriptional and epigenetic changes induced by cetuximab are heterogeneous and cell type dependent; and independent mechanisms of resistance arise while tumour cells are still sensitive to therapy.
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Affiliation(s)
- Luciane T Kagohara
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University - School of Medicine, Baltimore, MD, USA.
| | - Fernando Zamuner
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University - School of Medicine, Baltimore, MD, USA
| | - Emily F Davis-Marcisak
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University - School of Medicine, Baltimore, MD, USA
- McKusick-Nathans Institute of the Department of Genetic Medicine, Johns Hopkins University - School of Medicine, Baltimore, MD, USA
| | - Gaurav Sharma
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University - School of Medicine, Baltimore, MD, USA
| | - Michael Considine
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University - School of Medicine, Baltimore, MD, USA
| | - Jawara Allen
- Department of Medicine, Johns Hopkins University - School of Medicine, Baltimore, MD, USA
| | - Srinivasan Yegnasubramanian
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University - School of Medicine, Baltimore, MD, USA
| | - Daria A Gaykalova
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University - School of Medicine, Baltimore, MD, USA
| | - Elana J Fertig
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University - School of Medicine, Baltimore, MD, USA
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Differences of tumor-recruiting myeloid cells in murine squamous cell carcinoma influence the efficacy of immunotherapy combined with a TLR7 agonist and PD-L1 blockade. Oral Oncol 2019; 91:21-28. [PMID: 30926058 DOI: 10.1016/j.oraloncology.2019.02.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 02/07/2019] [Accepted: 02/14/2019] [Indexed: 01/25/2023]
Abstract
OBJECTIVES The immune status of the tumor microenvironment has a marked impact on clinical outcomes. Here we examined the immune environments of tumor-infiltrating leukocytes (TILes) in two murine models of squamous cell carcinoma and compared the effects of immunotherapeutic agents, including a TLR7 agonist and an immune checkpoint inhibitor, and a chemotherapeutic agent, gemcitabine, in these models. MATERIALS AND METHODS TILes from NR-S1- and SCCVII-grafted mice were analyzed by flow cytometry. NR-S1-inoculated mice received resiquimod (a synthetic TLR7 agonist), an anti-PD-L1 antibody, or both, and tumor growth and TILs were examined. Gemcitabine was administered to deplete CD11b+ cells. RESULTS More than 50% of TILes from NR-S1- and SCCVII-inoculated mice were CD11b+Gr-1+ cells. A major fraction of NR-S1 CD11b+ cells was Ly6GhighLy6Clow-negaF4/80- tumor-associated neutrophils (TANs) and the majority of SCCVII CD11b+ cells were Ly6GlowLy6C-F4/80+ tumor-associated macrophages. NR-S1 TANs did not express MHC class II and CD86, but did express reactive oxygen species and PD-L1. Resiquimod, alone and in combination with an anti-PD-L1 antibody, did not regress NR-S1 tumors, but the combination increased the CD8/regulatory T cell-ratio, and IFN-γ and PD-1 expression in CD8+ TILes. Pre-administration of low-dose gemcitabine prior to the combination treatment suppressed the progression of NR-S1 tumors. CONCLUSIONS NR-S1 tumors with abundant recruitment of TANs were resistant to treatments with a TLR7 agonist, alone and in combination with PD-1 blockade, and required an additional gemcitabine treatment. The phenotype and status of tumor-infiltrating CD11b+ myeloid cells may influence the efficacy of immunotherapeutic agents.
