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      Theaflavin-3, 3′-digallate induces apoptosis and G2 cell cycle arrest through the Akt/MDM2/p53 pathway in cisplatin-resistant ovarian cancer A2780/CP70 cells

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          Abstract

          Ovarian cancer is the most lethal gynecological cancer among women worldwide. Adverse side effects and acquired resistance to conventional platinum based chemotherapy are major impediments in ovarian cancer treatment, and drive the development of more selective anticancer drugs that target cancer-specific defects. In this study, theaflavin-3, 3′-digallate (TF3), the major theaflavin monomer in black tea, exhibited a potent growth inhibitory effect on the cisplatin-resistant ovarian cancer A2780/CP70 cells (IC 50, 23.81 μM), and was less cytotoxic to a normal ovarian IOSE-364 cells (IC 50, 59.58 μM) than to the cancer cells. Flow cytometry analysis indicated that TF3 induced preferential apoptosis and G2 cell cycle arrest in A2780/CP70 cells with respect to IOSE-364 cells. TF3 induced apoptosis through both the intrinsic and extrinsic apoptotic pathways, and caused G2 cell cycle arrest via cyclin B1 in A2780/CP70 cells. The p53 protein played an important role in TF3-induced apoptosis and G2 cell cycle arrest. TF3 might upregulate the p53 expression via the Akt/MDM2 pathway. Our findings help elucidate the mechanisms by which TF3 may contribute to the prevention and treatment of platinum-resistant ovarian cancer.

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          Targeting cell cycle regulation in cancer therapy.

          Anibal Miranda, Santiago Angulo-Díaz-Parreño, Marta Cascante … (2013)
          Cell proliferation is an essential mechanism for growth, development and regeneration of eukaryotic organisms; however, it is also the cause of one of the most devastating diseases of our era: cancer. Given the relevance of the processes in which cell proliferation is involved, its regulation is of paramount importance for multicellular organisms. Cell division is orchestrated by a complex network of interactions between proteins, metabolism and microenvironment including several signaling pathways and mechanisms of control aiming to enable cell proliferation only in response to specific stimuli and under adequate conditions. Three main players have been identified in the coordinated variation of the many molecules that play a role in cell cycle: i) The cell cycle protein machinery including cyclin-dependent kinases (CDK)-cyclin complexes and related kinases, ii) The metabolic enzymes and related metabolites and iii) The reactive-oxygen species (ROS) and cellular redox status. The role of these key players and the interaction between oscillatory and non-oscillatory species have proved essential for driving the cell cycle. Moreover, cancer development has been associated to defects in all of them. Here, we provide an overview on the role of CDK-cyclin complexes, metabolic adaptations and oxidative stress in regulating progression through each cell cycle phase and transitions between them. Thus, new approaches for the design of innovative cancer therapies targeting crosstalk between cell cycle simultaneous events are proposed. Copyright © 2013 Elsevier Inc. All rights reserved.
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            G2 checkpoint abrogators as anticancer drugs.

            Takumi Kawabe (2004)
            Many conventional anticancer treatments kill cells irrespective of whether they are normal or cancerous, so patients suffer from adverse side effects due to the loss of healthy cells. Anticancer insights derived from cell cycle research has given birth to the idea of cell cycle G2 checkpoint abrogation as a cancer cell specific therapy, based on the discovery that many cancer cells have a defective G1 checkpoint resulting in a dependence on the G2 checkpoint during cell replication. Damaged DNA in humans is detected by sensor proteins (such as hHUS1, hRAD1, hRAD9, hRAD17, and hRAD26) that transmit a signal via ATR to CHK1, or by another sensor complex (that may include gammaH2AX, 53BP1, BRCA1, NBS1, hMRE11, and hRAD50), the signal of which is relayed by ATM to CHK2. Most of the damage signals originated by the sensor complexes for the G2 checkpoint are conducted to CDC25C, the activity of which is modulated by 14-3-3. There are also less extensively explored pathways involving p53, p38, PCNA, HDAC, PP2A, PLK1, WEE1, CDC25B, and CDC25A. This review will examine the available inhibitors of CHK1 (Staurosporin, UCN-01, Go6976, SB-218078, ICP-1, and CEP-3891), both CHK1 and CHK2 (TAT-S216A and debromohymenialdisine), CHK2 (CEP-6367), WEE1 (PD0166285), and PP2A (okadaic acid and fostriecin), as well as the unknown checkpoint inhibitors 13-hydroxy-15-ozoapathin and the isogranulatimides. Among these targets, CHK1 seems to be the most suitable target for therapeutic G2 abrogation to date, although an unexplored target such as 14-3-3 or the strategy of targeting multiple proteins at once may be of interest in the future.
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              p53 regulates a G2 checkpoint through cyclin B1.

              S Innocente, Martin Abrahamson, Carol Cogswell … (1999)
              The p53 tumor suppressor controls multiple cell cycle checkpoints regulating the mammalian response to DNA damage. To identify the mechanism by which p53 regulates G2, we have derived a human ovarian cell that undergoes p53-dependent G2 arrest at 32 degrees C. We have found that p53 prevents G2/M transition by decreasing intracellular levels of cyclin B1 protein and attenuating the activity of the cyclin B1 promoter. Cyclin B1 is the regulatory subunit of the cdc2 kinase and is a protein required for mitotic initiation. The ability of p53 to control mitotic initiation by regulating intracellular cyclin B1 levels suggests that the cyclin B-dependent G2 checkpoint has a role in preventing neoplastic transformation.
              Article 0 comments Cited 73 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Oncol
                Journal ID (iso-abbrev): Int. J. Oncol
                Journal ID (publisher-id): IJO
                Title: International Journal of Oncology
                Publisher: D.A. Spandidos
                ISSN (Print): 1019-6439
                ISSN (Electronic): 1791-2423
                Publication date Collection: June 2016
                Publication date (Electronic): 06 April 2016
                Publication date PMC-release: 06 April 2016
                Volume: 48
                Issue: 6
                Pages: 2657-2665
                Affiliations
                [1 ]Department of Tea Science, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China
                [2 ]College of Science, Technology and Mathematics, Alderson Broaddus University, Philippi, WV 26416, USA
                [3 ]Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
                Author notes
                Correspondence to: Dr Bo Li, Department of Tea Science, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P.R. China, E-mail: drlib@ 123456zju.edu.cn . Dr Yi Charlie Chen, College of Science, Technology and Mathematics, Alderson Broaddus University, 101 College Park Dr, Philippi, WV 26416, USA, E-mail: chenyc@ 123456ab.edu
                Article
                Publisher ID: ijo-48-06-2657
                DOI: 10.3892/ijo.2016.3472
                PMC ID: 4863729
                PubMed ID: 27082635
                SO-VID: e848041a-cd11-4c8b-9e89-6acc65428840
                Copyright © Copyright © 2016, Spandidos Publications
                History
                Date received : 28 December 2015
                Date accepted : 11 February 2016
                Categories
                Subject: Articles

                Keywords: theaflavin-3,3′-digallate,ovarian cancer,apoptosis,cell cycle arrest,p53,akt
                Data availability:
                Keywords: theaflavin-3, 3′-digallate, ovarian cancer, apoptosis, cell cycle arrest, p53, akt

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