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1
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Liu Y, Liu HG, Zhao C. Intraperitoneal perfusion of endostatin improves the effectiveness and prolongs the prognosis of patients with gastric cancer. World J Gastrointest Oncol 2025; 17:103131. [DOI: 10.4251/wjgo.v17.i4.103131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 01/02/2025] [Accepted: 02/18/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Studies on the application of recombinant human endostatin (RH-endostatin) intraperitoneal perfusion in gastric cancer (GC) with malignant ascites are limited.
AIM To explore the effectiveness, prognosis, and safety of intraperitoneal RH-endostatin perfusion in treating patients with GC and malignant ascites.
METHODS Patients with GC and malignant ascites were divided into the cisplatin intraperitoneal perfusion (control group) group and the cisplatin combined with RH-endostatin intraperitoneal perfusion group (RH-endostatin group). Efficient ascites control, overall survival (OS), quality of life, and adverse events were observed, and possible influencing factors on prognosis outcomes analyzed.
RESULTS We identified no significant differences in baseline characteristics between the control and RH-endostatin groups. The latter group had higher ascites control rates than the control group. Treatment methods were identified as an independent OS factor. Clinically, RH-endostatin-treated patients had significantly improved OS rates when compared with control patients, particularly in those with small and moderate ascites volumes. Quality of life improvements in control patients were significantly lower when compared with RH-endostatin patients. Adverse events were balanced between the groups.
CONCLUSION Overall, intraperitoneal RH-endostatin improved treatment efficacy and prolonged prognosis in patients with GC and malignant ascites. This approach may benefit further clinical applications for treating GC.
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Affiliation(s)
- Yong Liu
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300000, China
- Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300000, China
- Tianjin Key Laboratory of Digestive Cancer, Tianjin Clinical Research Center for Cancer, Tianjin 300000, China
| | - Hong-Gen Liu
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300000, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin Cancer Institute of Traditional Chinese Medicine, Tianjin 300380, China
| | - Cheng Zhao
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300000, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin Cancer Institute of Traditional Chinese Medicine, Tianjin 300380, China
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Uciechowska-Kaczmarzyk U, Frank M, Samsonov SA, Maszota-Zieleniak M. Structural Insights into Endostatin-Heparan Sulfate Interactions Using Modeling Approaches. Molecules 2024; 29:4040. [PMID: 39274888 PMCID: PMC11397277 DOI: 10.3390/molecules29174040] [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: 07/19/2024] [Revised: 08/19/2024] [Accepted: 08/22/2024] [Indexed: 09/16/2024] Open
Abstract
Glycosaminoglycans (GAGs) play a key role in a variety of biological processes in the extracellular matrix (ECM) via interactions with their protein targets. Due to their high flexibility, periodicity and electrostatics-driven interactions, GAG-containing complexes are very challenging to characterize both experimentally and in silico. In this study, we, for the first time, systematically analyzed the interactions of endostatin, a proteolytic fragment of collagen XVIII known to be anti-angiogenic and anti-tumoral, with heparin (HP) and representative heparan sulfate (HS) oligosaccharides of various lengths, sequences and sulfation patterns. We first used conventional molecular docking and a docking approach based on a repulsive scaling-replica exchange molecular dynamics technique, as well as unbiased molecular dynamic simulations, to obtain dynamically stable GAG binding poses. Then, the corresponding free energies of binding were calculated and the amino acid residues that contribute the most to GAG binding were identified. We also investigated the potential influence of Zn2+ on endostatin-HP complexes using computational approaches. These data provide new atomistic details of the molecular mechanism of HP's binding to endostatin, which will contribute to a better understanding of its interplay with proteoglycans at the cell surface and in the extracellular matrix.
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Affiliation(s)
- Urszula Uciechowska-Kaczmarzyk
- Laboratory of Molecular Modeling, Department of Theoretical Chemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdańsk, Poland; (U.U.-K.); (S.A.S.)
| | - Martin Frank
- Biognos AB, P.O. Box 8963, 40274 Göteborg, Sweden;
| | - Sergey A. Samsonov
- Laboratory of Molecular Modeling, Department of Theoretical Chemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdańsk, Poland; (U.U.-K.); (S.A.S.)
| | - Martyna Maszota-Zieleniak
- Laboratory of Molecular Modeling, Department of Theoretical Chemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdańsk, Poland; (U.U.-K.); (S.A.S.)
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Kang Q, He L, Zhang Y, Zhong Z, Tan W. Immune-inflammatory modulation by natural products derived from edible and medicinal herbs used in Chinese classical prescriptions. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 130:155684. [PMID: 38788391 DOI: 10.1016/j.phymed.2024.155684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/29/2024] [Accepted: 04/24/2024] [Indexed: 05/26/2024]
Abstract
BACKGROUND Edible and medicinal herbs1 (EMHs) refer to a class of substances with dual attribution of food and medicine. These substances are traditionally used as food and also listed in many international pharmacopoeias, including the European Pharmacopoeia, the United States Pharmacopoeia, and the Chinese Pharmacopoeia. Some classical formulas that are widely used in traditional Chinese medicine include a series of EMHs, which have been shown to be effective with obvious characteristics and advantages. Notably, these EMHs and Chinese classical prescriptions2 (CCPs) have also attracted attention in international herbal medicine research because of their low toxicity and high efficiency as well as the rich body of experience for their long-term clinical use. PURPOSE Our purpose is to explore the potential therapeutic effect of EMHs with immune-inflammatory modulation for the study of modern cancer drugs. STUDY DESIGN In the present study, we present a detailed account of some EMHs used in CCPs that have shown considerable research potential in studies exploring modern drugs with immune-inflammatory modulation. METHODS Approximately 500 publications in the past 30 years were collected from PubMed, Web of Science and ScienceDirect using the keywords, such as natural products, edible and medicinal herbs, Chinese medicine, classical prescription, immune-inflammatory, tumor microenvironment and some related synonyms. The active ingredients instead of herbal extracts or botanical mixtures were focused on and the research conducted over the past decade were discussed emphatically and analyzed comprehensively. RESULTS More than ten natural products derived from EMHs used in CCPs are discussed and their immune-inflammatory modulation activities, including enhancing antitumor immunity, regulating inflammatory signaling pathways, lowering the proportion of immunosuppressive cells, inhibiting the secretion of proinflammatory cytokines, immunosuppressive factors, and inflammatory mediators, are summarized. CONCLUSION Our findings demonstrate the immune-inflammatory modulating role of those EMHs used in CCPs and provide new ideas for cancer treatment in clinical settings.
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Affiliation(s)
- Qianming Kang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Luying He
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Yang Zhang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Zhangfeng Zhong
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China.
| | - Wen Tan
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
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Liu X, Guo Z, Su L, Zuo A, Gao M, Ji X, Lu J, Yang S, Jiang Y, Lu D. The efficacy and safety of continuous intravenous infusion of rh-endostatin combined with platinum-based doublet chemotherapy for advanced non-small-cell lung cancer. Invest New Drugs 2024; 42:309-317. [PMID: 38700579 PMCID: PMC11164818 DOI: 10.1007/s10637-024-01439-x] [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: 04/02/2024] [Accepted: 04/19/2024] [Indexed: 06/11/2024]
Abstract
BACKGROUND Platinum-based doublet chemotherapy is commonly used in the treatment of non-small cell lung cancer (NSCLC). A growing body of evidence indicates that incorporating antiangiogenic agents into platinum-based chemotherapy may enhance the survival outcomes for NSCLC patients. However, the optimal administration protocol for intravenous recombinant human endostatin (rh-endostatin), an antiangiogenic agent, remains uncertain at present. AIM This study aims to investigate the efficacy and safety of 5-d continuous intravenous infusion of rh-endostatin in combination with chemotherapy for patients with advanced NSCLC. The predictive biomarkers for this treatment regimen were further probed. METHODS This prospective, single-arm multicenter study enrolled a total of 48 patients with advanced NSCLC who were histologically or cytologically confirmed but had not received any prior treatment from January 2021 to December 2022. Prior to the chemotherapy, these patients received a continuous intravenous infusion of rh-endostatin (210 mg) over a period of 120 h, using an infusion pump. The chemotherapy regimen included a combination of platinum with either pemetrexed or paclitaxel, given in 21-day cycles. The primary endpoint of the study was median progression-free survival (mPFS), and the secondary endpoints included median overall survival (mOS), objective response rate (ORR), disease control rate (DCR), and assessment of adverse events (AEs). RESULTS The mPFS was 6.5 months (95% confidence interval (CI): 3.8-9.1 m) while the mOS was 12.3 months (95% CI: 7.6-18.5 m). The ORR and DCR was 52.1% and 75.0%, respectively. Leukopenia (52.1%), anemia (33.3%), and thrombocytopenia (20.8%) were the most common adverse effects and these toxicities were deemed acceptable and manageable. In addition, a correlation was noted between elevated serum carcinoembryonic antigen (CEA) levels and decreased PFS and OS. CONCLUSIONS The incorporation of a 5-day continuous intravenous infusion of rh-endostatin into platinum-based doublet chemotherapy has demonstrated both safety and efficacy in the treatment of advanced NSCLC. Furthermore, the baseline serum levels of CEA may potentially function as a predictor for the efficacy of rh-endostatin when combined with chemotherapy in NSCLC patients. CLINICALTRIALS GOV: NCT05574998.
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Affiliation(s)
- Xinyi Liu
- Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Institute of Anesthesia and Respiratory Critical Medicine, The First Affiliated Hospital of Shandong First Medical University, 250014, Jinan, Shandong, P.R. China
| | - Zihan Guo
- Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Institute of Anesthesia and Respiratory Critical Medicine, The First Affiliated Hospital of Shandong First Medical University, 250014, Jinan, Shandong, P.R. China
| | - Lin Su
- Department of Respiratory, Jinan Fourth People's Hospital, 250000, Jinan, Shandong, P.R. China
| | - Anli Zuo
- Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Institute of Anesthesia and Respiratory Critical Medicine, The First Affiliated Hospital of Shandong First Medical University, 250014, Jinan, Shandong, P.R. China
| | - Min Gao
- Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Institute of Anesthesia and Respiratory Critical Medicine, The First Affiliated Hospital of Shandong First Medical University, 250014, Jinan, Shandong, P.R. China
| | - Xiang Ji
- Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Institute of Anesthesia and Respiratory Critical Medicine, The First Affiliated Hospital of Shandong First Medical University, 250014, Jinan, Shandong, P.R. China
| | - Jiameng Lu
- School of Microelectronics, Shandong University, 250100, Jinan, Shandong, China
| | - Shuran Yang
- Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Institute of Anesthesia and Respiratory Critical Medicine, The First Affiliated Hospital of Shandong First Medical University, 250014, Jinan, Shandong, P.R. China
| | - Yunxiu Jiang
- Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Institute of Anesthesia and Respiratory Critical Medicine, The First Affiliated Hospital of Shandong First Medical University, 250014, Jinan, Shandong, P.R. China
| | - Degan Lu
- Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Institute of Anesthesia and Respiratory Critical Medicine, The First Affiliated Hospital of Shandong First Medical University, 250014, Jinan, Shandong, P.R. China.
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Xia C, Zhao J, Huang Y, Miao H, Zhao F. Angiogenesis in nasopharyngeal carcinoma: insights, imaging, and therapeutic strategies. Front Oncol 2024; 14:1331064. [PMID: 38863627 PMCID: PMC11165036 DOI: 10.3389/fonc.2024.1331064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 05/09/2024] [Indexed: 06/13/2024] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a highly prevalent head and neck malignancy in southern China frequently diagnosed at advanced stages owing to subtle early symptoms and associated metastasis. Angiogenesis emerges as a pivotal factor in NPC progression, with numerous angiogenesis-related factors showing aberrant expression and contributing to increased neovascularization within NPC tumors. These abnormal vessels not only nourish tumor growth but also facilitate metastasis, culminating in unfavorable patient outcomes. Multiple studies have demonstrated the applicability of various imaging techniques for assessing angiogenesis in NPC tumors, thus serving as a foundation for personalized treatment strategies and prognostic assessments. Anti-angiogenic therapies have exhibited significant potential for inhibiting NPC angiogenesis and exerting anti-tumor effects. To enhance efficacy, anti-angiogenic drugs are frequently combined with other treatment modalities to synergistically enhance anti-tumor effects while mitigating the side effects associated with single-agent therapies, consequently improving patient prognosis. Identifying the potential mechanisms and key targets underlying NPC angiogenesis and exploring more effective detection and treatment approaches holds promise for shaping the future of NPC diagnosis, treatment, and prognosis, thereby offering new avenues and perspectives for research and clinical practice.
