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      Investigational drugs for the treatment of endometriosis, an update on recent developments

      1 , 2 , 1 , 2 , 3 , 3 , 1 , 2

      Expert Opinion on Investigational Drugs

      Informa UK Limited

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          Most cited references 136

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          p38 MAPK signalling cascades in inflammatory disease.

          Inflammatory mediators released during acute and chronic diseases activate multiple intracellular signalling cascades including the mitogen-activated protein kinase (MAPK) signal transduction pathway, which plays a significant role in the recruitment of leukocytes to sites of inflammation. Stimulation of leukocytes by pro-inflammatory cytokines is known to result in the activation of the MAPK isoform p38. However, the functional consequences of p38 MAPK activation during leukocyte recruitment, including adhesion, migration and effector functions such as oxidative burst and degranulation, are only just beginning to be elucidated. Specific p38 inhibitors aimed at reducing the production of inflammatory mediators are now being developed, and might in the future provide more effective treatment for inflammatory diseases.
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            Curcumin selectively induces apoptosis in deregulated cyclin D1-expressed cells at G2 phase of cell cycle in a p53-dependent manner.

            Curcumin (diferuloylmethane) is known to induce apoptosis in tumor cells. In asynchronous cultures, with time-lapse video-micrography in combination with quantitative fluorescence microscopy, we have demonstrated that curcumin induces apoptosis at G(2) phase of cell cycle in deregulated cyclin D1-expressed mammary epithelial carcinoma cells, leaving its normal counterpart unaffected. In our search toward delineating the molecular mechanisms behind such differential activities of curcumin, we found that it selectively increases p53 expression at G(2) phase of carcinoma cells and releases cytochrome c from mitochondria, which is an essential requirement for apoptosis. Further experiments using p53-null as well as dominant-negative and wild-type p53-transfected cells have established that curcumin induces apoptosis in carcinoma cells via a p53-dependent pathway. On the other hand, curcumin reversibly inhibits normal mammary epithelial cell cycle progression by down-regulating cyclin D1 expression and blocking its association with Cdk4/Cdk6 as well as by inhibiting phosphorylation and inactivation of retinoblastoma protein. In addition, curcumin significantly up-regulates cell cycle inhibitory protein (p21Waf-1) in normal cells and arrests them in G(0) phase of cell cycle. Therefore, these cells escape from curcumin-induced apoptosis at G(2) phase. Interestingly, these processes remain unaffected by curcumin in carcinoma cells where cyclin D1 expression is high. Similarly, in ectopically overexpressed system, curcumin cannot down-regulate cyclin D1 and thus block cell cycle progression. Hence, these cells progress into G(2) phase and undergo apoptosis. These observations together suggest that curcumin may have a possible therapeutic potential in breast cancer patients.
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              Antiangiogenesis therapy for endometriosis.

              It is known that angiogenesis is of pivotal importance for the development of endometriosis. However, in the treatment of endometriosis patients, prevention of endometriosis lesion development only will not be sufficient as a therapy. Treatment options, aimed at interfering with established lesions, have to be developed. In this study we evaluated whether inhibition of angiogenesis by angiostatic therapy is also effective in antagonizing the sustentation of endometriosis. We evaluated the effect of the angiostatic compounds antihuman vascular endothelial growth factor, TNP-470, endostatin, and anginex on the growth of established endometriosis lesions in the nude mouse model. We show that human endometrium in the proliferative endometrium is highly angiogenic and that vascular endothelial growth factor-A is the most important angiogenesis promotory factor. The angiostatic compounds significantly decreased microvessel densities and the number of established endometriosis lesions. In the remaining lesions, the number of pericyte-protected vessels is not different in control and treated mice; however, the number of unprotected vessels was significantly reduced in the groups treated with the angiostatic agents. Our data demonstrate that inhibitors of angiogenesis effectively interfere with the maintenance and growth of endometriosis by inhibiting angiogenesis. This suggests that the use of angiostatic agents may be promising as a therapy for endometriosis.
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                Author and article information

                Journal
                Expert Opinion on Investigational Drugs
                Expert Opinion on Investigational Drugs
                Informa UK Limited
                1354-3784
                1744-7658
                April 26 2018
                May 04 2018
                May 17 2018
                May 04 2018
                : 27
                : 5
                : 445-458
                Affiliations
                [1 ] Academic Unit of Obstetrics and Gynecology, Ospedale Policlinico San Martino, Genoa, Italy
                [2 ] Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
                [3 ] Department of Obstetrics and Gynecology, University of Cagliari, Policlinico Universitario Duilio Casula, Monserrato, Cagliari, Italy
                Article
                10.1080/13543784.2018.1471135
                © 2018

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