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Mahmudi H, Shahpouri M, Adili-Aghdam MA, Akbari M, Salemi A, Alimohammadvand S, Barzegari A, Mazloomi M, Jaymand M, Jahanban-Esfahlan R. Self-activating chitosan-based nanoparticles for sphingosin-1 phosphate modulator delivery and selective tumor therapy. Int J Biol Macromol 2024; 272:132940. [PMID: 38848845 DOI: 10.1016/j.ijbiomac.2024.132940] [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: 10/24/2023] [Revised: 05/27/2024] [Accepted: 06/04/2024] [Indexed: 06/09/2024]
Abstract
This study reports on the design and synthesis of hypoxia responsive nanoparticles (HRNPs) composed of methoxy polyethylene glycol-4,4 dicarboxylic azolinker-chitosan (mPEG-Azo-chitosan) as ideal drug delivery platform for Fingolimod (FTY720, F) delivery to achieve selective and highly enhanced TNBC therapy in vivo. Herein, HRNPs with an average size of 49.86 nm and a zeta potential of +3.22 mV were synthetized, which after PEG shedding can shift into a more positively-charged NPs (+30.3 mV), possessing self-activation ability under hypoxia situation in vitro, 2D and 3D culture. Treatment with lower doses of HRNPs@F significantly reduced MDA-MB-231 microtumor size to 15 %, induced apoptosis by 88 % within 72 h and reduced highly-proliferative 4 T1 tumor weight by 87.66 % vs. ∼30 % for Fingolimod compared to the untreated controls. To the best of our knowledge, this is the first record for development of hypoxia-responsive chitosan-based NPs with desirable physicochemical properties, and selective self-activation potential to generate highly-charged nanosized tumor-penetrating chitosan NPs. This formulation is capable of localized delivery of Fingolimod to the tumor core, minimizing its side effects while boosting its anti-tumor potential for eradication of TNBC solid tumors.
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Affiliation(s)
- Hossein Mahmudi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Shahpouri
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Morteza Akbari
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aysan Salemi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sajjad Alimohammadvand
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abolfazl Barzegari
- Innovation Center for Stem Cell Research and Regenerative Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - MirAhmad Mazloomi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Jaymand
- Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran; Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Rana Jahanban-Esfahlan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Davy M, Genest L, Legrand C, Pelouin O, Froget G, Castagné V, Rupp T. Evaluation of Temozolomide and Fingolimod Treatments in Glioblastoma Preclinical Models. Cancers (Basel) 2023; 15:4478. [PMID: 37760448 PMCID: PMC10527257 DOI: 10.3390/cancers15184478] [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: 07/31/2023] [Revised: 09/01/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
Glioblastomas are malignant brain tumors which remain lethal due to their aggressive and invasive nature. The standard treatment combines surgical resection, radiotherapy, and chemotherapy using Temozolomide, albeit with a minor impact on patient prognosis (15 months median survival). New therapies evaluated in preclinical translational models are therefore still required to improve patient survival and quality of life. In this preclinical study, we evaluated the effect of Temozolomide in different models of glioblastoma. We also aimed to investigate the efficacy of Fingolimod, an immunomodulatory drug for multiple sclerosis also described as an inhibitor of the sphingosine-1-phosphate (S1P)/S1P receptor axis. The effects of Fingolimod and Temozolomide were analyzed with in vitro 2D and 3D cellular assay and in vivo models using mouse and human glioblastoma cells implanted in immunocompetent or immunodeficient mice, respectively. We demonstrated both in in vitro and in vivo models that Temozolomide has a varied effect depending on the tumor type (i.e., U87MG, U118MG, U138MG, and GL261), demonstrating sensitivity, acquired resistance, and purely resistant tumor phenotypes, as observed in patients. Conversely, Fingolimod only reduced in vitro 2D tumor cell growth and increased cytotoxicity. Indeed, Fingolimod had little or no effect on 3D spheroid cytotoxicity and was devoid of effect on in vivo tumor progression in Temozolomide-sensitive models. These results suggest that the efficacy of Fingolimod is dependent on the glioblastoma tumor microenvironment. Globally, our data suggest that the response to Temozolomide varies depending on the cancer model, consistent with its clinical activity, whereas the potential activity of Fingolimod may merit further evaluation.
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Affiliation(s)
| | | | | | | | | | | | - Tristan Rupp
- Porsolt SAS, ZA de Glatigné, 53940 Le Genest-Saint-Isle, France
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3
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Pal P, Atilla-Gokcumen GE, Frasor J. Emerging Roles of Ceramides in Breast Cancer Biology and Therapy. Int J Mol Sci 2022; 23:ijms231911178. [PMID: 36232480 PMCID: PMC9569866 DOI: 10.3390/ijms231911178] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/15/2022] [Accepted: 09/20/2022] [Indexed: 11/16/2022] Open
Abstract
One of the classic hallmarks of cancer is the imbalance between elevated cell proliferation and reduced cell death. Ceramide, a bioactive sphingolipid that can regulate this balance, has long been implicated in cancer. While the effects of ceramide on cell death and therapeutic efficacy are well established, emerging evidence indicates that ceramide turnover to downstream sphingolipids, such as sphingomyelin, hexosylceramides, sphingosine-1-phosphate, and ceramide-1-phosphate, is equally important in driving pro-tumorigenic phenotypes, such as proliferation, survival, migration, stemness, and therapy resistance. The complex and dynamic sphingolipid network has been extensively studied in several cancers, including breast cancer, to find key sphingolipidomic alterations that can be exploited to develop new therapeutic strategies to improve patient outcomes. Here, we review how the current literature shapes our understanding of how ceramide synthesis and turnover are altered in breast cancer and how these changes offer potential strategies to improve breast cancer therapy.
