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      Curcumin inhibits proliferation, migration, invasion and promotes apoptosis of retinoblastoma cell lines through modulation of miR-99a and JAK/STAT pathway

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          Abstract

          Background

          Curcumin, a primary active ingredient extracted from the Curcuma longa, has been recently identified as a potential anti-tumor agent in multiple kinds of cancers. However, the effect of curcumin on retinoblastoma (Rb) is still unclear. Therefore, we attempted to reveal the functional impacts and the underlying mechanisms of curcumin in Rb cells.

          Methods

          Two Rb cell lines SO-Rb50 and Y79 were pre-treated with various doses of curcumin, and then cell proliferation, apoptosis, migration, and invasion were assessed, respectively. Further, regulatory effects of curcumin on miR-99a expression, as well as the activation of JAK/STAT pathway were studied.

          Results

          Data showed that curcumin significantly inhibited the viability, colony formation capacity, migration and invasion, while induced apoptosis of SO-Rb50 and Y79 cells. Up-regulation of miR-99a was observed in curcumin-treated cells. Curcumin suppressed the phosphorylation levels of JAK1, STAT1, and STAT3, while curcumin did not inhibit the activation of JAK/STAT pathway when miR-99a was knocked down.

          Conclusion

          Curcumin inhibited proliferation, migration, invasion, but promoted apoptosis of Rb cells. The anti-tumor activities of curcumin on Rb cells appeared to be via up-regulation of miR-99a, and thereby inhibition of JAK/STAT pathway.

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          Most cited references34

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          A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer.

          Curcumin, a plant-derived natural polyphenol, could be a promising anti-cancer drug and shows synergic effects with cytotoxic agents. We evaluated the safety and feasibility of combination therapy using curcumin with gemcitabine-based chemotherapy. Gemcitabine-resistant patients with pancreatic cancer received 8 g oral curcumin daily in combination with gemcitabine-based chemotherapy. The primary endpoint was safety for phase I and feasibility of oral curcumin for phase II study. Twenty-one patients were enrolled. No dose-limiting toxicities were observed in the phase I study and oral curcumin 8 g/day was selected as the recommended dose for the phase II study. No patients were withdrawn from this study because of the intolerability of curcumin, which met the primary endpoint of the phase II study, and the median compliance rate of oral curcumin was 100% (Range 79-100%). Median survival time after initiation of curcumin was 161 days (95% confidence interval 109-223 days) and 1-year survival rate was 19% (4.4-41.4%). Plasma curcumin levels ranged from 29 to 412 ng/ml in five patients tested. Combination therapy using 8 g oral curcumin daily with gemcitabine-based chemotherapy was safe and feasible in patients with pancreatic cancer and warrants further investigation into its efficacy.
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            Inhibition of MMP-2 and MMP-9 decreases cellular migration, and angiogenesis in in vitro models of retinoblastoma

            Background Retinoblastoma (Rb) is the most common primary intraocular tumor in children. Local treatment of the intraocular disease is usually effective if diagnosed early; however advanced Rb can metastasize through routes that involve invasion of the choroid, sclera and optic nerve or more broadly via the ocular vasculature. Metastatic Rb patients have very high mortality rates. While current therapy for Rb is directed toward blocking tumor cell division and tumor growth, there are no specific treatments targeted to block Rb metastasis. Two such targets are matrix metalloproteinases-2 and -9 (MMP-2, −9), which degrade extracellular matrix as a prerequisite for cellular invasion and have been shown to be involved in other types of cancer metastasis. Cancer Clinical Trials with an anti-MMP-9 therapeutic antibody were recently initiated, prompting us to investigate the role of MMP-2, −9 in Rb metastasis. Methods We compare MMP-2, −9 activity in two well-studied Rb cell lines: Y79, which exhibits high metastatic potential and Weri-1, which has low metastatic potential. The effects of inhibitors of MMP-2 (ARP100) and MMP-9 (AG-L-66085) on migration, angiogenesis, and production of immunomodulatory cytokines were determined in both cell lines using qPCR, and ELISA. Cellular migration and potential for invasion were evaluated by the classic wound-healing assay and a Boyden Chamber assay. Results Our results showed that both inhibitors had differential effects on the two cell lines, significantly reducing migration in the metastatic Y79 cell line and greatly affecting the viability of Weri-1 cells. The MMP-9 inhibitor (MMP9I) AG-L-66085, diminished the Y79 angiogenic response. In Weri-1 cells, VEGF was significantly reduced and cell viability was decreased by both MMP-2 and MMP-9 inhibitors. Furthermore, inhibition of MMP-2 significantly reduced secretion of TGF-β1 in both Rb models. Conclusions Collectively, our data indicates MMP-2 and MMP-9 drive metastatic pathways, including migration, viability and secretion of angiogenic factors in Rb cells. These two subtypes of matrix metalloproteinases represent new potential candidates for targeted anti-metastatic therapy for Rb. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3418-y) contains supplementary material, which is available to authorized users.
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              Rho kinases in cardiovascular physiology and pathophysiology.

              Rho kinases (ROCKs) are the first and the best-characterized effectors of the small G-protein RhoA. In addition to their effect on actin organization, or through this effect, ROCKs have been found to regulate a wide range of fundamental cell functions such as contraction, motility, proliferation, and apoptosis. Abnormal activation of the RhoA/ROCK pathway has been observed in major cardiovascular disorders such as atherosclerosis, restenosis, hypertension, pulmonary hypertension, and cardiac hypertrophy. This review, based on recent molecular, cellular, and animal studies, focuses on the current understanding of ROCK signaling and its roles in cardiovascular physiology and pathophysiology.
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                Author and article information

                Contributors
                mudanren8646ktd@163.com
                naibengpan0787jva@163.com
                huangzelan5530pfi@163.com
                rongdoupin0834fww@163.com
                +86-0431-84995999 , yindx523@yeah.net
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                10 December 2018
                10 December 2018
                2018
                : 18
                : 1230
                Affiliations
                [1 ]GRID grid.452829.0, Department of Ophthalmology, , The Second Hospital of Jilin University, ; Changchun, Jilin, 130041 China
                [2 ]ISNI 0000 0004 1760 5735, GRID grid.64924.3d, Department of Gastroenterological Surgery, , China-Japan Union Hospital of Jilin University, ; Changchun, Jilin, 130033 China
                [3 ]ISNI 0000 0004 1760 5735, GRID grid.64924.3d, Department of Vascular Surgery, , China-Japan Union Hospital of Jilin University, ; No.126, Xiantai Street, Changchun, Jilin, 130033 China
                Author information
                http://orcid.org/0000-0003-4933-5525
                Article
                5130
                10.1186/s12885-018-5130-y
                6288931
                30526546
                e3818a15-05ea-4509-be66-47f13993f7e3
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 24 May 2018
                : 26 November 2018
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Oncology & Radiotherapy
                curcumin,retinoblastoma,mir-99a,jak/stat pathway
                Oncology & Radiotherapy
                curcumin, retinoblastoma, mir-99a, jak/stat pathway

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