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Affiliation(s)
- Chenxi Xia
- Department of Otolaryngology-Head and Neck Surgery, the Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, Sichuan, China
| | - Jia Zhao
- Department of Otolaryngology-Head and Neck Surgery, the Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, Sichuan, China
| | - Yu Huang
- Department of Otolaryngology-Head and Neck Surgery, Chengdu Second People’s Hospital, Chengdu, Sichuan, China
| | - Hongbin Miao
- Department of Otolaryngology-Head and Neck Surgery, Bishan hospital of Chongqing Medical University, Bishan Hospital of Chongqing, Bishan, Chongqing, China
| | - Feipeng Zhao
- Department of Otolaryngology-Head and Neck Surgery, the Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, Sichuan, China
- Department of Otolaryngology-Head and Neck Surgery, Chengdu Second People’s Hospital, Chengdu, Sichuan, China
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Gao C, Gao C, Yuan Q. A meta-analysis of recombinant human endostatin combined with NP regimen for treating non-small cell lung cancer. Medicine (Baltimore) 2024; 103:e38027. [PMID: 38788043 PMCID: PMC11124762 DOI: 10.1097/md.0000000000038027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 04/05/2024] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND The aim of this study was to evaluate the efficacy and safety of recombinant human endostatin in combination with vinorelbine + cisplatin (NPE) for the treatment of advanced non-small cell lung cancer (NSCLC). METHODS Randomized controlled trials (RCTs) of NPE for advanced NSCLC in PubMed, Cochrane Library, EMBASE, Web of Science, China National Knowledge Infrastructure, and Wanfang databases were searched using a computerized search of the database from the time of creation to May 2023. Two investigators independently extracted literature information and assessed the quality of the included literature. Meta-analysis was performed using RevMan 5.4.0 software. RESULTS A total of 24 RCTs with 2114 patients with advanced NSCLC were finally included. The results of meta-analysis showed that the total effective rate in the group received NPE regimen was significantly higher than those in the group without NPE regimen (RR = 1.70, 95% CI: 1.48-1.95, P < .00001). Meanwhile, the clinical benefit rate in the group received NPE regimen was also significantly higher than those in the group without NPE regimen (RR = 1.22, 95% CI: 1.15-1.29, P < .00001). However, there was no significant difference in the incidence of adverse event rate between the 2 groups (RR = 0.98, 95% CI: 0.76-1.27, P = .88). CONCLUSIONS Compared with NP (vinorelbine + cisplatin) regimens for patients with advanced NSCLC, NPE regimens improve the total effective rate and clinical benefit rate of treatment, but there can be no significant difference in adverse effects. Prospective randomized trials are needed to further validate the safety and efficacy of this treatment modality.
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Affiliation(s)
- Chao Gao
- Department of Oncology, First People’s Hospital of Zaoyang, Zaoyang, Hubei, China
| | - Chaoqian Gao
- Department of Imaging Intervention, First People’s Hospital of Zaoyang, Zaoyang, Hubei, China
| | - Qin Yuan
- Department of Oncology Medicine, Hubei Aerospace Hospital, Xiaogan, Hubei, China
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7
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Sankar AP, Cho HM, Shin SU, Sneh T, Ramakrishnan S, Elledge C, Zhang Y, Das R, Gil-Henn H, Rosenblatt JD. Antibody-Drug Conjugate αEGFR-E-P125A Reduces Triple-negative Breast Cancer Vasculogenic Mimicry, Motility, and Metastasis through Inhibition of EGFR, Integrin, and FAK/STAT3 Signaling. CANCER RESEARCH COMMUNICATIONS 2024; 4:738-756. [PMID: 38315147 PMCID: PMC10926898 DOI: 10.1158/2767-9764.crc-23-0278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 11/14/2023] [Accepted: 01/24/2024] [Indexed: 02/07/2024]
Abstract
Primary tumor growth and metastasis in triple-negative breast cancer (TNBC) require supporting vasculature, which develop through a combination of endothelial angiogenesis and vasculogenic mimicry (VM), a process associated with aggressive metastatic behavior in which vascular-like structures are lined by tumor cells. We developed αEGFR-E-P125A, an antibody-endostatin fusion protein that delivers a dimeric, mutant endostatin (E-P125A) payload that inhibits TNBC angiogenesis and VM in vitro and in vivo. To characterize the mechanisms associated with induction and inhibition of VM, RNA sequencing (RNA-seq) of MDA-MB-231-4175 TNBC cells grown in a monolayer (two-dimensional) was compared with cells plated on Matrigel undergoing VM [three-dimensional (3D)]. We then compared RNA-seq between TNBC cells in 3D and cells in 3D with VM inhibited by αEGFR-E-P125A (EGFR-E-P125A). Gene set enrichment analysis demonstrated that VM induction activated the IL6-JAK-STAT3 and angiogenesis pathways, which were downregulated by αEGFR-E-P125A treatment.Correlative analysis of the phosphoproteome demonstrated decreased EGFR phosphorylation at Y1069, along with decreased phosphorylation of focal adhesion kinase Y397 and STAT3 Y705 sites downstream of α5β1 integrin. Suppression of phosphorylation events downstream of EGFR and α5β1 integrin demonstrated that αEGFR-E-P125A interferes with ligand-receptor activation, inhibits VM, and overcomes oncogenic signaling associated with EGFR and α5β1 integrin cross-talk. In vivo, αEGFR-E-P125A treatment decreased primary tumor growth and VM, reduced lung metastasis, and confirmed the inhibition of signaling events observed in vitro. Simultaneous inhibition of EGFR and α5β1 integrin signaling by αEGFR-E-P125A is a promising strategy for the inhibition of VM, tumor growth, motility, and metastasis in TNBC and other EGFR-overexpressing tumors. SIGNIFICANCE αEGFR-E-P125A reduces VM, angiogenesis, tumor growth, and metastasis by inhibiting EGFR and α5β1 integrin signaling, and is a promising therapeutic agent for TNBC treatment, used alone or in combination with chemotherapy.
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Affiliation(s)
- Ankita P. Sankar
- Department of Medicine, Division of Hematology, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Hyun-Mi Cho
- Department of Medicine, Division of Hematology, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Seung-Uon Shin
- Department of Medicine, Division of Hematology, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Tal Sneh
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Sundaram Ramakrishnan
- Sylvester Comprehensive Cancer Center, Miami, Florida
- Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Christian Elledge
- Department of Medicine, Division of Hematology, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Yu Zhang
- Department of Medicine, Division of Hematology, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Rathin Das
- Synergys Biotherapeutics, Inc., Alamo, California
| | - Hava Gil-Henn
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Joseph D. Rosenblatt
- Department of Medicine, Division of Hematology, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, Miami, Florida
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Tejerina-Miranda S, Pedrero M, Blázquez-García M, Serafín V, Montero-Calle A, Garranzo-Asensio M, Julio Reviejo A, Pingarrón JM, Barderas R, Campuzano S. Angiogenesis inhibitor or aggressiveness marker? The function of endostatin in cancer through electrochemical biosensing. Bioelectrochemistry 2024; 155:108571. [PMID: 37717337 DOI: 10.1016/j.bioelechem.2023.108571] [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: 08/08/2023] [Revised: 09/02/2023] [Accepted: 09/13/2023] [Indexed: 09/19/2023]
Abstract
This work reports the first electrochemical bioplatform developed for the determination of human endostatin (HE), a biomarker with recognized antiangiogenic potential whose elevated circulating levels have also been associated with the development of aggressive cancers. The developed electroanalytical biotool combines the benefits of using magnetic microparticles for the implementation of sandwich immunoassays and amperometric transduction on disposable carbon electrodes. A limit of detection (LOD) of 34.1 pg mL-1 for HE standards and a selectivity suitable for its foray into the clinical oncology area, are demonstrated. The determination of HE in clinical samples such as lysates and secretomes of colorectal cancer (CRC) cells, plasma, and tissue samples from patients with CRC in different stages, has been faced with satisfactory results showing the ability for discriminating the metastatic capabilities of cells and for identifying and staging CRC patients. The developed bioplatform allows precise quantitative determinations, requiring minimal pre-treatments and sample amounts in only 75 min. In addition, due to the instrumentation and the type of substrates used in the detection step, the biotool is compatible with implementation in multiplexed and/or point-of-need devices, features in which this bioplatform is advantageous with respect to the enzyme linked immunosorbent assay (ELISA) or immunoblotting technologies.
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Affiliation(s)
- Sandra Tejerina-Miranda
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, Pza. de las Ciencias 2, 28040 Madrid, Spain
| | - María Pedrero
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, Pza. de las Ciencias 2, 28040 Madrid, Spain
| | - Marina Blázquez-García
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, Pza. de las Ciencias 2, 28040 Madrid, Spain
| | - Verónica Serafín
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, Pza. de las Ciencias 2, 28040 Madrid, Spain
| | - Ana Montero-Calle
- Chronic Disease Programme, UFIEC, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain
| | - Maria Garranzo-Asensio
- Chronic Disease Programme, UFIEC, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain
| | - A Julio Reviejo
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, Pza. de las Ciencias 2, 28040 Madrid, Spain
| | - José M Pingarrón
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, Pza. de las Ciencias 2, 28040 Madrid, Spain
| | - Rodrigo Barderas
- Chronic Disease Programme, UFIEC, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain
| | - Susana Campuzano
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, Pza. de las Ciencias 2, 28040 Madrid, Spain.
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Anakha J, Dobariya P, Sharma SS, Pande AH. Recombinant human endostatin as a potential anti-angiogenic agent: therapeutic perspective and current status. Med Oncol 2023; 41:24. [PMID: 38123873 DOI: 10.1007/s12032-023-02245-w] [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: 08/01/2023] [Accepted: 11/09/2023] [Indexed: 12/23/2023]
Abstract
Angiogenesis is the physiological process that results in the formation of new blood vessels develop from pre-existing vasculature and plays a significant role in several physiological and pathological processes. Inhibiting angiogenesis, a crucial mechanism in the growth and metastasis of cancer, has been proposed as a potential anticancer therapy. Different studies showed the beneficial effects of angiogenesis inhibitors either in patients suffering from different cancers, alone or in combination with conventional therapies. Even though there are currently a number of efficient anti-angiogenic drugs, including monoclonal antibodies and kinase inhibitors, the associated toxicity profile and their affordability constraints are prompting researchers to search for a safe and affordable angiostatic agent for cancer treatment. Endostatin is one of the endogenous anti-angiogenic candidates that have been extensively pursued for the treatment of cancer, but even over three decades after its discovery, we have not made much advancement in employing it as an anticancer therapeutic despite of its remarkable anti-angiogenic effect with low toxicity profile. A recombinant human endostatin (rh-Es) variant for non-small cell lung cancer was approved by China in 2006 and has since been used effectively. Several other successful clinical trials related to endostatin for various malignancies are either ongoing or have already been completed with promising results. Thus, in this review, we have provided an overview of existing anti-angiogenic drugs developed for cancer therapy, with a summary of tumour angiogenesis in the context of Endostatin, and clinical status of rh-Es in cancer treatment. Furthermore, we briefly discuss the various strategies to improve endostatin features (poor pharmacokinetic properties) for developing rh-Es as a safe and effective agent for cancer treatment.
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Affiliation(s)
- J Anakha
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab, 160062, India
| | - Prakashkumar Dobariya
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab, 160062, India
| | - Shyam Sunder Sharma
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab, 160062, India
| | - Abhay H Pande
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab, 160062, India.
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Zhang J, Wang J, Li Y, Pan X, Qu J, Zhang J. A patent perspective of antiangiogenic agents. Expert Opin Ther Pat 2023; 33:821-840. [PMID: 38084667 DOI: 10.1080/13543776.2023.2294808] [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: 10/26/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]
Abstract
INTRODUCTION Angiogenesis plays a crucial role in the development of numerous vascular structures and is involved in a variety of physiologic and pathologic processes, including psoriasis, diabetic retinopathy, and especially cancer. By obstructing the process of angiogenesis, these therapies effectively inhibit the progression of the disease. Consequently, anti-angiogenic agents were subsequently developed. AREAS COVERED This review provides a comprehensive summary of the anti-angiogenic inhibitors developed in the past five years in terms of chemical structure, biochemical/pharmacological activity and potential clinical applications. A literature search was conducted using utilizing the databases Web of Science, SciFinder and PubMed with the key word 'anti-angiogenic agents' and 'angiogenesis inhibitor.' EXPERT OPINION This is despite the fact that the concept of antiangiogenesis has been proposed for more than 50 years and angiogenesis inhibitors are extensively employed in clinical practice. However, significant challenges continue to confront them. In recent years, there has been a significant increase in the number of patents focusing on angiogenesis inhibitors. These patents aim to enhance the selectivity of drugs against VEGF/VEGFR, explore new targets to overcome drug resistance, and explore potential drug combinations, thereby expanding the therapeutic possibilities in this field.