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Affiliation(s)
- Purab Pal
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - G. Ekin Atilla-Gokcumen
- Department of Chemistry, University at Buffalo, The State University of New York (SUNY), Buffalo, NY 14260, USA
- Correspondence: (G.E.A.-G.); (J.F.)
| | - Jonna Frasor
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
- Correspondence: (G.E.A.-G.); (J.F.)
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4
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Companioni O, Mir C, Garcia-Mayea Y, LLeonart ME. Targeting Sphingolipids for Cancer Therapy. Front Oncol 2021; 11:745092. [PMID: 34737957 PMCID: PMC8560795 DOI: 10.3389/fonc.2021.745092] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 09/30/2021] [Indexed: 12/14/2022] Open
Abstract
Sphingolipids are an extensive class of lipids with different functions in the cell, ranging from proliferation to cell death. Sphingolipids are modified in multiple cancers and are responsible for tumor proliferation, progression, and metastasis. Several inhibitors or activators of sphingolipid signaling, such as fenretinide, safingol, ABC294640, ceramide nanoliposomes (CNLs), SKI-II, α-galactosylceramide, fingolimod, and sonepcizumab, have been described. The objective of this review was to analyze the results from preclinical and clinical trials of these drugs for the treatment of cancer. Sphingolipid-targeting drugs have been tested alone or in combination with chemotherapy, exhibiting antitumor activity alone and in synergism with chemotherapy in vitro and in vivo. As a consequence of treatments, the most frequent mechanism of cell death is apoptosis, followed by autophagy. Aslthough all these drugs have produced good results in preclinical studies of multiple cancers, the outcomes of clinical trials have not been similar. The most effective drugs are fenretinide and α-galactosylceramide (α-GalCer). In contrast, minor adverse effects restricted to a few subjects and hepatic toxicity have been observed in clinical trials of ABC294640 and safingol, respectively. In the case of CNLs, SKI-II, fingolimod and sonepcizumab there are some limitations and absence of enough clinical studies to demonstrate a benefit. The effectiveness or lack of a major therapeutic effect of sphingolipid modulation by some drugs as a cancer therapy and other aspects related to their mechanism of action are discussed in this review.
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Affiliation(s)
- Osmel Companioni
- Biomedical Research in Cancer Stem Cells Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Cristina Mir
- Biomedical Research in Cancer Stem Cells Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Yoelsis Garcia-Mayea
- Biomedical Research in Cancer Stem Cells Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Matilde E LLeonart
- Biomedical Research in Cancer Stem Cells Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.,Spanish Biomedical Research Network Center in Oncology, CIBERONC, Madrid, Spain
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5
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Rupp T, Pelouin O, Genest L, Legrand C, Froget G, Castagné V. Therapeutic potential of Fingolimod in triple negative breast cancer preclinical models. Transl Oncol 2020; 14:100926. [PMID: 33157518 PMCID: PMC7649527 DOI: 10.1016/j.tranon.2020.100926] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 10/14/2020] [Accepted: 10/21/2020] [Indexed: 12/29/2022] Open
Abstract
Fingolimod represses triple negative breast cancer cells survival in vitro by inducing cell apoptosis. Fingolimod represses triple negative breast cancer progression in orthotopic graft murine in vivo models. Fingolimod represses spleen and liver metastases without affecting lung metastasis in murine in vivo models. In contrast with Cisplatin, Fingolimod is well tolerated in murine in vivo models. Surgery followed by a chemotherapy agent is the first-line treatment for breast cancer patients. Nevertheless, new targets are required for women with triple-negative breast cancer (TNBC) in order to improve the treatment of this aggressive cancer subtype. Multiple pro-inflammatory molecules including lipid-based substances such as sphingosine-1-phosphate (S1P) promote cancer progression. In this preclinical study, we aim to investigate the efficacy of Fingolimod, an inhibitor of S1P / S1P receptors axis, already approved as an immunomodulator in multiple sclerosis. The impact of Fingolimod was analyzed using in vitro 2D and 3D cell survival analysis and in vivo orthotopic graft models, using mouse and human TNBC cells implanted in immunocompetent or immunodeficient mice, respectively. Resection of the tumor primary mass was also performed to mimic the clinical standard of care. We demonstrated that Fingolimod repressed tumor cell survival in vitro. We also showed in preclinical mouse TNBC models that Fingolimod repressed tumor progression and liver and spleen metastases without apparent adverse effects on the animals. Our data indicate that Fingolimod induces tumor cells apoptosis and thereby represses tumor progression. Globally, our data suggest that Fingolimod merits further evaluation as a potential therapeutic opportunity for TNBC.
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Affiliation(s)
- Tristan Rupp
- Porsolt SAS, ZA de Glatigné, 53940 Le Genest-Saint-Isle, France.
| | - Océane Pelouin
- Porsolt SAS, ZA de Glatigné, 53940 Le Genest-Saint-Isle, France
| | - Laurie Genest
- Porsolt SAS, ZA de Glatigné, 53940 Le Genest-Saint-Isle, France
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6
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GPCR Modulation in Breast Cancer. Int J Mol Sci 2018; 19:ijms19123840. [PMID: 30513833 PMCID: PMC6321247 DOI: 10.3390/ijms19123840] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 11/22/2018] [Accepted: 11/27/2018] [Indexed: 12/15/2022] Open
Abstract
Breast cancer is the most prevalent cancer found in women living in developed countries. Endocrine therapy is the mainstay of treatment for hormone-responsive breast tumors (about 70% of all breast cancers) and implies the use of selective estrogen receptor modulators and aromatase inhibitors. In contrast, triple-negative breast cancer (TNBC), a highly heterogeneous disease that may account for up to 24% of all newly diagnosed cases, is hormone-independent and characterized by a poor prognosis. As drug resistance is common in all breast cancer subtypes despite the different treatment modalities, novel therapies targeting signaling transduction pathways involved in the processes of breast carcinogenesis, tumor promotion and metastasis have been subject to accurate consideration. G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors involved in the development and progression of many tumors including breast cancer. Here we discuss data regarding GPCR-mediated signaling, pharmacological properties and biological outputs toward breast cancer tumorigenesis and metastasis. Furthermore, we address several drugs that have shown an unexpected opportunity to interfere with GPCR-based breast tumorigenic signals.
