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      Drug Design, Development and Therapy (submit here)

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      Zinc supplementation induces apoptosis and enhances antitumor efficacy of docetaxel in non-small-cell lung cancer


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          Exposure to exogenous zinc results in increased apoptosis, growth inhibition, and altered oxidative stress in cancer cells. Previous studies also suggested that zinc sensitizes some cancer cells to cytotoxic agents depending on the p53 status. Therefore, zinc supplementation may show anticancer efficacy solely and may increase docetaxel-induced cytotoxicity in non-small-cell lung cancer cells.


          Here, we report the effects of several concentrations of zinc combined with docetaxel on p53-wild-type (A549) and p53-null (H1299) cells. We evaluated cellular viability, apoptosis, and cell cycle progression as well as oxidative stress parameters, including superoxide dismutase, glutathione peroxidase, and malondialdehyde levels.


          Zinc reduced the viability of A549 cells and increased the apoptotic response in both cell lines in a dose-dependent manner. Zinc also amplified the docetaxel effects and reduced its inhibitory concentration 50 (IC 50) values. The superoxide dismutase levels increased in all treatment groups; however, glutathione peroxidase was slightly increased in the combination treatments. Zinc also caused malondialdehyde elevations at 50 μM and 100 μM.


          Zinc has anticancer efficacy against non-small-cell lung cancer cells in the presence of functionally active p53 and enhances docetaxel efficacy in both p53-wild-type and p53-deficient cancer cells.

          Most cited references42

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          Awakening guardian angels: drugging the p53 pathway.

          Currently, around 11 million people are living with a tumour that contains an inactivating mutation of TP53 (the human gene that encodes p53) and another 11 million have tumours in which the p53 pathway is partially abrogated through the inactivation of other signalling or effector components. The p53 pathway is therefore a prime target for new cancer drug development, and several original approaches to drug discovery that could have wide applications to drug development are being used. In one approach, molecules that activate p53 by blocking protein-protein interactions with MDM2 are in early clinical development. Remarkable progress has also been made in the development of p53-binding molecules that can rescue the function of certain p53 mutants. Finally, cell-based assays are being used to discover compounds that exploit the p53 pathway by either seeking targets and compounds that show synthetic lethality with TP53 mutations or by looking for non-genotoxic activators of the p53 response.
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            Taxanes, microtubules and chemoresistant breast cancer.

            The taxanes, paclitaxel and docetaxel are microtubule-stabilizing agents that function primarily by interfering with spindle microtubule dynamics causing cell cycle arrest and apoptosis. However, the mechanisms underlying their action have yet to be fully elucidated. These agents have become widely recognized as active chemotherapeutic agents in the treatment of metastatic breast cancer and early-stage breast cancer with benefits gained in terms of overall survival (OS) and disease-free survival (DFS). However, even with response to taxane treatment the time to progression (TTP) is relatively short, prolonging life for a matter of months, with studies showing that patients treated with taxanes eventually relapse. This review focuses on chemoresistance to taxane treatment particularly in relation to the spindle assembly checkpoint (SAC) and dysfunctional regulation of apoptotic signaling. Since spindle microtubules are the primary drug targets for taxanes, important SAC proteins such as MAD2, BUBR1, Synuclein-gamma and Aurora A have emerged as potentially important predictive markers of taxane resistance, as have specific checkpoint proteins such as BRCA1. Moreover, overexpression of the drug efflux pump MDR-1/P-gp, altered expression of microtubule-associated proteins (MAPs) including tau, stathmin and MAP4 may help to identify those patients who are most at risk of recurrence and those patients most likely to benefit from taxane treatment.
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              Cell cycle and apoptosis.

              Apoptosis and proliferation are intimately coupled. Some cell cycle regulators can influence both cell division and programmed cell death. The linkage of cell cycle and apoptosis has been recognized for c-Myc, p53, pRb, Ras, PKA, PKC, Bcl-2, NF-kappa B, CDK, cyclins and CKI. This review summarizes the different functions of the proteins presently known to control both apoptosis and cell cycle progression. These proteins can influence apoptosis or proliferation but different variables, including cell type, cellular environment and genetic background, make it difficult to predict the outcome of cell proliferation, cell cycle arrest or cell death. These important decisions of cell proliferation or cell death are likely to be controlled by more than one signal and are necessary to ensure a proper cellular response.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                27 July 2015
                : 9
                : 3899-3909
                [1 ]Institute of Oncology, Dokuz Eylul University, Izmir Turkey
                [2 ]Department of Molecular Medicine, Institute of Health Sciences, Dokuz Eylul University, Izmir Turkey
                [3 ]Department of Biochemistry, Firat University School of Medicine, Elazig, Turkey
                [4 ]Department of Surgery, School of Medicine, Dokuz Eylul University, Izmir, Turkey
                Author notes
                Correspondence: Hilal Kocdor, Department of Basic Oncology, Institute of Oncology, Dokuz Eylul University, 35340 Inciralti, Izmir, Turkey, Tel +90 232 412 8203, Fax +90 232 278 4078, Email h.kocdor@ 123456gmail.com
                © 2015 Kocdor et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine
                lung cancer,zinc,docetaxel,a549,h1299
                Pharmacology & Pharmaceutical medicine
                lung cancer, zinc, docetaxel, a549, h1299


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