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Campos-Parra AD, López-Urrutia E, Orozco Moreno LT, López-Camarillo C, Meza-Menchaca T, Figueroa González G, Bustamante Montes LP, Pérez-Plasencia C. Long Non-Coding RNAs as New Master Regulators of Resistance to Systemic Treatments in Breast Cancer. Int J Mol Sci 2018; 19:2711. [PMID: 30208633 PMCID: PMC6164317 DOI: 10.3390/ijms19092711] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 08/30/2018] [Accepted: 09/04/2018] [Indexed: 12/28/2022] Open
Abstract
Predicting response to systemic treatments in breast cancer (BC) patients is an urgent, yet still unattained health aim. Easily detectable molecules such as long non-coding RNAs (lncRNAs) are the ideal biomarkers when they act as master regulators of many resistance mechanisms, or of mechanisms that are common to more than one treatment. These kinds of markers are pivotal in quasi-personalized treatment selection, and consequently, in improvement of outcome prediction. In order to provide a better approach to understanding development of disease and resistance to treatments, we reviewed current literature searching for lncRNA-associated systemic BC treatments including endocrine therapies, aromatase inhibitors, selective estrogen receptor modulators (SERMs), trastuzumab, paclitaxel, docetaxel, 5-fluorouracil (5-FU), anthracyclines, and cisplatin. We found that the engagement of lncRNAs in resistance is well described, and that lncRNAs such as urotelial carcinoma-associated 1 (UCA1) and regulator of reprogramming (ROR) are indeed involved in multiple resistance mechanisms, which offers tantalizing perspectives for wide usage of lncRNAs as treatment resistance biomarkers. Thus, we propose this work as the foundation for a wide landscape of functions and mechanisms that link more lncRNAs to resistance to current and new treatments in years of research to come.
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Affiliation(s)
- Alma D Campos-Parra
- Laboratorio de Genómica, Instituto Nacional de Cancerología (INCan), Av. San Fernando 22, Col. Sección XVI, Tlalpan, C.P. 14080 Ciudad de México, Mexico.
| | - Eduardo López-Urrutia
- Unidad de Biomedicina, FES-IZTACALA, Universidad Nacional Autónoma de México (UNAM), Av. De Los Barrios 1. Col. Los Reyes Iztacala, C.P. 54090 Tlalnepantla, Mexico.
| | - Luz Tonantzin Orozco Moreno
- Laboratorio de Genómica, Instituto Nacional de Cancerología (INCan), Av. San Fernando 22, Col. Sección XVI, Tlalpan, C.P. 14080 Ciudad de México, Mexico.
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, San Lorenzo 290, Del Valle Sur, Benito Juárez, C.P. 03100 Ciudad de México, Mexico.
| | - Thuluz Meza-Menchaca
- Laboratorio de Genómica Humana, Facultad de Medicina, Universidad Veracruzana (UV), Médicos, Unidad del Bosque, Xalapa, C.P. 91010 Veracruz, Mexico.
| | - Gabriela Figueroa González
- Laboratorio de Genómica, Instituto Nacional de Cancerología (INCan), Av. San Fernando 22, Col. Sección XVI, Tlalpan, C.P. 14080 Ciudad de México, Mexico.
| | - Lilia P Bustamante Montes
- Decanato. Ciencias de la salud. Universidad Autónoma de Guadalajara. Av. Patria 1201, Col. Lomas del Valle, C.P. 45129 Zapopan, Mexico.
| | - Carlos Pérez-Plasencia
- Laboratorio de Genómica, Instituto Nacional de Cancerología (INCan), Av. San Fernando 22, Col. Sección XVI, Tlalpan, C.P. 14080 Ciudad de México, Mexico.
- Unidad de Biomedicina, FES-IZTACALA, Universidad Nacional Autónoma de México (UNAM), Av. De Los Barrios 1. Col. Los Reyes Iztacala, C.P. 54090 Tlalnepantla, Mexico.