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De Francesco EM, Sotgia F, Clarke RB, Lisanti MP, Maggiolini M. G Protein-Coupled Receptors at the Crossroad between Physiologic and Pathologic Angiogenesis: Old Paradigms and Emerging Concepts. Int J Mol Sci 2017; 18:ijms18122713. [PMID: 29240722 PMCID: PMC5751314 DOI: 10.3390/ijms18122713] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/11/2017] [Accepted: 12/11/2017] [Indexed: 12/14/2022] Open
Abstract
G protein-coupled receptors (GPCRs) have been implicated in transmitting signals across the extra- and intra-cellular compartments, thus allowing environmental stimuli to elicit critical biological responses. As GPCRs can be activated by an extensive range of factors including hormones, neurotransmitters, phospholipids and other stimuli, their involvement in a plethora of physiological functions is not surprising. Aberrant GPCR signaling has been regarded as a major contributor to diverse pathologic conditions, such as inflammatory, cardiovascular and neoplastic diseases. In this regard, solid tumors have been demonstrated to activate an angiogenic program that relies on GPCR action to support cancer growth and metastatic dissemination. Therefore, the manipulation of aberrant GPCR signaling could represent a promising target in anticancer therapy. Here, we highlight the GPCR-mediated angiogenic function focusing on the molecular mechanisms and transduction effectors driving the patho-physiological vasculogenesis. Specifically, we describe evidence for the role of heptahelic receptors and associated G proteins in promoting angiogenic responses in pathologic conditions, especially tumor angiogenesis and progression. Likewise, we discuss opportunities to manipulate aberrant GPCR-mediated angiogenic signaling for therapeutic benefit using innovative GPCR-targeted and patient-tailored pharmacological strategies.
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Affiliation(s)
- Ernestina M De Francesco
- Department of Pharmacy, Health and Nutrition Sciences, University of Calabria via Savinio, 87036 Rende, Italy.
- Breast Cancer Now Research Unit, Division of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester M20 4GJ, UK.
| | - Federica Sotgia
- Translational Medicine, School of Environment and Life Sciences, Biomedical Research Centre, University of Salford, Greater Manchester M5 4WT, UK.
| | - Robert B Clarke
- Breast Cancer Now Research Unit, Division of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester M20 4GJ, UK.
| | - Michael P Lisanti
- Translational Medicine, School of Environment and Life Sciences, Biomedical Research Centre, University of Salford, Greater Manchester M5 4WT, UK.
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutrition Sciences, University of Calabria via Savinio, 87036 Rende, Italy.
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8
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Alshaker H, Wang Q, Srivats S, Chao Y, Cooper C, Pchejetski D. New FTY720-docetaxel nanoparticle therapy overcomes FTY720-induced lymphopenia and inhibits metastatic breast tumour growth. Breast Cancer Res Treat 2017; 165:531-543. [PMID: 28695300 PMCID: PMC5602005 DOI: 10.1007/s10549-017-4380-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2017] [Accepted: 07/05/2017] [Indexed: 01/21/2023]
Abstract
Purpose Combining molecular therapies with chemotherapy may offer an improved clinical outcome for chemoresistant tumours. Sphingosine-1-phosphate (S1P) receptor antagonist and sphingosine kinase 1 (SK1) inhibitor FTY720 (FTY) has promising anticancer properties, however, it causes systemic lymphopenia which impairs its use in cancer patients. In this study, we developed a nanoparticle (NP) combining docetaxel (DTX) and FTY for enhanced anticancer effect, targeted tumour delivery and reduced systemic toxicity. Methods Docetaxel, FTY and glucosamine were covalently conjugated to poly(lactic-co-glycolic acid) (PLGA). NPs were characterised by dynamic light scattering and electron microscopy. The cellular uptake, cytotoxicity and in vivo antitumor efficacy of CNPs were evaluated. Results We show for the first time that in triple negative breast cancer cells FTY provides chemosensitisation to DTX, allowing a four-fold reduction in the effective dose. We have encapsulated both drugs in PLGA complex NPs (CNPs), with narrow size distribution of ~ 100 nm and excellent cancer cell uptake providing sequential, sustained release of FTY and DTX. In triple negative breast cancer cells and mouse breast cancer models, CNPs had similar efficacy to systemic free therapies, but allowed an effective drug dose reduction. Application of CNPs has significantly reversed chemotherapy side effects such as weight loss, liver toxicity and, most notably, lymphopenia. Conclusions We show for the first time the DTX chemosensitising effects of FTY in triple negative breast cancer. We further demonstrate that encapsulation of free drugs in CNPs can improve targeting, provide low off-target toxicity and most importantly reduce FTY-induced lymphopenia, offering potential therapeutic use of FTY in clinical cancer treatment. Electronic supplementary material The online version of this article (doi:10.1007/s10549-017-4380-8) contains supplementary material, which is available to authorised users.
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Affiliation(s)
- Heba Alshaker
- School of Medicine, University of East Anglia, 2.53 BCRE, Norwich Research Park, Norwich, NR47UQ, UK
- Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan
| | - Qi Wang
- School of Medicine, University of East Anglia, 2.53 BCRE, Norwich Research Park, Norwich, NR47UQ, UK
| | - Shyam Srivats
- University of California San Francisco, Health Sciences East 1350, San Francisco, CA, 94143-0130, USA
| | - Yimin Chao
- School of Chemistry, University of East Anglia, Norwich, UK
| | - Colin Cooper
- School of Medicine, University of East Anglia, 2.53 BCRE, Norwich Research Park, Norwich, NR47UQ, UK
| | - Dmitri Pchejetski
- School of Medicine, University of East Anglia, 2.53 BCRE, Norwich Research Park, Norwich, NR47UQ, UK.