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Affiliation(s)
- Junyu Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China
| | - Jin Wang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China
| | - Yanchen Li
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China
| | - Xiaoyan Pan
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China
| | - Jingkun Qu
- Department of Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jie Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China
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11
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Patras L, Paul D, Matei IR. Weaving the nest: extracellular matrix roles in pre-metastatic niche formation. Front Oncol 2023; 13:1163786. [PMID: 37350937 PMCID: PMC10282420 DOI: 10.3389/fonc.2023.1163786] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 05/15/2023] [Indexed: 06/24/2023] Open
Abstract
The discovery that primary tumors condition distant organ sites of future metastasis for seeding by disseminating tumor cells through a process described as the pre-metastatic niche (PMN) formation revolutionized our understanding of cancer progression and opened new avenues for therapeutic interventions. Given the inherent inefficiency of metastasis, PMN generation is crucial to ensure the survival of rare tumor cells in the otherwise hostile environments of metastatic organs. Early on, it was recognized that preparing the "soil" of the distal organ to support the outgrowth of metastatic cells is the initiating event in PMN development, achieved through the remodeling of the organ's extracellular matrix (ECM). Remote restructuring of ECM at future sites of metastasis under the influence of primary tumor-secreted factors is an iterative process orchestrated through the crosstalk between resident stromal cells, such as fibroblasts, epithelial and endothelial cells, and recruited innate immune cells. In this review, we will explore the ECM changes, cellular effectors, and the mechanisms of ECM remodeling throughout PMN progression, as well as its impact on shaping the PMN and ultimately promoting metastasis. Moreover, we highlight the clinical and translational implications of PMN ECM changes and opportunities for therapeutically targeting the ECM to hinder PMN formation.
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Affiliation(s)
- Laura Patras
- Children’s Cancer and Blood Foundation Laboratories, Department of Pediatrics, Division of Hematology/Oncology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States
- Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania
| | - Doru Paul
- Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, United States
| | - Irina R. Matei
- Children’s Cancer and Blood Foundation Laboratories, Department of Pediatrics, Division of Hematology/Oncology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States
- Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania
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12
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Ji Y, Luan S, Yang X, Yin B, Jin X, Wang H, Jiang W. Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy. Open Med (Wars) 2023; 18:20230640. [PMID: 37025426 PMCID: PMC10071812 DOI: 10.1515/med-2023-0640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 11/20/2022] [Accepted: 12/22/2022] [Indexed: 04/05/2023] Open
Abstract
Bronchoscopy has been widely used for the therapy of lung cancer. This study aimed to evaluate the therapeutic efficacy and adverse reactions of bronchoscopic intratumoral injection of endostar and cisplatin in patients with lung squamous cell carcinoma (LSCC). A total of 40 LSCC patients who underwent conventional chemoradiotherapy were included in this study, and 20 of them received a bronchoscopic injection of endostar and cisplatin as an additive therapeutic modality (treatment group). The clinical response rate, progression-free survival (PFS), and adverse reactions of the patients were compared and analyzed. The treatment group had better short- and long-term therapeutic efficacy compared to the control group, but no significant differences were observed between the two therapeutic regimens in adverse reactions. Elderly and advanced LSCC patients had worse therapeutic efficacy and a high probability of adverse reactions after the therapy. Collectively, our analysis data demonstrated that the bronchoscopic intratumoral injection of endostar and cisplatin had improved therapeutic efficacy, and the cardiovascular adverse reactions were within the controllable range in the treatment of LSCC in clinical practices.
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Affiliation(s)
- Yanzhen Ji
- Otorhinolaryngological Department, Hiser Medical Center of Qingdao, Qingdao266033, Shandong, China
| | - Shuli Luan
- Department of Geriatrics, Hiser Medical Center of Qingdao, Qingdao266033, Shandong, China
| | - Xiaoping Yang
- Pneumology Department, Hiser Medical Center of Qingdao, Qingdao266033, Shandong, China
| | - Bin Yin
- Pneumology Department, Hiser Medical Center of Qingdao, Qingdao266033, Shandong, China
| | - Xiaojie Jin
- Pneumology Department, Hiser Medical Center of Qingdao, Qingdao266033, Shandong, China
| | - Haiyan Wang
- Pneumology Department, Hiser Medical Center of Qingdao, Qingdao266033, Shandong, China
| | - Wenqing Jiang
- Pneumology Department, Hiser Medical Center of Qingdao, No. 4 Renmin Road, Qingdao266033, Shandong, China
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13
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Guan X, Li W, Wang Y, Zhao Q, Yu X, Jiang J, Bian W, Xu C, Sun Y, Zhang C. The mechanism of rh-endostatin-induced cardiotoxicity and its protection by dihydromyricetin[in vivo/in vitro, C57BL/6 mice, AC16 and hiPSC-CMs]. Toxicol Lett 2023; 377:29-37. [PMID: 36739041 DOI: 10.1016/j.toxlet.2023.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/20/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023]
Abstract
Recombinant human endostatin (rh-endostatin) is an anti-angiogenic drug, which is used for the treatment of advanced non-small-cell lung cancer (NSCLC) and other cancers. However, its side effects, especially the cardiotoxicity with unclear mechanisms limit its wide application in clinical practice. In this study, human cardiomyocyte cell line AC16 and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with different doses of rh-endostatin were used to analyze its effect on cardiac cell toxicity. The results revealed that rh-endostatin dose-dependently enhanced cardiomyocyte apoptosis through Apaf-1 apoptotic factor and apoptosis-related proteins such as p53. rh-endostatin-induced changes of mitochondrial function and mitophagy were involved in rh-endostatin-mediated cardiac cell toxicity. Rh-endostatin-induced cardiotoxicity was further verified in vivo in mice. Interestingly, Rh-endostatin-induced cardiotoxicity was inhibited by dihydromyricetin (DHM) both in cultured cells in vitro and in mouse hearts in vivo. The study provides new inside into rh-endostatin-induced cardiotoxicity and identified a novel potential medication DHM to overcome the serious adverse effect.
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Affiliation(s)
- Xiaoran Guan
- School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Wuquan Li
- College of Pharmacy, Binzhou Medical University, Yantai 264003, China
| | - Yong Wang
- College of Pharmacy, Binzhou Medical University, Yantai 264003, China
| | - Qun Zhao
- Shandong Simcere Bio-Pharmaceutical Co., Ltd, Yantai 264006, China
| | - Xinru Yu
- School of Medical Imaging, Binzhou Medical University, Yantai 264003, China
| | - Jing Jiang
- College of Pharmacy, Binzhou Medical University, Yantai 264003, China
| | - Weihua Bian
- College of Pharmacy, Binzhou Medical University, Yantai 264003, China
| | - Cong Xu
- College of Pharmacy, Binzhou Medical University, Yantai 264003, China
| | - Yeying Sun
- College of Pharmacy, Binzhou Medical University, Yantai 264003, China.
| | - Chunxiang Zhang
- College of Pharmacy, Binzhou Medical University, Yantai 264003, China; Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Nucleic Acid Medicine of Luzhou Key Laboratory, Metabolic Vascular Disease Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou 646000, China.
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14
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Tian Y, Hu Q, Zhang R, Zhou B, Xie D, Wang Y, Yang L. Combining an adenovirus encoding human endostatin and PD‐1 blockade enhanced antitumor immune activity. MEDCOMM – ONCOLOGY 2023; 2. [DOI: 10.1002/mog2.21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 12/14/2022] [Indexed: 03/19/2025]
Abstract
AbstractTreatment with immune checkpoint inhibitors (ICIs) has recently achieved unprecedented clinical benefits, becoming a critical treatment for patients with cancer. However, a set of patients are resistant to immune checkpoint inhibitor therapy, likely due to the limited presence or lack of tumor‐infiltrating lymphocytes in their tumors. Increasing data indicate that antiangiogenic therapy substantially reduces cancer‐induced immunosuppression and is an effective way to enhance the efficacy of cancer immunotherapies by combination with ICIs. Endostatin, an angiogenesis inhibitor, has been widely used as an antiangiogenic therapy for cancer. We showed that combined therapy with an adenovirus encoding human endostatin, named Ad‐E, and programmed cell death‐1 (PD‐1) blockade dramatically abrogated tumor growth, inhibited microvessel density, and promoted tumor apoptosis, compared to treatment with the single agents. Further investigation using flow cytometry showed that combined therapy significantly increased CD8+ T‐cell infiltration into tumors and promoted the level of CD8+ IFN‐γ+ T cells. Moreover, combined therapy effectively reduced the frequencies of CD11b+ F4/80+ tumor‐associated macrophages (TAMs) and slightly increased M1/M2 ratio in the tumors. RNA‐seq analysis of tumor tissue following combined therapy also demonstrated upregulated expression of genes associated with the antitumor immune response. These data support the rationale for combining antiangiogenic and ICIs for cancer therapy.
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Affiliation(s)
- Yaomei Tian
- Department of Biotherapy, Cancer Center, West China Hospital Sichuan University Chengdu Chengdu Sichuan China
- College of Bioengineering Sichuan University of Science & Engineering Zigong Sichuan China
| | - Qieyue Hu
- Department of Biotherapy, Cancer Center, West China Hospital Sichuan University Chengdu Chengdu Sichuan China
| | - Rui Zhang
- Department of Biotherapy, Cancer Center, West China Hospital Sichuan University Chengdu Chengdu Sichuan China
| | - Bailing Zhou
- Department of Biotherapy, Cancer Center, West China Hospital Sichuan University Chengdu Chengdu Sichuan China
| | - Daoyuan Xie
- Department of Biotherapy, Cancer Center, West China Hospital Sichuan University Chengdu Chengdu Sichuan China
| | - Yuanda Wang
- Department of Biotherapy, Cancer Center, West China Hospital Sichuan University Chengdu Chengdu Sichuan China
| | - Li Yang
- Department of Biotherapy, Cancer Center, West China Hospital Sichuan University Chengdu Chengdu Sichuan China
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15
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Liu Y, Wang CL, Pang ZQ, Gao K, Shen LK, Xu WH, Ren MH. Endostatin 33 Peptide Is a Deintegrin α6β1 Agent That Exerts Antitumor Activity by Inhibiting the PI3K-Akt Signaling Pathway in Prostate Cancer. J Clin Med 2023; 12:1861. [PMID: 36902648 PMCID: PMC10003382 DOI: 10.3390/jcm12051861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 02/19/2023] [Accepted: 02/22/2023] [Indexed: 03/03/2023] Open
Abstract
BACKGROUND Prostate cancer (PCa) is the leading cause of death in men and has poor therapeutic outcomes. METHODS A novel endostatin 33 peptide was synthesized by adding a specific QRD sequence on the basis of the endostatin 30 peptide (PEP06) with antitumor activity. Then, bioinformatic analysis and subsequent experiments were performed to validate the antitumor function of this endostatin 33 peptide. RESULTS We found that the 33 polypeptides significantly inhibited growth, invasion and metastasis and promoted the apoptosis of PCa in vivo or vitro, which is more significant than PEP06 under the same conditions. According to 489 cases from the TCGA data portal, the α6β1 high expression group was closely associated with the poor prognosis (Gleason score, pathological N stage, etc.) of PCa and was mainly enriched in the PI3K-Akt pathway. Subsequently, we demonstrated that endostatin 33 peptide can down-regulate the PI3K-Akt pathway via the targeted inhibition of α6β1, thereby inhibiting the epithelial-mesenchymal transition and matrix metalloproteinase in C42 cell lines. CONCLUSION The endostatin 33 peptide can exert antitumor effects by inhibiting the PI3K-Akt pathway, especially in tumors with a high expression of the integrin α6β1 subtype, such as prostate cancer. Therefore, our study will provide a new method and theoretical basis for the treatment of prostate cancer.