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Corraliza-Gorjón I, Somovilla-Crespo B, Santamaria S, Garcia-Sanz JA, Kremer L. New Strategies Using Antibody Combinations to Increase Cancer Treatment Effectiveness. Front Immunol 2017; 8:1804. [PMID: 29312320 PMCID: PMC5742572 DOI: 10.3389/fimmu.2017.01804] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 11/30/2017] [Indexed: 12/14/2022] Open
Abstract
Antibodies have proven their high value in antitumor therapy over the last two decades. They are currently being used as the first-choice to treat some of the most frequent metastatic cancers, like HER2+ breast cancers or colorectal cancers, currently treated with trastuzumab (Herceptin) and bevacizumab (Avastin), respectively. The impressive therapeutic success of antibodies inhibiting immune checkpoints has extended the use of therapeutic antibodies to previously unanticipated tumor types. These anti-immune checkpoint antibodies allowed the cure of patients devoid of other therapeutic options, through the recovery of the patient’s own immune response against the tumor. In this review, we describe how the antibody-based therapies will evolve, including the use of antibodies in combinations, their main characteristics, advantages, and how they could contribute to significantly increase the chances of success in cancer therapy. Indeed, novel combinations will consist of mixtures of antibodies against either different epitopes of the same molecule or different targets on the same tumor cell; bispecific or multispecific antibodies able of simultaneously binding tumor cells, immune cells or extracellular molecules; immunomodulatory antibodies; antibody-based molecules, including fusion proteins between a ligand or a receptor domain and the IgG Fab or Fc fragments; autologous or heterologous cells; and different formats of vaccines. Through complementary mechanisms of action, these combinations could contribute to elude the current limitations of a single antibody which recognizes only one particular epitope. These combinations may allow the simultaneous attack of the cancer cells by using the help of the own immune cells and exerting wider therapeutic effects, based on a more specific, fast, and robust response, trying to mimic the action of the immune system.
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Affiliation(s)
- Isabel Corraliza-Gorjón
- Department of Immunology and Oncology, Centro Nacional de Biotecnologia (CNB-CSIC), Madrid, Spain
| | - Beatriz Somovilla-Crespo
- Department of Immunology and Oncology, Centro Nacional de Biotecnologia (CNB-CSIC), Madrid, Spain
| | - Silvia Santamaria
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biologicas (CIB-CSIC), Madrid, Spain
| | - Jose A Garcia-Sanz
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biologicas (CIB-CSIC), Madrid, Spain
| | - Leonor Kremer
- Department of Immunology and Oncology, Centro Nacional de Biotecnologia (CNB-CSIC), Madrid, Spain
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Feng F, Wang B, Sun X, Zhu Y, Tang H, Nan G, Wang L, Wu B, Huhe M, Liu S, Diao T, Hou R, Zhang Y, Zhang Z. Metuzumab enhanced chemosensitivity and apoptosis in non-small cell lung carcinoma. Cancer Biol Ther 2017; 18:51-62. [PMID: 28055291 PMCID: PMC5323017 DOI: 10.1080/15384047.2016.1276126] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Targeted therapeutics is used as an alternative treatment of non-small cell lung cancer (NSCLC); however, treatment effect is far from being satisfactory, and therefore identification of new targets is needed. We have previously shown that metuzumab inhibit tumor growth in vivo. The present study was performed to investigate the anti-tumor efficacy of metuzumab combined with gemcitabine and cisplatin (GP), paclitaxel and cisplatin (TP) or navelbine and cisplatin (NP) regimens in multiple NSCLC cell lines. Our results demonstrate that, in comparison to single agent metuzumab or GP treated cells, metuzumab combined with GP display inhibitory effects on tumor growth. Furthermore, we found that metuzumab elevated the sensitivity of cell lines to gemcitabine, which was identified by MTT assay. Flow cytometric analysis showed that metuzumab combined with gemcitabine (GEM) treatment led to an obvious G1 arrest and an elevated apoptosis in A549, NCI-H460 and NCI-H520 cells. Western blot analysis also demonstrated a significantly reduced level of cyclin D1, Bcl-2, and an obviously increase level of Bax and full-length caspase-3 in A549, NCI-H460 and NCI-H520 cells treated with metuzumab/gemcitabine combination in comparison with single agent treated cells. In addition, metuzumab/gemcitabine treated A549, NCI-H460 and NCI-H520 cells also demonstrated a significantly increase in deoxycytidine kinase (dCK) protein level compared with single agent metuzumab or gemcitabine treated cells. Xenograft models also demonstrated that this metuzumab/gemcitabine combination led to upregulation of dCK. Taken together, the mechanisms of metuzumab combined with GP repress tumor growth were that the combined treatment significantly inhibited the tumor cell proliferation, apoptosis and cell cycle in vitro and in vivo and at least partially by induction of dCK expression. Our results suggested that metuzumab could significantly enhance chemosensitivity of human NSCLC cells to gemcitabine. Metuzumab/gemcitabine combination treatment may be a potentially useful therapeutic regimen for NSCLC patients.
