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      Tetrandrine suppresses cervical cancer growth by inducing apoptosis in vitro and in vivo

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          Abstract

          Introduction and aim

          Cervical cancers are the most common forms of cancer that occur in women globally and are difficult to be cured in their terminal stages. Tetrandrine (TET), a monomeric compound isolated from a traditional Chinese medicine, Radix Stephania tetrandrae, exhibits anticancer effects on different tumor types. However, the mechanisms by which TET regulates the proliferation, apoptosis, migration, and invasion in cervical cancer remain unclear. Thus, this study aimed to investigate the therapeutic effects of TET on cervical cancer in vitro and in vivo.

          Methods

          Cell Counting Kit-8, immunofluorescence, flow cytometry, wound healing, and transwell migration assays were used to detect cell proliferation, apoptosis, and migration and invasion, respectively, in vitro. In addition, immunohistochemical assays were performed to evaluate tumor growth and apoptosis in vivo. Moreover, Western blotting was used to examine active caspase 3, matrix metalloproteinase (MMP)2, and MMP9 protein levels in vitro and in vivo.

          Results

          The results revealed that TET significantly inhibited SiHa cell proliferation in vitro and suppressed tumor growth in vivo. Meanwhile, TET was revealed to induce cervical cancer cell apoptosis by upregulating active caspase 3 in vitro and in vivo. Furthermore, the migration and invasion of SiHa cells were inhibited by TET accompanied with MMP2 and MMP9 downregulation.

          Conclusion

          We have shown that TET inhibited cervical tumor growth and migration in vitro and in vivo for the first time. The accumulating evidence suggests that TET could be a potential therapeutic agent for the treatment of cervical cancer.

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          Most cited references 21

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          Disruption of HPV16-E7 by CRISPR/Cas System Induces Apoptosis and Growth Inhibition in HPV16 Positive Human Cervical Cancer Cells

           Zheng Hu,  Lan Yu,  Da Zhu (2014)
          High-risk human papillomavirus (HR-HPV) has been recognized as a major causative agent for cervical cancer. Upon HPV infection, early genes E6 and E7 play important roles in maintaining malignant phenotype of cervical cancer cells. By using clustered regularly interspaced short palindromic repeats- (CRISPR-) associated protein system (CRISPR/Cas system), a widely used genome editing tool in many organisms, to target HPV16-E7 DNA in HPV positive cell lines, we showed for the first time that the HPV16-E7 single-guide RNA (sgRNA) guided CRISPR/Cas system could disrupt HPV16-E7 DNA at specific sites, inducing apoptosis and growth inhibition in HPV positive SiHa and Caski cells, but not in HPV negative C33A and HEK293 cells. Moreover, disruption of E7 DNA directly leads to downregulation of E7 protein and upregulation of tumor suppressor protein pRb. Therefore, our results suggest that HPV16-E7 gRNA guided CRISPR/Cas system might be used as a therapeutic strategy for the treatment of cervical cancer.
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            Development of an Innovative 3D Cell Culture System to Study Tumour - Stroma Interactions in Non-Small Cell Lung Cancer Cells

            Introduction We describe a novel 3D co-culture model using non-small cell lung cancer (NSCLC) cell lines in combination with lung fibroblasts. This model allows the investigation of tumour-stroma interactions and addresses the importance of having a more in vivo like cell culture model. Methods Automation-compatible multi-well hanging drop microtiter plates were used for the production of 3D mono- and co-cultures. In these hanging drops the two NSCLC cell lines A549 and Colo699 were cultivated either alone or co-cultured with lung fibroblasts. The viability of tumour spheroids was confirmed after five and ten days by using Annexin V/Propidium Iodide staining for flow-cytometry. Tumour fibroblast spheroid formation was characterized by scanning electron microscope (SEM), semi-thin sections, fluorescence microscope and immunohistochemistry (IHC). In addition to conventional histology, protein expression of E-Cadherin, vimentin, Ki67, fibronectin, cytokeratin 7 and α-smooth muscle actin (α-SMA) was investigated by IHC. Results Lower viability was observed in A549 monocultures compared to co-cultures, whereas Colo699 monocultures showed better viability compared to co-cultures. Ki67 expression varied significantly between mono- and co-cultures in both tumour cell lines. An increase of vimentin and decreased E-Cadherin expression could be detected during the course of the cultivation suggesting a transition to a more mesenchymal phenotype. Furthermore, the fibroblast cell line showed an expression of α-SMA only in co-culture with the cancer cell line A549, thereby indicating a mesenchymal to mesenchymal shift to an even more myofibroblast phenotype. Conclusion We demonstrate that our method is a promising tool for the generation of tumour spheroid co-cultures. Furthermore, these spheroids allow the investigation of tumour-stroma interactions and a better reflection of in vivo conditions of cancer cells in their microenvironment. Our method holds potential to contribute to the development of anti-cancer agents and support the search for biomarkers.
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              Tetrandrine induces apoptosis by activating reactive oxygen species and repressing Akt activity in human hepatocellular carcinoma.

              Tetrandrine, a bisbenzylisoquinoline alkaloid component of broadly used traditional Chinese medicine, has antitumor effects against some cancers. In our study, we investigated the effects of tetrandrine on the human hepatocellular carcinoma (HCC) in vitro and in vivo. The results showed that tetrandrine effectively induced apoptosis of liver cancer cell in a dose- and time-dependent manner accompanied by alteration of cell morphology, chromatin fragmentation and caspase activation. Tetrandrine treatment also induced intracellular accumulation of reactive oxygen species (ROS), and ROS scavengers (LNAC and GSH) completely blocked the effects of tetrandrine-induced apoptosis, suggesting that the generation of ROS plays an important role in tetrandrine-induced apoptosis. Although the activities of JNK and ERK were inhibited significantly by tetrandrine treatment, JNK and ERK are not involved in the tetrandrine-induced apoptosis. In contrast, Akt activity was found to be closely related to tetrandrine-induced apoptosis. The data demonstrated that Akt activity inhibitor LY294002 synergistically promoted tetrandrine-induced apoptosis of HCC, whereas ectopic expression of Akt contrastly abrogated partial of the tetrandrine-induced apoptosis. These data suggest that Akt signal is the downstream event of ROS generation in the tetrandrine-induced HCC cell apoptosis. Moreover, the results of xenograft in nude mice were consistent with that of the in vitro studies. Therefore, our data suggest that tetrandrine may be a promising agent for the treatment of HCC as a regulator of ROS/Akt pathway. Copyright © 2010 UICC.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2019
                20 December 2018
                : 13
                : 119-127
                Affiliations
                [1 ]Department of Gynecology, Affiliated Qilu Hospital of Shandong University, Linyi, People’s Republic of China, shiqian_zhang99@ 123456126.com
                [2 ]Department of Gynecology Ward-1, Linyi City People’s Hospital, Linyi, People’s Republic of China
                [3 ]Department of Gynecology, Cancer Hospital Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
                Author notes
                Correspondence: Shiqian Zhang, Department of Gynecology, Affiliated Qilu Hospital of Shandong University, No 27, Jiefang East Road, Lanshan District, Linyi, Shandong 276000, People’s Republic of China, Email shiqian_zhang99@ 123456126.com
                Article
                dddt-13-119
                10.2147/DDDT.S187776
                6304242
                © 2019 Zhang et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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