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9
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Wragg JW, Heath VL, Bicknell R. Sunitinib Treatment Enhances Metastasis of Innately Drug-Resistant Breast Tumors. Cancer Res 2017; 77:1008-1020. [PMID: 28011623 PMCID: PMC5321582 DOI: 10.1158/0008-5472.can-16-1982] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 11/08/2016] [Accepted: 11/30/2016] [Indexed: 12/19/2022]
Abstract
Antiangiogenic therapies have failed to confer survival benefits in patients with metastatic breast cancer (mBC). However, to date, there has not been an inquiry into the roles for acquired versus innate drug resistance in this setting. In this study, we report roles for these distinct phenotypes in determining therapeutic response in a murine model of mBC resistance to the antiangiogenic tyrosine kinase inhibitor sunitinib. Using tumor measurement and vascular patterning approaches, we differentiated tumors displaying innate versus acquired resistance. Bioluminescent imaging of tumor metastases to the liver, lungs, and spleen revealed that sunitinib administration enhances metastasis, but only in tumors displaying innate resistance to therapy. Transcriptomic analysis of tumors displaying acquired versus innate resistance allowed the identification of specific biomarkers, many of which have a role in angiogenesis. In particular, aquaporin-1 upregulation occurred in acquired resistance, mTOR in innate resistance, and pleiotrophin in both settings, suggesting their utility as candidate diagnostics to predict drug response or to design tactics to circumvent resistance. Our results unravel specific features of antiangiogenic resistance, with potential therapeutic implications. Cancer Res; 77(4); 1008-20. ©2016 AACR.
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Affiliation(s)
- Joseph W Wragg
- Institutes of Cardiovascular Sciences and Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Victoria L Heath
- Institutes of Cardiovascular Sciences and Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Roy Bicknell
- Institutes of Cardiovascular Sciences and Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
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10
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Alvarado A, Faustino-Rocha AI, Colaço B, Oliveira PA. Experimental mammary carcinogenesis - Rat models. Life Sci 2017; 173:116-134. [PMID: 28188729 DOI: 10.1016/j.lfs.2017.02.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 01/26/2017] [Accepted: 02/06/2017] [Indexed: 12/22/2022]
Abstract
Mammary cancer is one of the most common cancers, victimizing more than half a million of women worldwide every year. Despite all the studies in this field, the current therapeutic approaches are not effective and have several devastating effects for patients. In this way, the need to better understand the mammary cancer biopathology and find effective therapies led to the development of several rodent models over years. With this review, the authors intended to provide the readers with an overview of the rat models used to study mammary carcinogenesis, with a special emphasis on chemically-induced models.
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Affiliation(s)
- Antonieta Alvarado
- Área de Patología, Decanato de Ciencias Veterinarias, Universidad Centroccidental "Lisandro Alvarado", UCLA, Lara, Venezuela; Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
| | - Ana I Faustino-Rocha
- Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences, UTAD, Vila Real, Portugal
| | - Bruno Colaço
- Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Department of Zootechnics, School of Agrarian and Veterinary Sciences, UTAD, Vila Real, Portugal
| | - Paula A Oliveira
- Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences, UTAD, Vila Real, Portugal.
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11
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Rincón R, Cristóbal I, Zazo S, Arpí O, Menéndez S, Manso R, Lluch A, Eroles P, Rovira A, Albanell J, García-Foncillas J, Madoz-Gúrpide J, Rojo F. PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects. Oncotarget 2015; 6:4299-314. [PMID: 25726524 PMCID: PMC4414191 DOI: 10.18632/oncotarget.3012] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 12/31/2014] [Indexed: 11/26/2022] Open
Abstract
The protein phosphatase 2A (PP2A) is a key tumor suppressor which has emerged as a novel molecular target in some human cancers. Here, we show that PP2A inhibition is a common event in breast cancer and identified PP2A phosphorylation and deregulation SET and CIP2A as molecular contributing mechanisms to inactivate PP2A. Interestingly, restoration of PP2A activity after FTY720 treatment reduced cell growth, induced apoptosis and decreased AKT and ERK activation. Moreover, FTY720 led to PP2A activation then enhancing doxorubicin-induced antitumor effects both in vitro and in vivo. PP2A inhibition (CPscore: PP2A phosphorylation and/or CIP2A overexpression) was detected in 27% of cases (62/230), and associated with grade (p = 0.017), relapse (p < 0.001), negative estrogen (p < 0.001) and progesterone receptor expression (p < 0.001), HER2-positive tumors (p = 0.049), Ki-67 expression (p < 0.001), and higher AKT (p < 0.001) and ERK (p < 0.001) phosphorylation. Moreover, PP2A inhibition determined shorter overall (p = 0.006) and event-free survival (p = 0.003), and multivariate analysis confirmed its independent prognostic impact. Altogether, our results indicate that PP2A is frequently inactivated in breast cancer and determines worse outcome, and its restoration using PP2A activators represents an alternative therapeutic strategy in this disease.