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Affiliation(s)
- Fei Feng
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Bin Wang
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Xiuxuan Sun
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Yumeng Zhu
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Hao Tang
- b Pacific Meinuoke Biopharmaceutical Company , Changzhou , P.R. China
| | - Gang Nan
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Lijuan Wang
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Bo Wu
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Muren Huhe
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Shuangshuang Liu
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Tengyue Diao
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Rong Hou
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Yang Zhang
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
| | - Zheng Zhang
- a National Translational Science Center for Molecular Medicine , Department of Cell Biology , Fourth Military Medical University , Xi'an , P.R. China
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9
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EGFR-targeted micelles containing near-infrared dye for enhanced photothermal therapy in colorectal cancer. J Control Release 2017; 258:196-207. [DOI: 10.1016/j.jconrel.2017.04.031] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 02/08/2017] [Accepted: 04/22/2017] [Indexed: 02/06/2023]
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10
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Vesci L, Milazzo FM, Anastasi AM, Petronzelli F, Chiapparino C, Carollo V, Roscilli G, Marra E, Luberto L, Aurisicchio L, Pacello ML, Spagnoli LG, De Santis R. Intra-tumor AvidinOX allows efficacy of low dose systemic biotinylated Cetuximab in a model of head and neck cancer. Oncotarget 2016; 7:914-28. [PMID: 26575422 PMCID: PMC4808042 DOI: 10.18632/oncotarget.6089] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 10/26/2015] [Indexed: 12/15/2022] Open
Abstract
For locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC), the current clinical use of Cetuximab in chemo/radiotherapy protocols is often associated to severe systemic toxicity. Here we report in vitro data in human FaDu pharynx SCC cells, showing that inactive concentrations of biotinylated Cetuximab (bCet) become active upon anchorage to AvidinOX on the surface of tumor cells. AvidinOX-anchored bCet induces apoptosis and DNA damage as well as specific inhibition of signaling, degradation and abrogation of nuclear translocation of EGFR. In the mouse model of FaDu cancer, we show that intra-tumor injection of AvidinOX allows anti-tumor activity of an otherwise inactive, intraperitoneally delivered, low dose bCet. Consistently with in vitro data, in vivo tumor inhibition is associated to induction of apoptosis, DNA damage and reduced angiogenesis. AvidinOX is under clinical investigation for delivering radioactive biotin to inoperable tumors (ClinicalTrials.gov NCT02053324) and present data support its use for the local treatment of HNSCC in combination with systemic administration of low dose bCet.
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Affiliation(s)
- Loredana Vesci
- Biotechnology, Research & Development, Sigma-Tau SpA, 00071 Pomezia, Rome, Italy
| | | | - Anna Maria Anastasi
- Biotechnology, Research & Development, Sigma-Tau SpA, 00071 Pomezia, Rome, Italy
| | - Fiorella Petronzelli
- Biotechnology, Research & Development, Sigma-Tau SpA, 00071 Pomezia, Rome, Italy
| | - Caterina Chiapparino
- Biotechnology, Research & Development, Sigma-Tau SpA, 00071 Pomezia, Rome, Italy
| | - Valeria Carollo
- Tissue Macro Array Lab, University of Tor Vergata, via della Ricerca Scientifica, 00133, Rome, Italy