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Affiliation(s)
- Yang Liu
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Chang-Lin Wang
- Department of Urology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Zhong-Qi Pang
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Ke Gao
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Lin-Kun Shen
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Wan-Hai Xu
- Department of Urology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Ming-Hua Ren
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
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16
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Fu S, Huang H, Shang K, Tu G, Zhong P, Li S, Zhu X, Peng S, Liu Y, Lu Z, Chen L. Efficacy and safety of immune checkpoint inhibitors combined with recombinant human endostatin and chemotherapy as the first-line treatment of advanced non-small-cell lung cancer. Future Oncol 2023; 19:147-158. [PMID: 36779488 DOI: 10.2217/fon-2022-0861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/14/2023] Open
Abstract
Background: To assess the efficacy and safety of combination of PD-1 inhibitors, recombinant human endostatin (Rh-endostatin) and chemotherapy as first-line treatment for advanced non-small-cell lung cancer (NSCLC). Methods: A total of 100 patients with advanced NSCLC were retrospectively reviewed and analyzed (58 in the group receiving PD-1 inhibitors plus Rh-endostatin and chemotherapy; 42 in the group receiving Rh-endostatin and chemotherapy). The primary end point was progression-free survival. Results: Patients in the group receiving PD-1 inhibitors plus Rh-endostatin and chemotherapy had significantly improved progression-free survival (10.2 vs 6.5 months; p < 0.001) and objective response rate (67.2 vs 42.9%; p = 0.015), with acceptable toxicity. Conclusion: Our study showed the superiority of combination therapy of PD-1 inhibitors and Rh-endostatin as first-line treatment for advanced NSCLC.
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Affiliation(s)
- Silv Fu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China.,Department of Radiotherapy, Jiangxi Cancer Hospital, Nanchang, 330029, China
| | - Hongxiang Huang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Kai Shang
- Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Ganjie Tu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China.,Department of Radiotherapy, Jiangxi Cancer Hospital, Nanchang, 330029, China
| | - Peiyuan Zhong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Siling Li
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Xie Zhu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Sujuan Peng
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Yangyang Liu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Zhihui Lu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Li Chen
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
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17
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Zamborlin A, Voliani V. Gold nanoparticles as antiangiogenic and antimetastatic agents. Drug Discov Today 2023; 28:103438. [PMID: 36375738 DOI: 10.1016/j.drudis.2022.103438] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 10/27/2022] [Accepted: 11/08/2022] [Indexed: 11/13/2022]
Abstract
Angiogenesis and metastasis are two interdependent cancer hallmarks, the latter of which is the key cause of treatment failure. Thus, establishing effective antiangiogenesis/antimetastasis agents is the final frontier in cancer research. Gold nanoparticles (GNPs) may provide disruptive advancements in this regard due to their intrinsic physical and physiological features. Here, we comprehensively discuss recent potential therapeutical strategies to treat angiogenesis and metastasis and present a critical review on the state-of-the-art in vitro and in vivo evaluations of the antiangiogenic/antimetastatic activity of GNPs. Finally, we provide perspectives on the contribution of GNPs to the advancement of cancer management.
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Affiliation(s)
- Agata Zamborlin
- Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro, 12 - 56127 Pisa, Italy; NEST-Scuola Normale Superiore, Piazza San Silvestro, 12 - 56127 Pisa, Italy
| | - Valerio Voliani
- Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro, 12 - 56127 Pisa, Italy; Department of Pharmacy, University of Genoa, Viale Cembrano, 4 - 16148 Genoa, Italy.
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18
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Cunningham C, Bolcaen J, Bisio A, Genis A, Strijdom H, Vandevoorde C. Recombinant Endostatin as a Potential Radiosensitizer in the Treatment of Non-Small Cell Lung Cancer. Pharmaceuticals (Basel) 2023; 16:219. [PMID: 37259367 PMCID: PMC9961924 DOI: 10.3390/ph16020219] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/22/2023] [Accepted: 01/24/2023] [Indexed: 11/03/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer, which is the leading cause of cancer-related deaths worldwide. Over the past decades, tumour angiogenesis has been intensely studied in the treatment of NSCLC due to its fundamental role in cancer progression. Several anti-angiogenic drugs, such as recombinant endostatin (RE), have been evaluated in several preclinical and clinical trials, with mixed and often disappointing results. However, there is currently an emerging interest in RE due to its ability to create a vascular normalization window, which could further improve treatment efficacy of the standard NSCLC treatment. This review provides an overview of preclinical and clinical studies that combined RE and radiotherapy for NSCLC treatment. Furthermore, it highlights the ongoing challenges that have to be overcome in order to maximize the benefit; as well as the potential advantage of combinations with particle therapy and immunotherapy, which are rapidly gaining momentum in the treatment landscape of NSCLC. Different angiogenic and immunosuppressive effects are observed between particle therapy and conventional X-ray radiotherapy. The combination of RE, particle therapy and immunotherapy presents a promising future therapeutic triad for NSCLC.
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Affiliation(s)
- Charnay Cunningham
- Centre for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Stellenbosch University, Cape Town 7602, South Africa
- Radiation Biophysics Division, SSC Laboratory, NRF Ithemba LABS, Cape Town 7131, South Africa
| | - Julie Bolcaen
- Radiation Biophysics Division, SSC Laboratory, NRF Ithemba LABS, Cape Town 7131, South Africa
| | - Alessandra Bisio
- Department of Cellular, Computational and Integrative Biology—CIBIO, University of Trento, 38123 Trento, Italy
| | - Amanda Genis
- Centre for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Stellenbosch University, Cape Town 7602, South Africa
| | - Hans Strijdom
- Centre for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Stellenbosch University, Cape Town 7602, South Africa
| | - Charlot Vandevoorde
- Biophysics Department, GSI Helmholtzzentrum für Schwerionenforschung, Planckstr. 1, 64291 Darmstadt, Germany
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Wang H, Luo Y, Ou S, Ni T, Chu Z, Feng X, Dai X, Zhang X, Liu Y. Celastrus orbiculatus Thunb. extract inhibits EMT and metastasis of gastric cancer by regulating actin cytoskeleton remodeling. JOURNAL OF ETHNOPHARMACOLOGY 2023; 301:115737. [PMID: 36179952 DOI: 10.1016/j.jep.2022.115737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 09/08/2022] [Accepted: 09/14/2022] [Indexed: 06/16/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The traditional Chinese medicine herb Celastrus orbiculatus Thunb. is an important folk medicinal plant in China that has been used as an anti-inflammatory, antitumor, and analgesic in various diseases. Recent years, many studies have reported the significant effects of Celastrus orbiculatus Thunb. extract (COE) on gastric cancer. However, the specific mechanism by which COE regulates gastric cancer cytoskeleton remodeling and thus inhibits EMT has not yet been reported. AIM OF STUDY To study the effect and mechanism of COE in inhibiting the epithelial-mesenchymal transition (EMT) and metastasis of gastric cancer cells, laying an experimental foundation for the clinical application and further development of COE. METHODS The high-content cell dynamic tracking system was used to continuously track the trajectory of cell movement in real time. Through the high-content data, the average movement distance and movement speed of the cells are calculated. Additionally, the dynamic images of the cell movement in the high-content imaging system are derived to analyze the impact of COE on the movement of gastric cancer cells. Cytoskeleton staining experiment was performed to detect the effect of COE on the assembly of gastric cancer cell cytoskeleton proteins. Western blot was employed to detect the changes of EMT and metastasis-related proteins in the gastric cancer cells treated by COE. The effect of COE on the key regulatory protein Cofilin-1 (CFL1) of cell movement was examined by Western blot and protein degradation experiment. The effect of COE on EMT and metastasis of the gastric cancer cells lacking CFL1 was assessed by a transwell assay. The in vivo inhibitory effect of COE on EMT and metastasis of gastric cancer was determined by the animal living image system. IHC assays were used to detect the levels of EMT-related proteins in COE reversal in vivo. RESULT The results showed that the movement distance and average movement speed of gastric cancer cells after COE treatment were significantly lower than those of the control group. Cytoskeleton staining experiments revealed that COE can significantly change the distribution of skeletal proteins in gastric cancer cells. Additionally, COE treatment significantly reduced the expression of Matrix metalloproteinases (MMP-2, MMP-9) and other proteins. Furthermore, COE can significantly accelerate the degradation of CFL1 protein, and both COE treatment and CFL1 deletion can significantly inhibit EMT and metastasis of gastric cancer cells. Lastly, the number of peritoneal metastases of gastric cancer cells was significantly reduced in animals after COE treatment. COE can reverse the levels of EMT-related proteins while reducing the expression levels of CFL1 protein in vivo. CONCLUSION COE can significantly inhibit EMT and metastasis of gastric cancer cells in vivo and in vitro. This effect may be achieved by reducing the stability of CFL1 and inhibiting the assembly of actin in gastric cancer cells.
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Affiliation(s)
- Haibo Wang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China; The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225001, PR China.
| | - YuanYuan Luo
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China.
| | - Shiya Ou
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China; The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225001, PR China.
| | - Tengyang Ni
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China; The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225001, PR China.
| | - Zewen Chu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China; The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225001, PR China.
| | - Xinyi Feng
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China; The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225001, PR China.
| | - Xiaojun Dai
- The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225001, PR China; Yangzhou Hospital of Traditional Chinese Medicine, Yangzhou, 225001, PR China.
| | - Xiaochun Zhang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China; The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225001, PR China; Yangzhou Hospital of Traditional Chinese Medicine, Yangzhou, 225001, PR China.
| | - Yanqing Liu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China; The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225001, PR China.
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20
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Sarabi N, Chamani R, Assareh E, Saberi O, Asghari SM. Combination Therapy in Cancer: Doxorubicin in Combination with an N-terminal Peptide of Endostatin Suppresses Angiogenesis and Stimulates Apoptosis in the Breast Cancer. INTERNATIONAL JOURNAL OF MOLECULAR AND CELLULAR MEDICINE 2023; 12:120-134. [PMID: 38313376 PMCID: PMC10837914 DOI: 10.22088/ijmcm.bums.12.2.120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 10/12/2023] [Accepted: 11/12/2023] [Indexed: 02/06/2024]
Abstract
The combination of chemotherapy drugs with angiogenesis inhibitors improves response and survival and reduces the cytotoxic side effects and drug resistance in patients compared to chemotherapy alone. Here, we investigated the efficacy of the concomitant administration of doxorubicin and a peptide derived from the N-terminal domain of Endostatin (called ES-SS) in the 4T1 mammary carcinoma tumor model. Tumor-bearing mice were divided into the control and three treatment groups, including ES-SS, doxorubicin, and the combination. Injections were performed daily for two weeks and tumor volumes were measured during the treatment. Immunohistochemical analysis of Ki-67, CD31, CD34, Bcl-2, p53 expression, and TUNEL assay were performed on tumor tissues at the end of treatment. Besides, molecular dynamics and docking simulations were performed. It was demonstrated that tumor growth was inhibited in mice treated with peptide plus doxorubicin more significantly than in each treatment alone (P<0.05). No weight loss or adverse effects were observed. Moreover, combination therapy was more effective in tumor angiogenesis suppression and apoptosis stimulation (P<0.05). Docking simulations by ClusPro server demonstrated that ES-SS binds to integrin α5β1, Transglu-taminase 2, and Matrix metalloproteinase 2 with more negative binding energy and hydrogen bonds compared to the native peptide. Generally, we proposed that ES-SS can augment the therapeutic efficacy of doxorubicin through angiogenesis prevention and apoptosis induction in breast tumor. Owing to the advantages of peptides to recombinant proteins or monoclonal antibodies, further preclinical and clinical evaluations of this combination strategy are worth taking into consideration.
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Affiliation(s)
- Narges Sarabi
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran.
| | | | - Elham Assareh
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran.
| | - Omid Saberi
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran.
| | - S. Mohsen Asghari
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
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Eulberg D, Frömming A, Lapid K, Mangasarian A, Barak A. The prospect of tumor microenvironment-modulating therapeutical strategies. Front Oncol 2022; 12:1070243. [PMID: 36568151 PMCID: PMC9772844 DOI: 10.3389/fonc.2022.1070243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 11/10/2022] [Indexed: 12/13/2022] Open
Abstract
Multiple mechanisms promote tumor prosperity, which does not only depend on cell-autonomous, inherent abnormal characteristics of the malignant cells that facilitate rapid cell division and tumor expansion. The neoplastic tissue is embedded in a supportive and dynamic tumor microenvironment (TME) that nurtures and protects the malignant cells, maintaining and perpetuating malignant cell expansion. The TME consists of different elements, such as atypical vasculature, various innate and adaptive immune cells with immunosuppressive or pro-inflammatory properties, altered extracellular matrix (ECM), activated stromal cells, and a wide range of secreted/stroma-tethered bioactive molecules that contribute to malignancy, directly or indirectly. In this review, we describe the various TME components and provide examples of anti-cancer therapies and novel drugs under development that aim to target these components rather than the intrinsic processes within the malignant cells. Combinatory TME-modulating therapeutic strategies may be required to overcome the resistance to current treatment options and prevent tumor recurrence.