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Affiliation(s)
- Raúl Rincón
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital "Fundación Jiménez Diaz", Madrid, Spain
| | - Ion Cristóbal
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital "Fundación Jiménez Diaz", Madrid, Spain
| | - Sandra Zazo
- Pathology Department, IIS "Fundación Jiménez Diaz", Madrid, Spain
| | - Oriol Arpí
- Medical Oncology Department, Hospital del Mar, Barcelona, Spain
| | - Silvia Menéndez
- Medical Oncology Department, Hospital del Mar, Barcelona, Spain
| | - Rebeca Manso
- Pathology Department, IIS "Fundación Jiménez Diaz", Madrid, Spain
| | - Ana Lluch
- Institute of Health Research INCLIVA, Valencia, Spain
| | - Pilar Eroles
- Institute of Health Research INCLIVA, Valencia, Spain
| | - Ana Rovira
- Medical Oncology Department, Hospital del Mar, Barcelona, Spain
| | - Joan Albanell
- Medical Oncology Department, Hospital del Mar, Barcelona, Spain
| | - Jesús García-Foncillas
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital "Fundación Jiménez Diaz", Madrid, Spain
| | | | - Federico Rojo
- Pathology Department, IIS "Fundación Jiménez Diaz", Madrid, Spain.,Medical Oncology Department, Hospital del Mar, Barcelona, Spain
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12
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Kornienko A, Evidente A, Vurro M, Mathieu V, Cimmino A, Evidente M, van Otterlo WAL, Dasari R, Lefranc F, Kiss R. Toward a Cancer Drug of Fungal Origin. Med Res Rev 2015; 35:937-67. [PMID: 25850821 PMCID: PMC4529806 DOI: 10.1002/med.21348] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Although fungi produce highly structurally diverse metabolites, many of which have served as excellent sources of pharmaceuticals, no fungi-derived agent has been approved as a cancer drug so far. This is despite a tremendous amount of research being aimed at the identification of fungal metabolites with promising anticancer activities. This review discusses the results of clinical testing of fungal metabolites and their synthetic derivatives, with the goal to evaluate how far we are from an approved cancer drug of fungal origin. Also, because in vivo studies in animal models are predictive of the efficacy and toxicity of a given compound in a clinical situation, literature describing animal cancer testing of compounds of fungal origin is reviewed as well. Agents showing the potential to advance to clinical trials are also identified. Finally, the technological challenges involved in the exploitation of fungal biodiversity and procurement of sufficient quantities of clinical candidates are discussed, and potential solutions that could be pursued by researchers are highlighted.
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Affiliation(s)
- Alexander Kornienko
- Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas 78666, USA
| | - Antonio Evidente
- Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte S. Angelo, Via Cintia 4, 80126 Napoli, Italy
| | - Maurizio Vurro
- Institute of Sciences of Food Production, National Research Council, Via Amendola 122/0, 70126 Bari, Italy
| | - Véronique Mathieu
- Laboratorie de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Alessio Cimmino
- Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte S. Angelo, Via Cintia 4, 80126 Napoli, Italy
| | - Marco Evidente
- Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte S. Angelo, Via Cintia 4, 80126 Napoli, Italy
| | - Willem A. L. van Otterlo
- Department of Chemistry and Polymer Science, University of Stellenbosch, Private Bag X1, Matieland 7602, South Africa
| | - Ramesh Dasari
- Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas 78666, USA
| | - Florence Lefranc
- Service de Neurochirurgie, Hôpital Erasme; Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Robert Kiss
- Laboratorie de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Brussels, Belgium
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13
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Ahmed D, de Verdier PJ, Ryk C, Lunqe O, Stål P, Flygare J. FTY720 (Fingolimod) sensitizes hepatocellular carcinoma cells to sorafenib-mediated cytotoxicity. Pharmacol Res Perspect 2015; 3:e00171. [PMID: 26516583 PMCID: PMC4618642 DOI: 10.1002/prp2.171] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 06/26/2015] [Accepted: 06/27/2015] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The multityrosine kinase inhibitor sorafenib is used in the therapy of advanced disease. However, the effects of sorafenib are limited, and combination treatments aiming at improved survival are encouraged. The sphingosine analog FTY720 (Fingolimod), which is approved for treatment of multiple sclerosis, has shown tumor suppressive effects in cell lines and animal models of HCC. In the present study, we combined sorafenib with FTY720 in order to sensitize the HCC cell lines Huh7 and HepG2 to sorafenib treatment. Using the XTT assay we show that noncytotoxic doses of FTY720 synergistically enhanced the decrease in viability caused by treatment of both cell lines with increasing doses of sorafenib. Further studies in Huh7 revealed that combined treatment with FTY720 and sorafenib resulted in G1 arrest and enhanced cell death measured using flow cytometry analysis of cells labeled with propidium iodide (PI)/Annexin-V and PI and 4′,6-diamidino-2-phenylindole-staining of nuclei. In addition, signs of both caspase-dependent and – independent apoptosis were observed, as cotreatment with FTY720 and sorafenib caused cytochrome c release and poly-ADP ribose polymerase-cleavage as well as translocation of Apoptosis-inducing factor into the cytosol. We also detected features of autophagy blockage, as the protein levels of LC3-II and p62 were affected by combined treatment with FTY720 and sorafenib. Together, our results suggest that FTY720 sensitizes HCC cells to cytotoxic effects induced by treatment with sorafenib alone. These findings warrant further investigations of combined treatment with sorafenib and FTY720 in vivo in order to develop more effective treatment of HCC.
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Affiliation(s)
- Dilruba Ahmed
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Huddinge, Stockholm, Sweden
| | - Petra J de Verdier
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Huddinge, Stockholm, Sweden
| | - Charlotta Ryk
- Urology Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet 171 76, Stockholm, Sweden
| | - Oscar Lunqe
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Huddinge, Stockholm, Sweden
| | - Per Stål
- Division of Gastroenterology and Hepatology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge Stockholm, Sweden
| | - Jenny Flygare
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Huddinge, Stockholm, Sweden
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14
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Patmanathan SN, Yap LF, Murray PG, Paterson IC. The antineoplastic properties of FTY720: evidence for the repurposing of fingolimod. J Cell Mol Med 2015; 19:2329-40. [PMID: 26171944 PMCID: PMC4594675 DOI: 10.1111/jcmm.12635] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 05/20/2015] [Indexed: 12/20/2022] Open
Abstract
Almost all drugs approved for use in humans possess potentially beneficial 'off-target' effects in addition to their principal activity. In some cases this has allowed for the relatively rapid repurposing of drugs for other indications. In this review we focus on the potential for re-purposing FTY720 (also known as fingolimod, Gilenya(™)), an immunomodulatory drug recently approved for the treatment of multiple sclerosis (MS). The therapeutic benefit of FTY720 in MS is largely attributed to the immunosuppressive effects that result from its modulation of sphingosine 1-phosphate receptor signalling. However, this drug has also been shown to inhibit other cancer-associated signal transduction pathways in part because of its structural similarity to sphingosine, and consequently shows efficacy as an anti-cancer agent both in vitro and in vivo. Here, we review the effects of FTY720 on signal transduction pathways and cancer-related cellular processes, and discuss its potential use as an anti-cancer drug.