| | | | | | | | | | | | - Luigi Giusto Spagnoli
- Tissue Macro Array Lab, University of Tor Vergata, via della Ricerca Scientifica, 00133, Rome, Italy
| | - Rita De Santis
- Biotechnology, Research & Development, Sigma-Tau SpA, 00071 Pomezia, Rome, Italy
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11
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111In-cetuximab as a diagnostic agent by accessible epidermal growth factor (EGF) receptor targeting in human metastatic colorectal carcinoma. Oncotarget 2016; 6:16601-10. [PMID: 26062654 PMCID: PMC4599292 DOI: 10.18632/oncotarget.3968] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 04/30/2015] [Indexed: 02/07/2023] Open
Abstract
Colorectal adenocarcinoma is a common cause death cancer in the whole world. The aim of this study is to define the 111In-cetuximab as a diagnosis tracer of human colorectal adenocarcinoma. In this research, cell uptake, nano-SPECT/CT scintigraphy, autoradiography, biodistribution and immunohitochemical staining of EGF receptor were included. HCT-116 and HT-29 cell expressed a relatively high and moderate level of EGF receptor, respectively. The nano-SPECT/CT image of 111In-cetuximab showed tumor radiation uptake of subcutaneous HCT-116 xenograft tumor was higher than SW-620. Autoradiography image also showed that tumor of HCT-116 had high 111In-cetuximab uptake. Mice that bearing CT-26 in situ xenograft colorectal tumors showed similar high uptake in vivo and ex vivo through nano-SPECT/CT imaging at 72 hours. Metastatic HCT-116/Luc tumors demonstrated the highest uptake at 72 hours after the injection of 111In-cetuximab. Relatively, results of 111In-DTPA showed that metabolism through urinary system, especially in the kidney. The quantitative analysis of biodistribution showed count value of metastatic HCT-116/Luc tumors that treated with 111In-cetuximab had a significant difference (P < 0.05) compared with that treated with 111In-DTPA after injection 72 hours. Result of immunohistologic staining of EGF receptor also showed high EGF receptor expression and uptake in metastatic colorectal tumors. In summary, we suggested that 111In-cetuximab will be a potential tool for detecting EGF receptor expression in human metastatic colorectal carcinoma.
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12
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Wang Y, Lei F, Rong W, Zeng Q, Sun W. Positive feedback between oncogenic KRAS and HIF-1α confers drug resistance in colorectal cancer. Onco Targets Ther 2015; 8:1229-37. [PMID: 26060408 PMCID: PMC4454194 DOI: 10.2147/ott.s80017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Approximately 30%-50% of colorectal cancers (CRCs) harbor the somatic mutated KRAS gene. KRAS G12V, one of the most common KRAS mutations in CRCs, is linked to increased tumor aggressiveness, less response to anti-epidermal growth factor receptor (EGFR) therapy, and poor survival rate. In this study, we sought to determine whether resistance to EGFR inhibitors in colorectal cancer cells harboring KRAS G12V mutation is associated with hypoxia. Our data indicated that HIF-1α was induced by KRAS G12V signaling at transcription level. Hypoxia or HIF-1α overexpression could increase KRAS G12V activity. Therefore, a positive feedback between hypoxia and KRAS G12V activation was formed. Cetuximab, an EGFR inhibitor, which has a minor effect on KRAS-mutant CRCs, could effectively inhibit the proliferation of CRC cells harboring KRAS G12V mutation when combined with HIF-1α inhibitor PX-478. Our data indicated that hypoxia was involved in resistance to anti-EGFR therapy, and a combination therapy might be necessary for CRC patients with KRAS mutation.