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22
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Wang Y, Cui C, Ren X, Dong X, Cui W. Cardiovascular toxicity associated with angiogenesis inhibitors: A comprehensive pharmacovigilance analysis based on the FDA Adverse Event Reporting System database from 2014 to 2021. Front Cardiovasc Med 2022; 9:988013. [PMID: 36312283 PMCID: PMC9606330 DOI: 10.3389/fcvm.2022.988013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 09/14/2022] [Indexed: 01/31/2023] Open
Abstract
Background The profiles of cardiovascular toxicity associated with angiogenesis inhibitors, including intravenous monoclonal antibodies (mAbs) and oral tyrosine kinase inhibitors (TKIs), targeting vascular endothelial growth factor (VEGF) remain poorly elucidated in real-world settings. This pharmacovigilance analysis aimed to comprehensively investigate the frequency, spectrum, timing, and outcomes of cardiovascular toxicities associated with angiogenesis inhibitors and to explore the differences in such patterns between mAbs and TKIs. Methods Disproportionality analysis was performed by leveraging reports from the FDA Adverse Event Reporting System (FAERS) database from 2014 to 2021. Cardiovascular adverse events (AEs) were grouped into nine narrow categories using the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs). Reporting odds ratio (ROR) and information components (ICs) were calculated with statistical shrinkage transformation formulas and a lower limit of 95% confidence interval (CI) for ROR (ROR025) > 1 or IC (IC025) > 0, with at least three reports being considered statistically significant. Results A total of 757,577 reports of angiogenesis inhibitors and 70,668 (9.3%) reports of cardiovascular AEs were extracted. Significant disproportionality was detected in angiogenesis inhibitors for cardiovascular AEs (IC025/ROR025 = 0.35/1.27). Bevacizumab (31.8%), a mAb, presented the largest number of reports, followed by sunitinib (12.4%), a TKI. Hypertension (SMQ) was detected with the strongest signal value (IC025/ROR025 = 1.73/3.33), followed by embolic and thrombotic events (SMQ) (IC025/ROR025 = 0.32/1.26). Hypertension showed the shortest time to onset with a median (interquartile range) value of 23 (8, 69) days, while embolic and thrombotic events had the longest value of 51 (16, 153) days. Notably, hypertension presented the lowest proportions of death and life-threatening events (10.9%), whereas embolic and thrombotic events posed the highest (29.3%). Furthermore, both mAbs (IC025/ROR025 = 0.47/1.39) and TKIs (IC025/ROR025 = 0.30/1.23) showed increased cardiovascular AEs. Hypertension was detected in both agents (IC025/ROR025 = 1.53/2.90 for mAbs and IC025/ROR025 = 1.83/3.56 for TKIs) with a shorter time to onset of 17 (6, 48) days for TKIs than mAbs of 42 (14, 131) days. By contrast, embolic and thrombotic events were detected for mAbs (IC025/ROR025 = 0.90/1.87) without TKI (IC025/ROR025 = −0.08/0.95). Conclusion Angiogenesis inhibitors were associated with increased cardiovascular toxicity with a discrepancy between intravenous mAbs and oral TKIs, deserving distinct monitoring and appropriate management.
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Affiliation(s)
- YanFeng Wang
- Department of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chanjuan Cui
- Department of Laboratory Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiayang Ren
- Department of Pharmacy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinran Dong
- School of Electronics Engineering and Computer Science, Peking University, Beijing, China
| | - Wei Cui
- Department of Laboratory Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China,*Correspondence: Wei Cui
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Anti-Angiogenic Therapy in ALK Rearranged Non-Small Cell Lung Cancer (NSCLC). Int J Mol Sci 2022; 23:ijms23168863. [PMID: 36012123 PMCID: PMC9407780 DOI: 10.3390/ijms23168863] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/07/2022] [Accepted: 08/08/2022] [Indexed: 11/17/2022] Open
Abstract
The management of advanced lung cancer has been transformed with the identification of targetable oncogenic driver alterations. This includes anaplastic lymphoma kinase (ALK) gene rearrangements. ALK tyrosine kinase inhibitors (TKI) are established first-line treatment options in advanced ALK rearranged non-small cell lung cancer (NSCLC), with several next-generation ALK TKIs (alectinib, brigatinib, ensartinib and lorlatinib) demonstrating survival benefit compared with the first-generation ALK TKI crizotinib. Still, despite high objective response rates and durable progression-free survival, drug resistance inevitably ensues, and treatment options beyond ALK TKI are predominantly limited to cytotoxic chemotherapy. Anti-angiogenic therapy targeting the vascular endothelial growth factor (VEGF) signaling pathway has shown efficacy in combination with platinum-doublet chemotherapy in advanced NSCLC without a driver alteration, and with EGFR TKI in advanced EGFR mutated NSCLC. The role for anti-angiogenic therapy in ALK rearranged NSCLC, however, remains to be elucidated. This review will discuss the pre-clinical rationale, clinical trial evidence to date, and future directions to evaluate anti-angiogenic therapy in ALK rearranged NSCLC.
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Wu X, Zou Y, Du K, Du Y, Firempong CK, Yu Y, He H, Liu H, Sun C. Construction and Evaluation of Traceable rhES-QDs-M-MS Protein Delivery System: Sustained-Release Properties, Targeted Effect, and Antitumor Activity. AAPS PharmSciTech 2022; 23:207. [PMID: 35896916 DOI: 10.1208/s12249-022-02326-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 06/07/2022] [Indexed: 11/30/2022] Open
Abstract
Recombinant human endostatin (rhES) is a protein drug with poor stability and short in vivo circulation time. The present study was therefore aimed at developing sustained-release lung targeted microspheres drug delivery system and evaluating its targeting efficiency using in vivo imaging techniques with quantum dots (QDs) as the imaging material. The oil-soluble QDs were coated with amphiphilic polymers to obtain a polymer-quantum dots micelle (QDs-M) with the potential to stably disperse in water. The rhES and QDs-M were combined using covalent bonds. The rhES-QDs-M microspheres (rhES-QDs-M-MS) were prepared using electrostatic spray technology and also evaluated via in vivo imaging techniques. The pharmacodynamics was further studied in mice. The rhES-QDs-M-MS (4-8 μm) were stable in an aqueous medium with good optical properties. The in vitro studies showed that the rhES-QDs-M-MS had sustained release which was maintained for at least 15 days (cumulative release >80%) without any burst release. The rhES-QDs-M-MS had a very high safety profile and also effectively inhibited the in vitro proliferation of human umbilical vein endothelial cells by about 70%. The pharmacokinetic results showed that the rhES could still be detected at 72 h in the experimental group which meant that the rhES-QDs-M-MS had a significant sustained-release effect. The rhES-QDs-M-MS had a better lung targeting effect and higher antitumor activity compared with the rhES. The traceable rhES-QDs-M-MS served as a promising drug delivery system for the poorly stable rhES proteins and significantly increased its lung-targeted effect, sustained-release properties, and antitumor activities.
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Affiliation(s)
- Xiaowen Wu
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529000, People's Republic of China
| | - Yi Zou
- College of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China
| | - Kunyu Du
- College of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China
| | - Yi Du
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529000, People's Republic of China
| | - Caleb Kesse Firempong
- College of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China
| | - Yang Yu
- Jiangsu Sunan Pharmaceutical Industrial Co., LTD, Zhenjiang, 212400, People's Republic of China
| | - Haibing He
- Department of Pharmaceutics, College of Pharmacy, Shenyang pharmaceutical university, Shenyang, 110016, People's Republic of China.,Jiangsu Haizhihong Biomedical Co., Ltd, Nantong, 226001, People's Republic of China
| | - Hongfei Liu
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529000, People's Republic of China. .,College of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China. .,Jiangsu Sunan Pharmaceutical Industrial Co., LTD, Zhenjiang, 212400, People's Republic of China.
| | - Changshan Sun
- Department of Pharmaceutics, College of Pharmacy, Shenyang pharmaceutical university, Shenyang, 110016, People's Republic of China. .,Shanghai Meiyou Pharmaceutical Co., Ltd, Shanghai, 201400, People's Republic of China.
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Ouyang W, Fu S, Zhao X, Su S, Zhang J, Luo D, Liu L, Ding W, Cao D, Liu L, He Z, Lu B. Recombinant human endostatin combined with radiotherapy promotes cardiomyocyte apoptosis in rats via TGFβ1/Smads/CTGF signaling pathway. BMC Cardiovasc Disord 2022; 22:97. [PMID: 35279096 PMCID: PMC8917752 DOI: 10.1186/s12872-022-02499-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 02/03/2022] [Indexed: 11/21/2022] Open
Abstract
PURPOSE The aim of the present study was to investigate the efficacy of recombinant human endostatin (ES) (rh-ES) combined with radiation on rat cardiomyocyte apoptosis and the regulatory mechanism of transforming growth factor beta1 (TGF-β1)/Sma and Mad-related protein 3 (Smad3)/connective tissue growth factor (CTGF) signaling. METHOD The primary cardiomyocytes were isolated from neonatal Sprague-Dawley rats for culture in vitro and divided into blank control group (without treatment), 10 Gy radiation + siTGF-β1 siRNA (gene silencing) group, ES + siTGF-β1 siRNA group, and 10 Gy radiation + ES + siTGF-β1 siRNA group. Methyl thiazolyl tetrazolium assay was used to calculate the half-maximal inhibitory concentration (IC50) of rh-ES on cardiomyocytes. Adenoviral vector was constructed for virus packaging to silence TGF-β1 expression in cardiomyocytes. Quantitative real-time polymerase chain reaction and Western blot were carried out to analyze TGF-β1, Smad2, Smad3 and CTGF expression at both gene and protein levels. Flow cytometry and electron microscope were used to examine cell apoptosis. RESULTS ES had a dose-dependent inhibitory effect on the proliferation of primary rat cardiomyocytes. ES combined with radiotherapy significantly inhibited cardiomyocyte proliferation and promoted cell apoptosis (P < 0.01). The gene and protein expression of TGF-β1, Smad2, Smad3 and CTGF were significantly up-regulated in primary cardiomyocytes transfected with TGF-β1 gene (P < 0.05). CONCLUSION The combination therapy with rh-ES and radiation can promote cardiomyocyte apoptosis and aggravate myocardial cell damage via TGF-β1/Smad3/CTGF signaling pathway.
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Affiliation(s)
- Weiwei Ouyang
- Department of Thoracic Oncology, The Affiliated Hospital of Guizhou Medical University and The Affiliated Cancer Hospital of Guizhou Medical University, No. 1 Beijing Road West, Guiyang, 550004, China
| | - Shimei Fu
- Department of Thoracic Oncology, The Affiliated Hospital of Guizhou Medical University and The Affiliated Cancer Hospital of Guizhou Medical University, No. 1 Beijing Road West, Guiyang, 550004, China
| | - Xing Zhao
- Stem Cell and Tissue Engineering Research Center, Guizhou Medical University, Guiyang, 550025, China
| | - Shengfa Su
- Department of Thoracic Oncology, The Affiliated Hospital of Guizhou Medical University and The Affiliated Cancer Hospital of Guizhou Medical University, No. 1 Beijing Road West, Guiyang, 550004, China
| | - Jun Zhang
- Department of Pathology, The Affiliated Hospital of Guizhou Medical University and the Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Daxian Luo
- Department of Thoracic Oncology, The Affiliated Hospital of Guizhou Medical University and The Affiliated Cancer Hospital of Guizhou Medical University, No. 1 Beijing Road West, Guiyang, 550004, China
| | - Lina Liu
- Department of Thoracic Oncology, The Affiliated Hospital of Guizhou Medical University and The Affiliated Cancer Hospital of Guizhou Medical University, No. 1 Beijing Road West, Guiyang, 550004, China
| | - Wenjin Ding
- Department of Thoracic Oncology, The Affiliated Hospital of Guizhou Medical University and The Affiliated Cancer Hospital of Guizhou Medical University, No. 1 Beijing Road West, Guiyang, 550004, China
| | - Dongdong Cao
- Department of Thoracic Oncology, The Affiliated Hospital of Guizhou Medical University and The Affiliated Cancer Hospital of Guizhou Medical University, No. 1 Beijing Road West, Guiyang, 550004, China
| | - Likun Liu
- Department of Thoracic Oncology, The Affiliated Hospital of Guizhou Medical University and The Affiliated Cancer Hospital of Guizhou Medical University, No. 1 Beijing Road West, Guiyang, 550004, China
| | - Zhixu He
- Stem Cell and Tissue Engineering Research Center, Guizhou Medical University, Guiyang, 550025, China
| | - Bing Lu
- Department of Thoracic Oncology, The Affiliated Hospital of Guizhou Medical University and The Affiliated Cancer Hospital of Guizhou Medical University, No. 1 Beijing Road West, Guiyang, 550004, China.
