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      Emodin enhances antitumor effect of paclitaxel on human non-small-cell lung cancer cells in vitro and in vivo

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          Abstract

          Background: Non-small-cell lung cancer (NSCLC) was known as the most malignant tumor. Paclitaxel (PTX) is the effective drug used for the treatment of NSCLC; however, it also exhibits severe side effects. Emodin could induce apoptosis of NSCLC cells and serve as a potential cancer therapeutic agent. However, the effects of combination of emodin with PTX on NSCLC remain unclear. Thus, this study aimed to investigate the effects of emodin in combination with PTX on A549 cells.

          Materials and methods: The effects of combination treatment on the proliferation, apoptosis and invasion of NSCLC cells were evaluated by CCK-8, flow cytometric and TUNEL assays, respectively. In addition, Western blotting was used to detect the expressions of Bax, Bcl-2, active caspase 3, p-Akt and ERK in cells.

          Results: Combination of emodin with PTX synergistically inhibited the proliferation of A549 cells in vitro. In addition, we found that emodin significantly enhanced PTX-induced apoptosis in A549 cells via increasing the expressions of Bax and active caspase 3 and decreasing the levels of Bcl-2, p-Akt and p-ERK. Moreover, emodin markedly enhanced antitumor effect of PTX on A549 xenograft without significant side effects in vivo.

          Conclusion: Our findings indicated that emodin could significantly enhance antitumor effect of PTX in vitro and in vivo. Therefore, the combination of emodin with PTX may serve as a potential strategy for the treatment of patients with NSCLC.

          Most cited references26

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          Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.

          A generalized method for analyzing the effects of multiple drugs and for determining summation, synergism and antagonism has been proposed. The derived, generalized equations are based on kinetic principles. The method is relatively simple and is not limited by whether the dose-effect relationships are hyperbolic or sigmoidal, whether the effects of the drugs are mutually exclusive or nonexclusive, whether the ligand interactions are competitive, noncompetitive or uncompetitive, whether the drugs are agonists or antagonists, or the number of drugs involved. The equations for the two most widely used methods for analyzing synergism, antagonism and summation of effects of multiple drugs, the isobologram and fractional product concepts, have been derived and been shown to have limitations in their applications. These two methods cannot be used indiscriminately. The equations underlying these two methods can be derived from a more generalized equation previously developed by us (59). It can be shown that the isobologram is valid only for drugs whose effects are mutually exclusive, whereas the fractional product method is valid only for mutually nonexclusive drugs which have hyperbolic dose-effect curves. Furthermore, in the isobol method, it is laborious to find proper combinations of drugs that would produce an iso-effective curve, and the fractional product method tends to give indication of synergism, since it underestimates the summation of the effect of mutually nonexclusive drugs that have sigmoidal dose-effect curves. The method described herein is devoid of these deficiencies and limitations. The simplified experimental design proposed for multiple drug-effect analysis has the following advantages: It provides a simple diagnostic plot (i.e., the median-effect plot) for evaluating the applicability of the data, and provides parameters that can be directly used to obtain a general equation for the dose-effect relation; the analysis which involves logarithmic conversion and linear regression can be readily carried out with a simple programmable electronic calculator and does not require special graph paper or tables; and the simplicity of the equation allows flexibility of application and the use of a minimum number of data points. This method has been used to analyze experimental data obtained from enzymatic, cellular and animal systems.
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            Emodin induces apoptosis in human lung adenocarcinoma cells through a reactive oxygen species-dependent mitochondrial signaling pathway.

            Emodin, a natural anthraquinone derivative isolated from Rheum palmatum L., has been reported to exhibit anti-cancer effect on several human cancers such as liver cancers and lung cancers. However, the molecular mechanisms of emodin-mediated tumor regression have not been fully defined. In this study, we show that treatment with 50 microM emodin resulted in a pronounced release of cytochrome c, activation of caspase-2, -3, and -9, and apoptosis in human lung adenocarcinoma A549 cells. These events were accompanied by the inactivation of ERK and AKT, generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential ((Delta)psi(m)), decrease of mitochondrial Bcl-2, and increase of mitochondrial Bax content. Ectopic expression of Bcl-2, or treatment with aurintricarboxylic acid, furosemide or caspase inhibitors markedly blocked emodin-induced apoptosis. Conversely, pharmacologic ERK and AKT inhibition promoted emodin-induced apoptosis. Furthermore, the free radical scavenger ascorbic acid and N-acetylcysteine attenuated emodin-mediated ROS production, ERK and AKT inactivation, mitochondrial dysfunction, Bcl-2/Bax modulation, and apoptosis. Take together, these findings suggest that in A549 cells, emodin-mediated oxidative injury acts as an early and upstream change in the cell death cascade to antagonize cytoprotective ERK and AKT signaling, triggers mitochondrial dysfunction, Bcl-2 and Bax modulation, mitochondrial cytochrome c release, caspase activation, and consequent leading to apoptosis.
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              Synergistic combination therapy of lung cancer using paclitaxel- and triptolide-coloaded lipid–polymer hybrid nanoparticles

              Purpose Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer. Lipid–polymer hybrid nanoparticles (LPNs) combine the advantages of both polymeric nanoparticles and liposomes into a single delivery platform. In this study, we engineered LPNs as the co-delivery system of paclitaxel (PTX) and triptolide (TL) to achieve synergistic therapeutic effect and reduced drug resistance. Materials and methods In this study, PTX- and TL-coloaded LPNs (P/T-LPNs) were fabricated by nanoprecipitation method using lipid and polymeric materials. The P/T-LPNs combination effects on human lung cancer cells were studied. Therapeutic potentials of P/T-LPNs were further determined using lung cancer cells-bearing mice model. Results The average particle sizes of LPNs were around 160 nm, with narrow size distribution below 0.2. The zeta potential value of LPNs was about −30 mV. The encapsulating efficiency (EE) of PTX and TL loaded in LPNs was over 85%. The cytotoxicity of dual drug loaded LPNs was higher than single drug loaded LPNs. The combination therapy showed synergistic when PTX:TL weight ratio was 5:3, indicating the synergy effects of the LPNs. In vivo tumor growth curve of the experimental group was more gentle opposed to the control group, and tumor volumes of P/T-LPNs and control group were 392 and 1,737 mm3, respectively. The inhibition rate on day 20 was 77.4% in the P/T-LPNs group, which is higher than the free drugs solution. Conclusion The in vivo and in vitro results proved the synergetic effect of the two drugs coloaded in LPNs on the lung cancer xenografts, with the least systemic toxic side effect.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                10 April 2019
                2019
                : 13
                : 1145-1153
                Affiliations
                [1 ]Department of Respiratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University , Hangzhou, Zhejiang 310003, People’s Republic of China
                Author notes
                Correspondence: Shuifang ChenDepartment of Respiratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University , No. 79, Qingchun Road, Hangzhou, Zhejiang310003, People’s Republic of ChinaTel +86 571 8696 0983Fax +86 571 8723 6877Email chen-sf@ 123456zju.edu.cn
                Article
                196319
                10.2147/DDDT.S196319
                6489594
                aba9a0c9-4f9a-46fe-ad18-806c9f886b50
                © 2019 Chen 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. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 28 November 2018
                : 04 March 2019
                Page count
                Figures: 5, Tables: 1, References: 29, Pages: 9
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                non-small-cell lung cancer,emodin,paclitaxel,apoptosis
                Pharmacology & Pharmaceutical medicine
                non-small-cell lung cancer, emodin, paclitaxel, apoptosis

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