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Affiliation(s)
- Yanzhao Wang
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Fuming Lei
- Department of General Surgery, Peking University Shougang Hospital, Beijing, People's Republic of China
| | - Wanshui Rong
- Department of General Surgery, Peking University Shougang Hospital, Beijing, People's Republic of China
| | - Qingmin Zeng
- Department of General Surgery, Peking University Shougang Hospital, Beijing, People's Republic of China
| | - Wenbing Sun
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People's Republic of China
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13
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Zhen L, Fan D, Yi X, Cao X, Chen D, Wang L. Curcumin inhibits oral squamous cell carcinoma proliferation and invasion via EGFR signaling pathways. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2014; 7:6438-6446. [PMID: 25400722 PMCID: PMC4230161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 09/01/2014] [Indexed: 06/04/2023]
Abstract
Epidermal growth factor receptor (EGFR) is an effective molecular target of anti-cancer therapies. Curcumin is known to inhibit growth, invasion and metastasis by downregulating EGFR expression in some cancer cells. However, the mechanism underlying the effect of curcumin in human oral squamous cell carcinoma (OSCC) remains unclear. In this study, we investigated the efficacy of curcumin on proliferation and invasion in SCC-25 cell line. We also explored the effect of curcumin on the activition of EGFR and its downstream signaling molecules Akt, ERK1/2 and STAT3. Furthermore, we examined the inhibition effect of curcumin on EGF-induced EGFR phosphorylation and SCC-25 cells invasion. Our results showed that curcumin inhibited SCC-25 cells proliferation and induced G2/M phase arrest in a dose-dependent manner. Curcumin also inhibited SCC-25 cells invasion and downregulated MMP-2, MMP-9, uPA and uPAR expression. We further revealed that curcumin regulated the p-EGFR and EGFR downstream signaling molecules including Akt, ERK1/2 and STAT3. Finally, our data showed that crucumin reduced the EGF-induced phosphorylation of EGFR and suppressed EGF-triggered SCC-25 cells invasion. Taken together, our results suggest that curcumin reduced SCC-25 cells proliferation and invasion through inhibiting the phosphorylation of EGFR and EGFR downstream signaling molecules Akt, ERK1/2 and STAT3.
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Affiliation(s)
- Lei Zhen
- Department of Periodontology, Shanghai Stomatological Disease CenterShanghai 200001, China
| | - Desheng Fan
- Department of Pathology, Shanghai Tongji Hospital, Tongji UniversityShanghai 200065, China
| | - Xianghua Yi
- Department of Pathology, Shanghai Tongji Hospital, Tongji UniversityShanghai 200065, China
| | - Xinming Cao
- Department of Periodontology, Shanghai Stomatological Disease CenterShanghai 200001, China
| | - Dong Chen
- Department of Periodontology, Shanghai Stomatological Disease CenterShanghai 200001, China
| | - Liming Wang
- Department of Periodontology, Shanghai Stomatological Disease CenterShanghai 200001, China
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14
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Qian M, Qian D, Jing H, Li Y, Ma C, Zhou Y. Combined cetuximab and celecoxib treatment exhibits a synergistic anticancer effect on human oral squamous cell carcinoma in vitro and in vivo. Oncol Rep 2014; 32:1681-1688. [PMID: 25198789 DOI: 10.3892/or.2014.3334] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Accepted: 05/19/2014] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to evaluate the potency of epidermal growth factor receptor (EGFR) pathway inhibition achieved by combining cetuximab (CET), an anti-EGFR monoclonal antibody, and celecoxib (CXB), a cyclooxygenase-2 (COX-2) inhibitor, in oral squamous cell carcinoma (OSCC) in vitro and in vivo. The OSCC cell line, HSC3, was treated with CET (0-400 µg/ml), CXB (0-40 µM), or a combination of both at a range of concentrations. Cell proliferation, apoptosis, migration and invasion were determined to assess the anticancer effects in vitro. The in vivo effects of CET and CXB on tumor cell growth were examined using an OSCC xenograft nude mouse model. In addition, downstream protein expression levels of EGFR, p-EGFR, PI3K, p-PI3K, AKT and p-Akt were evaluated by western blot analysis. It was found that the combination of low concentrations of CET and CXB significantly suppressed the proliferation, migration and invasion of the HSC3 tumor cells and decreased PEG2 production and VEGF expression in vitro, and inhibited tumor growth in vivo compared to the action of either agent alone. The results also showed that this combination significantly induced apoptosis and increased caspase-3 and caspase-8 activity compared to the action of either agent alone (P<0.01). Furthermore, the combination treatment significantly reduced the expression of p-EGFR, p-PI3K and p-Akt in the HSC3 cell line, which may contribute to the inhibition of tumor growth. Taken together, our findings revealed that the additive combination of CET and CXB is a potential drug candidate for the treatment of OSCC.
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Affiliation(s)
- Ming Qian
- Prosthodontics Department of the Stomatological Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Donghua Qian
- Department of Respiration, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Hongyu Jing
- Department of Respiration, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yang Li
- Department of Respiration, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Chengyuan Ma
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yanmin Zhou
- Implantology Department of the Stomatological Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
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