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Lepucki A, Orlińska K, Mielczarek-Palacz A, Kabut J, Olczyk P, Komosińska-Vassev K. The Role of Extracellular Matrix Proteins in Breast Cancer. J Clin Med 2022; 11:jcm11051250. [PMID: 35268340 PMCID: PMC8911242 DOI: 10.3390/jcm11051250] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 01/16/2022] [Accepted: 02/22/2022] [Indexed: 12/12/2022] Open
Abstract
The extracellular matrix is a structure composed of many molecules, including fibrillar (types I, II, III, V, XI, XXIV, XXVII) and non-fibrillar collagens (mainly basement membrane collagens: types IV, VIII, X), non-collagenous glycoproteins (elastin, laminin, fibronectin, thrombospondin, tenascin, osteopontin, osteonectin, entactin, periostin) embedded in a gel of negatively charged water-retaining glycosaminoglycans (GAGs) such as non-sulfated hyaluronic acid (HA) and sulfated GAGs which are linked to a core protein to form proteoglycans (PGs). This highly dynamic molecular network provides critical biochemical and biomechanical cues that mediate the cell–cell and cell–matrix interactions, influence cell growth, migration and differentiation and serve as a reservoir of cytokines and growth factors’ action. The breakdown of normal ECM and its replacement with tumor ECM modulate the tumor microenvironment (TME) composition and is an essential part of tumorigenesis and metastasis, acting as key driver for malignant progression. Abnormal ECM also deregulate behavior of stromal cells as well as facilitating tumor-associated angiogenesis and inflammation. Thus, the tumor matrix modulates each of the classically defined hallmarks of cancer promoting the growth, survival and invasion of the cancer. Moreover, various ECM-derived components modulate the immune response affecting T cells, tumor-associated macrophages (TAM), dendritic cells and cancer-associated fibroblasts (CAF). This review article considers the role that extracellular matrix play in breast cancer. Determining the detailed connections between the ECM and cellular processes has helped to identify novel disease markers and therapeutic targets.
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Affiliation(s)
- Arkadiusz Lepucki
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland; (A.L.); (K.O.)
| | - Kinga Orlińska
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland; (A.L.); (K.O.)
| | - Aleksandra Mielczarek-Palacz
- Department of Immunology and Serology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 41-200 Sosnowiec, Poland; (A.M.-P.); (J.K.)
| | - Jacek Kabut
- Department of Immunology and Serology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 41-200 Sosnowiec, Poland; (A.M.-P.); (J.K.)
| | - Pawel Olczyk
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland; (A.L.); (K.O.)
- Correspondence:
| | - Katarzyna Komosińska-Vassev
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 41-200 Sosnowiec, Poland;
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Clinical Efficacy and Safety of Bevacizumab, Apatinib, and Recombinant Human Endothelial Inhibitor in the Treatment of Advanced Gastric Cancer. JOURNAL OF ONCOLOGY 2022; 2022:6189833. [PMID: 35251174 PMCID: PMC8894022 DOI: 10.1155/2022/6189833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/14/2022] [Accepted: 01/25/2022] [Indexed: 11/17/2022]
Abstract
Objective To investigate the clinical efficacy and safety of bevacizumab, apatinib, and recombinant human endothelial inhibitor in the treatment of advanced gastric cancer. Methods The medical data of 204 patients with a medium to advanced gastric cancer assessed for eligibility treated in our hospital from February 2019 to April 2020 were retrospectively analyzed. The eligible patients were assigned at a ratio of 1 : 1:1 : 1 to either the control group (chemotherapy), study group I (bevacizumab combined with chemotherapy), study group II (apatinib combined with chemotherapy), or study group III (recombinant human endothelial inhibitor combined with chemotherapy) according to different treatment methods. The treatment efficacy, drug toxicity, quality of life, and serum tumor marker levels before and after treatment were compared among the four groups. Results Regarding the treatment effects, the effective rate of study group II (68.63%) was significantly higher than that of the control group (33.33%), study group I (58.82%), and study group III (49.02%) (P < 0.05). The four groups showed similar safety and tolerability profiles (P > 0.05). The treatment in study group II led to a significantly higher physiological function score vs. the other three groups, but the scores of other items were not significantly different. Significant reduction was observed in the serum tumor markers after treatment in the four groups (P < 0.05), but treatment in study group II led to a significantly greater reduction than the other three groups (P < 0.05). Conclusion The addition of apatinib, bevacizumab, and recombinant human endothelial inhibitor injection to chemotherapy for the treatment of medium to advanced gastric cancer can significantly improve the clinical treatment efficacy, among which the use of apatinib combined with chemotherapy achieves the best results, which is worthy of clinical promotion.
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Liao Z, Zhang C, Yang T, Liu H, Yang S, Li T, Xing R, Teng S, Yang Y, Zhao J, Zhao G, Bai X, Zhu L, Yang J. Chemotherapy Combined With Recombinant Human Endostatin (Endostar) Significantly Improves the Progression-Free Survival of Stage IV Soft Tissue Sarcomas. Front Oncol 2022; 11:778774. [PMID: 35047396 PMCID: PMC8761904 DOI: 10.3389/fonc.2021.778774] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/08/2021] [Indexed: 11/13/2022] Open
Abstract
Purpose Our previously study showed that recombinant human endostatin (Endostar) combined with chemotherapy had significant activity to increase the mPFS in patients with advanced sarcomas with tolerable side effects. However, the small cohort size and short follow-up time made it difficult to screen sensitive sarcoma subtypes and determine whether there is an overall survival benefit. With the largest sarcoma cohort to our knowledge, we try to confirm the efficacy and safety of chemotherapy combined with Endostar in stage IV sarcomas, with the specific purpose of finding out the sensitive sarcoma types for this combined treatment. Methods After the exclusion of ineligible patients, 156 patients with stage IV bone and soft tissue sarcomas were included in this study according to the inclusion criteria. Results By the end of follow-up, the ORR was 10.7% (9/84) vs 1.4% (1/72) (p=0.041), the DCR was 26.2% (22/84) vs 5.6% (4/72) (p=0.001) in the combined group and chemotherapy group, respectively. The mPFS of combined group was significantly longer than the chemotherapy group (10.42 vs 6.87 months, p=0.003). The mOS were 26.84 months and 23.56 months, without significant difference (p= 0.481). In osteogenic sarcoma, there was no statistically significant difference in the mPFS between the two groups (p=0.59), while in the soft tissue sarcoma, the mPFS in the combined group was significantly higher than that of the chemotherapy group (11.27 vs 8.05 months, p=0.004). Specifically, undifferentiated polymorphic sarcoma (UPS) was the possible sarcoma subtypes that benefited from the combined therapy. For the 38 UPS patients (28 patients in the combined group and 10 patients in the chemotherapy group), the mPFS in the combined group was up to 14.88 months, while it was only 7.1 months in the chemotherapy group, with a significant difference (p=0.006). The most common adverse events in the combined group were myelosuppression, gastrointestinal reactions and abnormal liver function, without significant difference in two groups. Conclusion Chemotherapy plus Endostar could prolong mPFS and improve ORR and DCR in patients with stage IV soft tissue sarcoma, suggesting that the combined therapy could improve the patient prognosis in soft tissue sarcomas, especially the UPS patients.
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Affiliation(s)
- Zhichao Liao
- Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Chao Zhang
- Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Tielong Yang
- Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Haotian Liu
- Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Songwei Yang
- Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Departments of Bone and Soft Tissue Tumor, Chongqing University Cancer Hospital, Chongqing, China
| | - Ting Li
- Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Ruwei Xing
- Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Sheng Teng
- Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yun Yang
- Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Jun Zhao
- Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Gang Zhao
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Xu Bai
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Lei Zhu
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Department of Molecular Imaging and Nuclear Medicine, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Jilong Yang
- Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
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Liang K, Zhang R, Luo H, Zhang J, Tian Z, Zhang X, Zhang Y, Ali MK, Kong Q. Optimized Attenuated Salmonella Typhimurium Suppressed Tumor Growth and Improved Survival in Mice. Front Microbiol 2022; 12:774490. [PMID: 35003007 PMCID: PMC8733734 DOI: 10.3389/fmicb.2021.774490] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 12/02/2021] [Indexed: 01/03/2023] Open
Abstract
The gram-negative facultative anaerobic bacteria Salmonella enterica serovar Typhimurium (hereafter S. Typhimurium) has always been considered as one candidate of anti-tumor agents or vectors for delivering drug molecules. In this study, we compared several widely studied S. Typhimurium strains in their anti-tumor properties aiming to screen out the best one for further optimization and use in cancer therapy. In terms of the motility, virulence and anti-tumor efficacy, the three strains 14028, SL1344, and UK-1 were similar and obviously better than LT-2, and UK-1 showed the best phenotypes among them. Therefore, the strain UK-1 (D) was selected for the following studies. Its auxotrophic mutant strain (D1) harboring ∆aroA and ∆purM mutations was further optimized through the modification of lipid A structure, generating a new strain named D2 with stronger immunostimulatory activity. Finally, the ∆asd derivative of D2 was utilized as one live vector to deliver anti-tumor molecules including the angiogenesis inhibitor endostatin and apoptosis inducer TRAIL and the therapeutic and toxic-side effects were evaluated in mouse models of colon carcinoma and melanoma. After intraperitoneal infection, engineered Salmonella bacteria equipped with endostatin and/or TRAIL significantly suppressed the tumor growth and prolonged survival of tumor-bearing mice compared to PBS or bacteria carrying the empty plasmid. Consistently, immunohistochemical studies confirmed the colonization of Salmonella bacteria and the expression of anti-tumor molecules inside tumor tissue, which were accompanied by the increase of cell apoptosis and suppression of tumor angiogenesis. These results demonstrated that the beneficial anti-tumor efficacy of attenuated S. Typhimurium bacteria could be improved through delivery of drug molecules with powerful anti-tumor activities.
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Affiliation(s)
- Kang Liang
- College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Rui Zhang
- College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Haiyan Luo
- College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Jinlong Zhang
- College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Zhenyuan Tian
- College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Xiaofen Zhang
- College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Yulin Zhang
- College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Md Kaisar Ali
- College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Qingke Kong
- College of Veterinary Medicine, Southwest University, Chongqing, China
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30
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Popova NV, Jücker M. The Functional Role of Extracellular Matrix Proteins in Cancer. Cancers (Basel) 2022; 14:238. [PMID: 35008401 PMCID: PMC8750014 DOI: 10.3390/cancers14010238] [Citation(s) in RCA: 89] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/23/2021] [Accepted: 12/27/2021] [Indexed: 02/04/2023] Open
Abstract
The extracellular matrix (ECM) is highly dynamic as it is constantly deposited, remodeled and degraded to maintain tissue homeostasis. ECM is a major structural component of the tumor microenvironment, and cancer development and progression require its extensive reorganization. Cancerized ECM is biochemically different in its composition and is stiffer compared to normal ECM. The abnormal ECM affects cancer progression by directly promoting cell proliferation, survival, migration and differentiation. The restructured extracellular matrix and its degradation fragments (matrikines) also modulate the signaling cascades mediated by the interaction with cell-surface receptors, deregulate the stromal cell behavior and lead to emergence of an oncogenic microenvironment. Here, we summarize the current state of understanding how the composition and structure of ECM changes during cancer progression. We also describe the functional role of key proteins, especially tenascin C and fibronectin, and signaling molecules involved in the formation of the tumor microenvironment, as well as the signaling pathways that they activate in cancer cells.