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Affiliation(s)
- Sathya Narayanan Patmanathan
- Department of Oral Biology and Biomedical Sciences and Oral Cancer Research & Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Lee Fah Yap
- Department of Oral Biology and Biomedical Sciences and Oral Cancer Research & Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Paul G Murray
- School of Cancer Sciences, University of Birmingham, Birmingham, UK
| | - Ian C Paterson
- Department of Oral Biology and Biomedical Sciences and Oral Cancer Research & Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
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15
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The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer. Oncogenesis 2015; 4:e156. [PMID: 26053034 PMCID: PMC4753524 DOI: 10.1038/oncsis.2015.16] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 04/28/2015] [Indexed: 12/13/2022] Open
Abstract
Estrogen receptor-α (ERα)-negative breast cancer is clinically aggressive and does not respond to conventional hormonal therapies. Strategies that lead to re-expression of ERα could sensitize ERα-negative breast cancers to selective ER modulators. FTY720 (fingolimod, Gilenya), a sphingosine analog, is the Food and Drug Administration (FDA)-approved prodrug for treatment of multiple sclerosis that also has anticancer actions that are not yet well understood. We found that FTY720 is phosphorylated in breast cancer cells by nuclear sphingosine kinase 2 and accumulates there. Nuclear FTY720-P is a potent inhibitor of class I histone deacetylases (HDACs) that enhances histone acetylations and regulates expression of a restricted set of genes independently of its known effects on canonical signaling through sphingosine-1-phosphate receptors. High-fat diet (HFD) and obesity, which is now endemic, increase breast cancer risk and have been associated with worse prognosis. HFD accelerated the onset of tumors with more advanced lesions and increased triple-negative spontaneous breast tumors and HDAC activity in MMTV-PyMT transgenic mice. Oral administration of clinically relevant doses of FTY720 suppressed development, progression and aggressiveness of spontaneous breast tumors in these mice, reduced HDAC activity and strikingly reversed HFD-induced loss of estrogen and progesterone receptors in advanced carcinoma. In ERα-negative human and murine breast cancer cells, FTY720 reactivated expression of silenced ERα and sensitized them to tamoxifen. Moreover, treatment with FTY720 also re-expressed ERα and increased therapeutic sensitivity of ERα-negative syngeneic breast tumors to tamoxifen in vivo more potently than a known HDAC inhibitor. Our work suggests that a multipronged attack with FTY720 is a novel combination approach for effective treatment of both conventional hormonal therapy-resistant breast cancer and triple-negative breast cancer.
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16
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Raza A, Huang WC, Takabe K. Advances in the management of peritoneal mesothelioma. World J Gastroenterol 2014; 20:11700-11712. [PMID: 25206274 PMCID: PMC4155360 DOI: 10.3748/wjg.v20.i33.11700] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2013] [Revised: 03/21/2014] [Accepted: 06/05/2014] [Indexed: 02/06/2023] Open
Abstract
Malignant peritoneal mesothelioma (PM) is an infrequent disease which has historically been associated with a poor prognosis. Given its long latency period and non-specific symptomatology, a diagnosis of PM can be suggested by occupational exposure history, but ultimately relies heavily on imaging and diagnostic biopsy. Early treatment options including palliative operative debulking, intraperitoneal chemotherapy, and systemic chemotherapy have marginally improved the natural course of the disease with median survival being approximately one year. The advent of cytoreduction (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has dramatically improved survival outcomes with wide median survival estimates between 2.5 to 9 years; these studies however remain largely heterogeneous, with differing study populations, tumor biology, and specific treatment regimens. More recent investigations have explored extent of cytoreduction, repeated operative intervention, and choice of chemotherapy but have been unable to offer definitive conclusions. CRS and HIPEC remain morbid procedures with complication rates ranging between 30% to 46% in larger series. Accordingly, an increasing interest in identifying molecular targets and developing targeted therapies is emerging. Among such novel targets is sphingosine kinase 1 (SphK1) which regulates the production of sphingosine-1-phosphate, a biologically active lipid implicated in various cancers including malignant mesothelioma. The known action of specific SphK inhibitors may warrant further exploration in peritoneal disease.
