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      In vitro combination therapy of pathologic angiogenesis using anti-vascular endothelial growth factor and anti-neuropilin-1 nanobodies

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          Abstract

          Objective(s):

          Emergence of resistant tumor cells to the current therapeutics is the main hindrance in cancer treatment. Combination therapy, which mixes two or more drugs, is a way to overcome resistant problems of cancer cells to current treatments. Nanobodies are promising tools in cancer therapy due to their high affinity as well as high penetration to tumor sites.

          Materials and Methods:

          Here, the inhibitory effect of mixtures of two nanobodies (anti-vascular endothelial growth factor (VEGF) and anti-neuropilin-1 (NRP-1) nanobodies) on tube formation of human endothelial cells in vitro and ex vivo were analyzed.

          Results:

          Results showed that combination of two drugs significantly inhibited proliferation and tube formation of human endothelial cells. In addition, mixtures of two nanobodies inhibited angiogenesis in chick chorioallantoic membrane (CAM) assay efficiently compared with each individual nanobody.

          Conclusion:

          Results highlight the efficacy of combination therapy of cancer compared with mono-therapy and promises development of novel anti-cancer therapeutics based on nanobodies targeting two or more targets of tumor cells.

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          Most cited references31

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          The biology of VEGF and its receptors.

          Napoleone Ferrara, Hans-Peter Gerber, Jennifer LeCouter (2003)
          Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions. VEGF has also been implicated in pathological angiogenesis associated with tumors, intraocular neovascular disorders and other conditions. The biological effects of VEGF are mediated by two receptor tyrosine kinases (RTKs), VEGFR-1 and VEGFR-2, which differ considerably in signaling properties. Non-signaling co-receptors also modulate VEGF RTK signaling. Currently, several VEGF inhibitors are undergoing clinical testing in several malignancies. VEGF inhibition is also being tested as a strategy for the prevention of angiogenesis, vascular leakage and visual loss in age-related macular degeneration.
          Article 0 comments Cited 645 times – based on 0 reviews     Review now
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            Combination therapy in combating cancer

            Reza Bayat Mokhtari, Tina Homayouni, Narges Baluch … (2017)
            Combination therapy, a treatment modality that combines two or more therapeutic agents, is a cornerstone of cancer therapy. The amalgamation of anti-cancer drugs enhances efficacy compared to the mono-therapy approach because it targets key pathways in a characteristically synergistic or an additive manner. This approach potentially reduces drug resistance, while simultaneously providing therapeutic anti-cancer benefits, such as reducing tumour growth and metastatic potential, arresting mitotically active cells, reducing cancer stem cell populations, and inducing apoptosis. The 5-year survival rates for most metastatic cancers are still quite low, and the process of developing a new anti-cancer drug is costly and extremely time-consuming. Therefore, new strategies that target the survival pathways that provide efficient and effective results at an affordable cost are being considered. One such approach incorporates repurposing therapeutic agents initially used for the treatment of different diseases other than cancer. This approach is effective primarily when the FDA-approved agent targets similar pathways found in cancer. Because one of the drugs used in combination therapy is already FDA-approved, overall costs of combination therapy research are reduced. This increases cost efficiency of therapy, thereby benefiting the “medically underserved”. In addition, an approach that combines repurposed pharmaceutical agents with other therapeutics has shown promising results in mitigating tumour burden. In this systematic review, we discuss important pathways commonly targeted in cancer therapy. Furthermore, we also review important repurposed or primary anti-cancer agents that have gained popularity in clinical trials and research since 2012.
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              Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases.

              Masabumi Shibuya (2013)
              Vascular endothelial growth factors (VEGFs) belong to the platelet-derived growth factor supergene family, and they play central roles in the regulation of angiogenesis and lymphangiogenesis. VEGF-A, the major factor for angiogenesis, binds to two tyrosine kinase (TK) receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), and regulates endothelial cell proliferation, migration, vascular permeability, secretion and other endothelial functions. VEGFR-2 exhibits a strong TK activity towards pro-angiogenic signals, whereas the soluble VEGFR-1 (sFlt-1) functions as an endogenous VEGF inhibitor. sFlt-1 is abnormally overexpressed in the placenta of preeclampsia patients, resulting in the major symptoms of the disease due to abnormal trapping of VEGFs. The VEGF-VEGFR system is crucial for tumour angiogenesis, and anti-VEGF-VEGFR molecules are now widely used in the clinical field to treat cancer patients. The efficacy of these molecules in prolonging the overall survival of patients has been established; however, some cancers do not respond well and reduced tumour sensitivity to anti-VEGF signals may occur after long-term treatment. The molecular basis of tumour refractoriness should be determined to improve anti-angiogenic therapy.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Iran J Basic Med Sci
                Journal ID (iso-abbrev): Iran J Basic Med Sci
                Journal ID (publisher-id): ijbms
                Title: Iranian Journal of Basic Medical Sciences
                Publisher: Mashhad University of Medical Sciences (Mashhad, Iran )
                ISSN (Print): 2008-3866
                ISSN (Electronic): 2008-3874
                Publication date (Print): October 2020
                Volume: 23
                Issue: 10
                Pages: 1335-1339
                Affiliations
                [1 ]Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
                Author notes
                [* ]Corresponding author: Fatemeh Kazemi-Lomedasht, Biotechnology Research Center, Venom and Biotherapeutics Molecules Laboratory, Pasteur Institute of Iran, Tehran, Iran. Tel: +98-2166480780; Email: fa_kazemi@pasteur.ac.ir
                Article
                DOI: 10.22038/ijbms.2020.47782.11000
                PMC ID: 7585540
                SO-VID: eb51bedf-d5df-4444-9744-51ede9399083
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, ( http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 11 August 2020
                Date accepted : 5 July 2020
                Categories
                Subject: Original Article

                Keywords: cancer,dual targeting,nanobody,nrp-1,single domain antibody,vegf
                Data availability:
                Keywords: cancer, dual targeting, nanobody, nrp-1, single domain antibody, vegf

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