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Affiliation(s)
- Nadezhda V. Popova
- Laboratory of Receptor Cell Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, 117997 Moscow, Russia;
| | - Manfred Jücker
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
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31
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Wang X, Shi Y, Jia Y, Zhao W, Zhang L, Bai G, Ren Y, Chen YZ, Tong Z. Tolerance and Pharmacokinetics of Recombinant Human Endostatin Administered as Single-Dose or Multiple-Dose Infusions in Patients With Advanced Solid Tumors: A Phase I Clinical Trial. Technol Cancer Res Treat 2021; 20:15330338211064434. [PMID: 34931914 PMCID: PMC8721376 DOI: 10.1177/15330338211064434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objective: This study aimed to investigate the tolerance and pharmacokinetic characteristics of recombinant human endostatin (rh-endostatin) administered as single-dose or multiple-dose infusions in patients with advanced solid tumors. Methods: This phase I trial was designed as a single-center, single-arm, nonrandomized, open-label, dose-escalation study. The trial consisted of 2 parts: a single-dose part and a multiple-dose part, each with 3 dose comparison groups. Rh-endostatin was administered as an intravenous injection only once at a dose of 5 mg/m2, 7.5 mg/m2, or 10 mg/m2 in the single-dose part and as a daily intravenous injection for 14 days at the same doses in the multiple-dose part. The serum pharmacokinetics, toxicity and immunogenicity of rh-endostatin were evaluated. Results: Dose-limiting toxicity (DLT) was not observed in any group. A few patients developed cardiotoxicity, such as QT prolongation or narrow arrhythmia. Other adverse events were slight coagulation abnormalities and haematological abnormalities. For rh-endostatin doses of 5 mg/m2, 7.5 mg/m2, and 10 mg/m2, the mean Cmax values in the single-dose part were 344 ± 38.7 ng/mL, 524 ± 157 ng/mL, and 800 ± 201 ng/mL, respectively, and the average AUC0-t values were 3290 ± 3790 ng•h/mL, 4940 ± 4380 ng•h/mL, and 5050 ± 3980 ng•h/mL, respectively. The Cmax ss values of the 3 doses in the multiple-dose part were 575 ± 270 ng/mL, 531 ± 106 ng/mL, and 864 ± 166 ng/mL, respectively, and the AUC0-τ values were 3610 ± 1040 ng•h/mL, 3290 ± 1090 ng•h/mL, and 5180 ± 1210 ng•h/mL, respectively. The Cmax of a single-dose regimen showed linear kinetic characteristics. The patients in the single-dose group were negative for serum antibodies against rh-endostatin, while one patient in the multiple-dose group was positive. Conclusions: Rh-endostatin as a daily intravenous injection for 14 days in patients with advanced solid tumors is safe and well tolerated, without DLT, at doses of 5 mg/m2, 7.5 mg/m2, and 10 mg/m2. Serum antibodies against rh-endostatin were very low after multiple infusions. For phase II trials, the recommended rh-endostatin dose is 10 mg/m2 as a daily intravenous injection for 14 days.
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Affiliation(s)
- Xu Wang
- Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yehui Shi
- Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yongsheng Jia
- Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Weipeng Zhao
- Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Li Zhang
- Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Guiying Bai
- Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yulin Ren
- Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yong-Zi Chen
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Laboratory of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
| | - Zhongsheng Tong
- Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
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32
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Girma B, Makonnen E, Shibeshi W. Characteristics of recent clinical investigations into systemic therapy against cervical cancer: systematic analysis of trial details from Clinicaltrials.gov. J OBSTET GYNAECOL 2021; 42:793-801. [PMID: 34907843 DOI: 10.1080/01443615.2021.1980507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
A review that systematically assessed the current state of clinical research into systematic therapy-based interventions against invasive cervical cancer. It analysed registry details of 59 systemic therapy-based cervical cancer trials on ClinicalTrials.gov with study start dates between January 2010 and June 2018. The review characterised the present cervical cancer trial landscape in terms of trial design features, systemic therapy (chemotherapy, targeted therapy, immunotherapy, and repurposed therapy), and disease stages of interest. It also made an attempt to qualitatively synthesise the trial landscape in terms of the nature and trend of research focus, alignment with existing clinical needs, novelty of treatments or concepts pursued, and promise of new treatments.
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Affiliation(s)
- Biniyam Girma
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.,School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Eyasu Makonnen
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.,School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Workineh Shibeshi
- School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
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33
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Xiao C, Xu F, Wang R, Liang Q, Shen K, Xu J, Liu L. Endostar Plus Apatinib Successfully Achieved Long Term Progression-Free Survival in Refractory Ovarian Cancer: A Case Report and Literature Review. Onco Targets Ther 2021; 14:5363-5372. [PMID: 34880628 PMCID: PMC8646866 DOI: 10.2147/ott.s335139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 11/10/2021] [Indexed: 12/18/2022] Open
Abstract
Background Ovarian cancer (OC) is a common malignancy in the gynecological tumor. Standard treatment for ovarian cancer is surgery and chemotherapy based on paclitaxel and platinum. However, traditional chemotherapy for ovarian cancer is limited by drug resistance and systemic side effects. It is imperative to explore effective treatment options for refractory ovarian cancer. Case Presentation A 52-year-old female initially presented with lower abdominal distension and migratory pain. After the laparoscopic exploration and biopsy, immunohistochemistry showed poorly differentiated adenocarcinoma originated from ovarian (cT3NxM1, stage IV, peritoneal and abdominal wall metastasis). The next generation sequence detected ERRFI1 (T187A, exon4) mutation. Results The patient received first-line chemotherapy (paclitaxel, nedaplatin plus avastin), followed by maintenance therapy with gefitinib, achieving a 15-month progression-free survival (PFS). After disease progression and second-line treatment failure, endostar plus apatinib was administered for 14 cycles and she obtained a PFS of 14 months without long-term adverse events. Conclusion We believe that the ERRFI1 gene may be a potential target of gefitinib. Importantly, endostar combined with apatinib is worth recommending for maintenance treatment in refractory ovarian cancer.
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Affiliation(s)
- Chunmei Xiao
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Fangye Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Rong Wang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Qi Liang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Kai Shen
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Jiali Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Lianke Liu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China
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34
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Guo H, Zhou L, Guo J, Huang X, Gu J. Endostatin inhibits the proliferation and migration of B16 cells by inducing macrophage polarity to M1‑type. Mol Med Rep 2021; 24:841. [PMID: 34633057 DOI: 10.3892/mmr.2021.12481] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 04/23/2021] [Indexed: 11/06/2022] Open
Abstract
Malignant melanoma is a common skin tumor that easily metastasizes and has a poor prognosis. Endostatin is an endogenous vascular endothelial inhibitor that mainly suppresses tumor growth by inhibiting the proliferation of vascular endothelial cells and by reducing the formation of tumor microvessels, however the immunological function of endostatin remains unclear. Previously, we have found that an over‑expression endostatin (pEndostatin) plasmid induced RAW264.7 cells' polarity to M1‑type macrophage. To elucidate the effect of M1‑type macrophages induced by endostatin on melanoma B16 cells, the present study transfected RAW264.7 cells with pEndostatin plasmid and co‑cultured them with B16 cells. Compared with the control group, the expression of matrix metalloproteinase (MMP)‑2, MMP‑9 and proliferating cell nuclear antigen in B16 cells was inhibited by M1‑type macrophages, but cleaved Caspase‑3 and cleaved Caspase‑8 were significantly upregulated and the ratio of Bax/Bcl‑2 was increased. These results indicated that M1 macrophages induced by pEndostatin plasmid inhibited the proliferation and migration of B16 cells and promoted their apoptosis. These findings suggest that the inhibitory effect of endostatin on melanoma is not limited to directly inhibiting tumor microvessel formation, but it may also be related to regulating changes in macrophage polarity.
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Affiliation(s)
- Hua Guo
- Department of Pathology and Pathogen Biology, Ningbo University School of Medical, Ningbo, Zhejiang 315211, P.R. China
| | - Longyuan Zhou
- Department of Anesthesiology, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang 315211, P.R. China
| | - Jun Guo
- Department of Pathology, Sanquan College of Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
| | - Xueqin Huang
- Department of Pathology and Pathogen Biology, Ningbo University School of Medical, Ningbo, Zhejiang 315211, P.R. China
| | - Junlian Gu
- School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shangdong University, Jinan, Shandong 250012, P.R. China
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35
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Wang Y, Li Y, Yin B, Yang X, Wang F, Wang H, Jiang W. Papillary squamous cell carcinoma successfully treated with bronchoscopic intratumoral injections of cisplatin and Endostar: a case report. J Int Med Res 2021; 49:3000605211047077. [PMID: 34579594 PMCID: PMC8485288 DOI: 10.1177/03000605211047077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Squamous cell carcinoma (SCC) is a malignant epithelial tumor originating from the bronchial epithelium that shows keratosis and/or intercellular bridges. Papillary squamous cell carcinoma (PSCC) is an extremely rare subtype of SCC that manifests with a unique intrabronchial papillary growth pattern. Surgical resection is still the first recommendation for localized noninvasive SCC. However, some patients are not candidates for surgical resection. With the development of interventional pulmonology, bronchoscopic interventional therapy has played a key role in the treatment of central airway tumors. Here, we report a case of noninvasive PSCC in the airway treated with an electric snare, argon plasma coagulation (APC), and cryotherapy. After removing the tumor by electrotomy, cryotherapy, and APC, the tumor was injected with Endostar 15 mg (3 ml) and cisplatin 20 mg (diluted to 3 ml with 0.9% normal saline) in six separate sites, once every 21 days. The tumor was eliminated, and the treatment was stopped after four treatment cycles. During the 1-year follow-up, there was no recurrence of PSCC in the airway. In this case, submucosal injections of Endostar combined with cisplatin was a feasible and effective endoscopic method for treating a low-grade intratracheal malignant tumor.
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Affiliation(s)
- Yong Wang
- Department of Respiratory Diseases, 155177Qingdao Haici Hospital, Qingdao Haici Hospital, Qingdao, China.,Department of Pulmonary and Critical Care Medicine, Qingdao Haici Hospital, Qingdao, China
| | - Yue Li
- Department of Respiratory Diseases, 155177Qingdao Haici Hospital, Qingdao Haici Hospital, Qingdao, China.,Department of Pulmonary and Critical Care Medicine, Qingdao Haici Hospital, Qingdao, China
| | - Bin Yin
- Department of Respiratory Diseases, 155177Qingdao Haici Hospital, Qingdao Haici Hospital, Qingdao, China.,Department of Pulmonary and Critical Care Medicine, Qingdao Haici Hospital, Qingdao, China
| | - Xiaoping Yang
- Department of Respiratory Diseases, 155177Qingdao Haici Hospital, Qingdao Haici Hospital, Qingdao, China.,Department of Pulmonary and Critical Care Medicine, Qingdao Haici Hospital, Qingdao, China
| | - Fengchan Wang
- Department of Respiratory Diseases, 155177Qingdao Haici Hospital, Qingdao Haici Hospital, Qingdao, China.,Department of Pulmonary and Critical Care Medicine, Qingdao Haici Hospital, Qingdao, China
| | - Haiyan Wang
- Department of Respiratory Diseases, 155177Qingdao Haici Hospital, Qingdao Haici Hospital, Qingdao, China.,Department of Pulmonary and Critical Care Medicine, Qingdao Haici Hospital, Qingdao, China
| | - Wenqing Jiang
- Department of Respiratory Diseases, 155177Qingdao Haici Hospital, Qingdao Haici Hospital, Qingdao, China.,Department of Pulmonary and Critical Care Medicine, Qingdao Haici Hospital, Qingdao, China
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36
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Zhao Y, Zheng X, Zheng Y, Chen Y, Fei W, Wang F, Zheng C. Extracellular Matrix: Emerging Roles and Potential Therapeutic Targets for Breast Cancer. Front Oncol 2021; 11:650453. [PMID: 33968752 PMCID: PMC8100244 DOI: 10.3389/fonc.2021.650453] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 03/25/2021] [Indexed: 12/12/2022] Open
Abstract
Increasing evidence shows that the extracellular matrix (ECM) is an important regulator of breast cancer (BC). The ECM comprises of highly variable and dynamic components. Compared with normal breast tissue under homeostasis, the ECM undergoes many changes in composition and organization during BC progression. Induced ECM proteins, including fibrinogen, fibronectin, hyaluronic acid, and matricellular proteins, have been identified as important components of BC metastatic cells in recent years. These proteins play major roles in BC progression, invasion, and metastasis. Importantly, several specific ECM molecules, receptors, and remodeling enzymes are involved in promoting resistance to therapeutic intervention. Additional analysis of these ECM proteins and their downstream signaling pathways may reveal promising therapeutic targets against BC. These potential drug targets may be combined with new nanoparticle technologies. This review summarizes recent advances in functional nanoparticles that target the ECM to treat BC. Accurate nanomaterials may offer a new approach to BC treatment.