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17
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Quint K, Stiel N, Neureiter D, Schlicker HU, Nimsky C, Ocker M, Strik H, Kolodziej MA. The role of sphingosine kinase isoforms and receptors S1P1, S1P2, S1P3, and S1P5 in primary, secondary, and recurrent glioblastomas. Tumour Biol 2014; 35:8979-8989. [PMID: 24903384 DOI: 10.1007/s13277-014-2172-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 05/28/2014] [Indexed: 01/07/2023] Open
Abstract
Sphingosine-1-phosphate (S1P), the corresponding kinases SphK1-2, and receptors S1P1-3 and S1P5 are involved in cell survival and growth. Pathway components are overexpressed in many tumors including glioblastoma. Previous studies showed that the expression of SphK1 influenced survival of glioblastoma patients, yet the roles of SphK1-2 and receptors S1P1-3 and S1P5 have not been investigated in different forms of glioblastoma. Samples from 59 patients (37 males, 22 females, age 55.1 ± 17.1 years) suffering from primary (n = 35), recurrent (n = 18), and secondary (n = 6) glioblastomas were analyzed using quantitative real-time PCR and immunohistochemistry for expression levels of SphK1 and SphK2 and S1P1-3 and S1P5. Sixteen autopsy nontumorous brain specimens were used as controls. Expression data was correlated with clinical data and patient survival. All markers were overexpressed in the glioblastoma specimens compared to the non-neoplastic brain tissue. SphK1 and all S1P receptors were expressed in increasing order of magnitude from primary, up to recurrent and secondary glioblastomas, with values of up to 44-fold compared to normal brain tissue. In contrast, SphK2 levels were highest in primary tumors (25-fold). Expression of the sphingosine signaling pathway components was influenced by radio/radiochemotherapy in distinct ways. Immunohistochemistry for SphK1 and S1P1 confirmed the overexpression in glioblastoma. Uni- and multivariate survival analyses identified S1P5 messenger RNA levels as an independent prognostic factor of survival. The sphingosine pathway is overexpressed in glioma. Its components show distinct expression patterns in the tumor subgroups. S1P5 is identified as an independent prognostic factor in multivariate analysis, and this pathway promises to be a candidate for targeted therapies.
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Affiliation(s)
- Karl Quint
- Institute for Surgical Research, University of Marburg, Marburg, Germany
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18
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Mousseau Y, Mollard S, Qiu H, Richard L, Cazal R, Nizou A, Vedrenne N, Rémi S, Baaj Y, Fourcade L, Funalot B, Sturtz FG. In vitro 3D angiogenesis assay in egg white matrix: comparison to Matrigel, compatibility to various species, and suitability for drug testing. J Transl Med 2014; 94:340-9. [PMID: 24395110 DOI: 10.1038/labinvest.2013.150] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 10/23/2013] [Indexed: 02/07/2023] Open
Abstract
In vitro angiogenesis assays are commonly used to assess pro- or anti-angiogenic drug properties. Extracellular matrix (ECM) substitutes such as Matrigel and collagen gel became very popular in in vitro 3D angiogenesis assays as they enable tubule formation by endothelial cells from culture or aortic rings. However, these assays are usually used with a single cell type, lacking the complex cellular interactions occurring during angiogenesis. Here, we report a novel angiogenesis assay using egg white as ECM substitute. We found that, similar to Matrigel, egg white elicited prevascular network formation by endothelial and/or smooth muscle cell coculture. This matrix was suitable for various cells from human, mouse, and rat origin. It is compatible with aortic ring assay and also enables vascular and tumor cell coculture. Through simple labeling (DAPI, Hoechst 33258), cell location and resulting prevascular network formation can easily be quantified. Cell transfection with green fluorescent protein improved whole cell visualization and 3D structure characterization. Finally, egg-based assay dedicated to angiogenesis studies represents a reliable and cost-effective way to produce and analyze data regarding drug effects on vascular cells.
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Affiliation(s)
- Yoanne Mousseau
- Department of Biochemistry and Molecular Genetics, EA 6063, CHU Dupuytren, Limoges, France
| | - Séverine Mollard
- Department of Biochemistry and Molecular Genetics, EA 6063, CHU Dupuytren, Limoges, France
| | - Hao Qiu
- Department of Biochemistry and Molecular Genetics, EA 6063, CHU Dupuytren, Limoges, France
| | - Laurence Richard
- Department of Biochemistry and Molecular Genetics, EA 6063, CHU Dupuytren, Limoges, France
| | - Raphael Cazal
- Department of Biochemistry and Molecular Genetics, EA 6063, CHU Dupuytren, Limoges, France
| | - Angélique Nizou
- Department of Biochemistry and Molecular Genetics, EA 6063, CHU Dupuytren, Limoges, France
| | - Nicolas Vedrenne
- Department of Biochemistry and Molecular Genetics, EA 6063, CHU Dupuytren, Limoges, France
| | | | - Yasser Baaj
- Department of Biochemistry and Molecular Genetics, EA 6063, CHU Dupuytren, Limoges, France
| | - Laurent Fourcade
- Department of Biochemistry and Molecular Genetics, EA 6063, CHU Dupuytren, Limoges, France
| | - Benoit Funalot
- Department of Biochemistry and Molecular Genetics, EA 6063, CHU Dupuytren, Limoges, France
| | - Franck G Sturtz
- Department of Biochemistry and Molecular Genetics, EA 6063, CHU Dupuytren, Limoges, France
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19
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Sinclair A, Latif AL, Holyoake TL. Targeting survival pathways in chronic myeloid leukaemia stem cells. Br J Pharmacol 2014; 169:1693-707. [PMID: 23517124 DOI: 10.1111/bph.12183] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Revised: 02/11/2013] [Accepted: 02/19/2013] [Indexed: 12/19/2022] Open
Abstract
UNLABELLED Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder characterized by the presence of a fusion oncogene BCR-ABL, which encodes a protein with constitutive TK activity. The implementation of tyrosine kinase inhibitors (TKIs) marked a major advance in CML therapy; however, there are problems with current treatment. For example, relapse occurs when these drugs are discontinued in the majority of patients who have achieved a complete molecular response on TKI and these agents are less effective in patients with mutations in the BCR-ABL kinase domain. Importantly, TKI can effectively target proliferating mature cells, but do not eradicate quiescent leukaemic stem cells (LSCs), therefore allowing disease persistence despite treatment. It is essential that alternative strategies are used to target the LSC population. BCR-ABL activation is responsible for the modulation of different signalling pathways, which allows the LSC fraction to evade cell death. Several pathways have been shown to be modulated by BCR-ABL, including PI3K/AKT/mTOR, JAK-STAT and autophagy signalling pathways. Targeting components of these survival pathways, alone or in combination with TKI, therefore represents an attractive potential therapeutic approach for targeting the LSC. However, many pathways are also active in normal stem cells. Therefore, potential targets must be validated to effectively eradicate CML stem cells while sparing normal counterparts. This review summarizes the main pathways modulated in CML stem cells, the recent developments and the use of novel drugs to target components in these pathways which may be used to target the LSC population. LINKED ARTICLES This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8.