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Affiliation(s)
- Yunchun Zhao
- Department of Pharmacy, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Lab Women's Reproductive Health, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoling Zheng
- Department of Pharmacy, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Lab Women's Reproductive Health, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yongquan Zheng
- Department of Pharmacy, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Lab Women's Reproductive Health, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yue Chen
- Department of Pharmacy, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Lab Women's Reproductive Health, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Weidong Fei
- Department of Pharmacy, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Lab Women's Reproductive Health, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Fengmei Wang
- Department of Pharmacy, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Lab Women's Reproductive Health, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Caihong Zheng
- Department of Pharmacy, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Lab Women's Reproductive Health, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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37
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Anti-Angiogenic Therapy: Current Challenges and Future Perspectives. Int J Mol Sci 2021; 22:ijms22073765. [PMID: 33916438 PMCID: PMC8038573 DOI: 10.3390/ijms22073765] [Citation(s) in RCA: 199] [Impact Index Per Article: 49.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 02/07/2023] Open
Abstract
Anti-angiogenic therapy is an old method to fight cancer that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new blood vessels formation. Most of the anti-angiogenic agents approved for cancer treatment rely on targeting vascular endothelial growth factor (VEGF) actions, as VEGF signaling is considered the main angiogenesis promotor. In addition to the control of angiogenesis, these drugs can potentiate immune therapy as VEGF also exhibits immunosuppressive functions. Despite the mechanistic rational that strongly supports the benefit of drugs to stop cancer progression, they revealed to be insufficient in most cases. We hypothesize that the rehabilitation of old drugs that interfere with mechanisms of angiogenesis related to tumor microenvironment might represent a promising strategy. In this review, we deepened research on the molecular mechanisms underlying anti-angiogenic strategies and their failure and went further into the alternative mechanisms that impact angiogenesis. We concluded that the combinatory targeting of alternative effectors of angiogenic pathways might be a putative solution for anti-angiogenic therapies.
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38
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Karamanos NK, Theocharis AD, Piperigkou Z, Manou D, Passi A, Skandalis SS, Vynios DH, Orian-Rousseau V, Ricard-Blum S, Schmelzer CEH, Duca L, Durbeej M, Afratis NA, Troeberg L, Franchi M, Masola V, Onisto M. A guide to the composition and functions of the extracellular matrix. FEBS J 2021; 288:6850-6912. [PMID: 33605520 DOI: 10.1111/febs.15776] [Citation(s) in RCA: 459] [Impact Index Per Article: 114.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/13/2021] [Accepted: 02/18/2021] [Indexed: 12/13/2022]
Abstract
Extracellular matrix (ECM) is a dynamic 3-dimensional network of macromolecules that provides structural support for the cells and tissues. Accumulated knowledge clearly demonstrated over the last decade that ECM plays key regulatory roles since it orchestrates cell signaling, functions, properties and morphology. Extracellularly secreted as well as cell-bound factors are among the major members of the ECM family. Proteins/glycoproteins, such as collagens, elastin, laminins and tenascins, proteoglycans and glycosaminoglycans, hyaluronan, and their cell receptors such as CD44 and integrins, responsible for cell adhesion, comprise a well-organized functional network with significant roles in health and disease. On the other hand, enzymes such as matrix metalloproteinases and specific glycosidases including heparanase and hyaluronidases contribute to matrix remodeling and affect human health. Several cell processes and functions, among them cell proliferation and survival, migration, differentiation, autophagy, angiogenesis, and immunity regulation are affected by certain matrix components. Structural alterations have been also well associated with disease progression. This guide on the composition and functions of the ECM gives a broad overview of the matrisome, the major ECM macromolecules, and their interaction networks within the ECM and with the cell surface, summarizes their main structural features and their roles in tissue organization and cell functions, and emphasizes the importance of specific ECM constituents in disease development and progression as well as the advances in molecular targeting of ECM to design new therapeutic strategies.
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Affiliation(s)
- Nikos K Karamanos
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece.,Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), Patras, Greece
| | - Achilleas D Theocharis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
| | - Zoi Piperigkou
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece.,Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), Patras, Greece
| | - Dimitra Manou
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
| | - Alberto Passi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Spyros S Skandalis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
| | - Demitrios H Vynios
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
| | - Véronique Orian-Rousseau
- Karlsruhe Institute of Technology, Institute of Biological and Chemical Systems- Functional Molecular Systems, Eggenstein-Leopoldshafen, Germany
| | - Sylvie Ricard-Blum
- University of Lyon, UMR 5246, ICBMS, Université Lyon 1, CNRS, Villeurbanne Cedex, France
| | - Christian E H Schmelzer
- Fraunhofer Institute for Microstructure of Materials and Systems IMWS, Halle (Saale), Germany.,Institute of Pharmacy, Faculty of Natural Sciences I, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Laurent Duca
- UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Team 2: Matrix Aging and Vascular Remodelling, Université de Reims Champagne Ardenne (URCA), UFR Sciences Exactes et Naturelles, Reims, France
| | - Madeleine Durbeej
- Department of Experimental Medical Science, Unit of Muscle Biology, Lund University, Sweden
| | - Nikolaos A Afratis
- Department Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Linda Troeberg
- Norwich Medical School, University of East Anglia, Bob Champion Research and Education Building, Norwich, UK
| | - Marco Franchi
- Department for Life Quality Study, University of Bologna, Rimini, Italy
| | | | - Maurizio Onisto
- Department of Biomedical Sciences, University of Padova, Italy
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39
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Mukherjee T, Behl T, Sehgal A, Bhatia S, Singh H, Bungau S. Exploring the molecular role of endostatin in diabetic neuropathy. Mol Biol Rep 2021; 48:1819-1836. [PMID: 33559819 DOI: 10.1007/s11033-021-06205-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023]
Abstract
For over a decade, diabetic neuropathy has exhibited great emergence in diabetic patients. Though there are numerous impediments in understanding the underlying pathology it is not that enough to conclude. Initially, there was no intricate protocol for diagnosis as its symptoms mimic most of the neurodegenerative disorders and demyelinating diseases. Continuous research on this, reveals many pathological correlates which are also detectable clinically. The most important pathologic manifestation is imbalanced angiogenesis/neo-vascularization. This review is completely focused on established pathogenesis and anti-angiogenic agents which are physiological signal molecules by the origin. Those agents can also be used externally to inhibit those pathogenic pathways. Pathologically DN demonstrates the misbalanced expression of many knotty factors like VEGF, FGF2, TGFb, NF-kb, TNF-a, MMP, TIMP, and many minor factors. Their pathway towards the incidence of DN is quite interrelated. Many anti-angiogenic agents inhibit neovascularization to many extents, but out of them predominantly inhibition of angiogenic activity is shared by endostatin which is now in clinical trial phase II. It inhibits almost all angiogenic factors and it is possible because they share interrelated pathogenesis towards imbalanced angiogenesis. Endostatin is a physiological signal molecule produced by the proteolytic cleavage of collagen XVIII. It has also a broad research profile in the field of medical research and further investigation can show promising therapeutic effects for benefit of mankind.
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Affiliation(s)
- Tuhin Mukherjee
- Guru Nanak Institute of Pharmaceutical Science and Technology, Kolkata, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Saurabh Bhatia
- Amity Institute of Pharmacy, Amity University, Gurgaon, Haryana, India.,Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Sultanate of Oman
| | | | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
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40
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de Oliveira Costa B, Franco OL. Cryptic Host Defense Peptides: Multifaceted Activity and Prospects for Medicinal Chemistry. Curr Top Med Chem 2021; 20:1274-1290. [PMID: 32209042 DOI: 10.2174/1568026620666200325112425] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 02/03/2020] [Accepted: 02/24/2020] [Indexed: 01/22/2023]
Abstract
Host defense peptides (HDPs) comprise a heterogeneous group of evolutionarily conserved and biologically active small molecules that are produced by different organisms. HDPs are widely researched because they often have multiple biological activities, for example antimicrobial, immunomodulatory and anticancer activity. In this context, in this review we focus on cryptic HDPs, molecules derived specifically from proteolytic processing of endogenous precursor proteins. Here, we explore the biological activity of such molecules and we further discuss the development of optimized sequences based on these natural cryptic HDPs. In addition, we present clinical-phase studies of cryptic HDPs (natural or optimized), and point out the possible applicability of these molecules in medicinal chemistry.
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Affiliation(s)
- Bruna de Oliveira Costa
- S-inova Biotech, Graduate Program in Biotechnology, Universidade Catolica Dom Bosco, Campo Grande, MS, Brazil
| | - Octávio Luiz Franco
- S-inova Biotech, Graduate Program in Biotechnology, Universidade Catolica Dom Bosco, Campo Grande, MS, Brazil.,Department of Genomic Sciences and Biotechnology, Center for Analysis of Proteomics and Biochemistry, Catholic University of Brasília, Brasília, DF, Brazil.,Department of Molecular Pathology, Faculty of Medicine, University of Brasília, Brasília-DF, Brazil
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41
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Jiang W, Yang X, Wang X, Li Y, Yang X, Wang N, Yin B. Bronchoscopic intratumoral injections of cisplatin and endostar as concomitants of standard chemotherapy to treat malignant central airway obstruction. Postgrad Med J 2020; 98:104-112. [PMID: 33070116 DOI: 10.1136/postgradmedj-2020-138823] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 08/31/2020] [Accepted: 10/03/2020] [Indexed: 12/16/2022]
Abstract
STUDY PURPOSE Malignant central airway obstruction (CAO) in non-small cell lung cancer (NSCLC) is associated with high morbidity and requires endobronchial palliative treatment to re-establish a free air passage. We investigate intratumoral therapy combining anti-angiogenic and cytotoxic as a feasible therapeutic modality to treat malignant CAO. STUDY DESIGN Ten NSCLC subjects with symptomatic malignant CAO underwent endobronchial intratumoral cisplatin and Endostar co-injection after tumour debulking next to systemic cisplatin-based chemotherapy. Injection was performed immediately after debulking surgery and was then carried out on day 2, day 6 and day 10 past systemic chemotherapy. Nine subjects of control group constantly received traditional cisplatin-based chemotherapy. Bronchoscopy, CT scanning, histology, FEV1/FVC ratio, Karnofsky performance (KPS) and shortness of breath scores were analysed to assess therapeutic efficacy. RESULTS All 10 subjects benefited from the intratumoral cisplatin and endostar co-injection and systemic chemotherapy combination therapy. Bronchoscopy and CT scanning analyses showed a massive airway widening after treatment. Increased KPS and reduced shortness of breath score were also observed. A substantial improvement of lung function was further confirmed by increased FEV1/FVC ratio. For subjects of control group, the improvement was moderate and obviously not as optimal as the 10 subjects with intratumoral injection. CONCLUSIONS We have shown that the intratumoral injection of cytotoxic cisplatin plus anti-angiogenic Endostar is an effective and safe adjuvant therapeutic option to treat malignant CAO in clinical practice. This time-staggered local and systemic treatment combination improves quality of life and clinical parameters, thus may provide a feasible therapeutic option for symptomatic CAO.
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Affiliation(s)
- Wenqing Jiang
- Department of Respiratory Diseases, Qingdao Haici Hospital, Qingdao, China
| | - Xiaoping Yang
- Department of Respiratory Diseases, Qingdao Haici Hospital, Qingdao, China
| | - Xuekun Wang
- Department of Respiration, Qingdao Central Hospital, Qingdao, China
| | - Yue Li
- Department of Respiratory Diseases, Qingdao Haici Hospital, Qingdao, China
| | - Xinai Yang
- Department of Respiratory Diseases, Qingdao Haici Hospital, Qingdao, China
| | - Na Wang
- Department of Respiratory Diseases, Qingdao Haici Hospital, Qingdao, China
| | - Bin Yin
- Department of Respiratory Diseases, Qingdao Haici Hospital, Qingdao, China
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Le QV, Suh J, Oh YK. Nanomaterial-Based Modulation of Tumor Microenvironments for Enhancing Chemo/Immunotherapy. AAPS JOURNAL 2019; 21:64. [PMID: 31102154 DOI: 10.1208/s12248-019-0333-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 04/08/2019] [Indexed: 02/07/2023]
Abstract
The tumor microenvironment (TME) has drawn considerable research attention as an alternative target for nanomedicine-based cancer therapy. Various nanomaterials that carry active substances have been designed to alter the features or composition of the TME and thereby improve the delivery and efficacy of anticancer chemotherapeutics. These alterations include disruption of the extracellular matrix and tumor vascular systems to promote perfusion or modulate hypoxia. Nanomaterials have also been used to modulate the immunological microenvironment of tumors. In this context, nanomaterials have been shown to alter populations of cancer-associated fibroblasts, tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells. Despite considerable progress, nanomaterial-based TME modulation must overcome several limitations before this strategy can be translated to clinical trials, including issues related to limited tumor tissue penetration, tumor heterogeneity, and immune toxicity. In this review, we summarize recent progress and challenges of nanomaterials used to modulate the TME to enhance the efficacy of anticancer chemotherapy and immunotherapy.
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Affiliation(s)
- Quoc-Viet Le
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak gu, Seoul, 08826, Republic of Korea
| | - Juhan Suh
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak gu, Seoul, 08826, Republic of Korea
| | - Yu-Kyoung Oh
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak gu, Seoul, 08826, Republic of Korea.
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