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Affiliation(s)
- A Sinclair
- Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
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20
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Abstract
Non-surgical therapies for human malignancies must negotiate complex cell signaling pathways to impede cancer cell growth, ideally promoting death of cancer cells while sparing healthy tissue. For most of the past half century, medical approaches for treating cancer have relied primarily on cytotoxic chemotherapeutics that interfere with DNA replication and cell division, susceptibilities of rapidly dividing cancer cells. As a consequence, these therapies exert considerable cell stress, promoting the generation of ceramide through de novo synthesis and recycling of complex glycosphingolipids and sphingomyelin into apoptotic ceramide. Radiotherapy of cancer exerts similar geno- and cytotoxic cell stresses, and generation of ceramide following ionizing radiation therapy is a well-described feature of radiation-induced cell death. Emerging evidence now describes sphingolipids as mediators of death in response to newer targeted therapies, cementing ceramide generation as a common mechanism of cell death in response to cancer therapy. Many studies have now shown that dysregulation of ceramide accumulation-whether by reduced generation or accelerated metabolism-is a common mechanism of resistance to standard cancer therapies. The aims of this chapter will be to discuss described mechanisms of cancer resistance to therapy related to dysregulation of sphingolipid metabolism and to explore clinical and preclinical approaches to interdict sphingolipid metabolism to improve outcomes of standard cancer therapies.
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21
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Aoyagi T, Nagahashi M, Yamada A, Takabe K. The role of sphingosine-1-phosphate in breast cancer tumor-induced lymphangiogenesis. Lymphat Res Biol 2013; 10:97-106. [PMID: 22984905 DOI: 10.1089/lrb.2012.0010] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Sphingosine-1-phosphate (S1P) is a potent sphingolipid metabolite that regulates a number of biological processes critical for cancer. S1P produced inside cancer cells is exported and exerts its extracellular functions by binding to its specific receptors in an autocrine, paracrine, and/or endocrine manner, which is known as inside-out signaling. S1P is also known to exert its intracellular functions especially in the inflammatory process, but its relevance to cancer biology remains to be elucidated. Recently, there have been growing interests in the role of S1P in breast cancer progression, including angiogenesis and lymphangiogenesis. Our group demonstrated that activation of sphingosine kinase 1, the enzyme that catalyzes the phosphorylation of sphingosine to S1P, is a key step of this process. In this review, we will cover our current knowledge on the role of S1P signaling pathway in breast cancer progression with an emphasis on its role in tumor-induced lymphangiogenesis.
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Affiliation(s)
- Tomoyoshi Aoyagi
- Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, Virginia 23298-0011, USA
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22
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Stessin AM, Gursel DB, Schwartz A, Parashar B, Kulidzhanov FG, Sabbas AM, Boockvar J, Nori D, Wernicke AG. FTY720, sphingosine 1-phosphate receptor modulator, selectively radioprotects hippocampal neural stem cells. Neurosci Lett 2012; 516:253-8. [PMID: 22507238 DOI: 10.1016/j.neulet.2012.04.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2012] [Revised: 03/30/2012] [Accepted: 04/01/2012] [Indexed: 12/27/2022]
Abstract
Cranial irradiation is an effective treatment modality for both primary and metastatic brain tumors, yet it induces cognitive decline in a substantial number of patients. At present, there are no established methods for neuroprotection. Recent investigations have revealed a link between radiation-induced cognitive dysfunction and the loss of neural precursor cells in the hippocampus. Hence, identifying pharmacological agents, capable of protecting this cell population, is of interest. FTY720 (fingolimod), an FDA-approved oral drug for the treatment of multiple sclerosis, has been shown to promote the survival and differentiation of neural progenitors, as well as remyelination and repair after brain injury. In this study, we show that FTY720, used at nanomolar concentrations, is capable of increasing the viability and neurogenicity of irradiated neural stem cells from the hippocampus. In contrast, it does not provide radioprotection in a human breast cancer cell line and two glioma cell lines. These results suggest a potential therapeutic role for FTY720 as a neuroprotector during cranial irradiation. Further preclinical studies are warranted to evaluate this possibility.
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Affiliation(s)
- Alexander M Stessin
- Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA.
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23
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Herr DR. Potential use of G protein-coupled receptor-blocking monoclonal antibodies as therapeutic agents for cancers. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2012; 297:45-81. [PMID: 22608557 DOI: 10.1016/b978-0-12-394308-8.00002-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The therapeutic use of monoclonal antibodies (mAbs) is the fastest growing area of pharmaceutical development and has enjoyed significant clinical success since approval of the first mAb drug in1984. However, despite significant effort, there are still no approved therapeutic mAbs directed against the largest and most attractive family of drug targets: G protein-coupled receptors (GPCRs). GPCRs regulate essentially all cellular processes, including those that are fundamental to cancer pathology, such as proliferation, survival/drug resistance, migration, differentiation, tissue invasion, and angiogenesis. Many different GPCR isoforms are enhanced or dysregulated in multiple tumor types, and several GPCRs have known oncogenic activity. With approximately 350 distinct GPCRs in the genome, these receptors provide a rich landscape for the design of effective, targeted therapies for cancer, a uniquely heterogeneous disease family. While the generation of selective, efficacious mAbs has been problematic for these structurally complex integral membrane proteins, progress in the development of immunotherapeutics has been made by several independent groups. This chapter provides an overview of the roles of GPCRs in cancer and describes the current state of the art of GPCR-targeted mAb drugs.
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Affiliation(s)
- Deron R Herr
- Expression Drug Designs, LLC, San Marcos, California, USA
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