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      Drug Design, Development and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the design and development of drugs, as well as the clinical outcomes, patient safety, and programs targeted at the effective and safe use of medicines. Sign up for email alerts here.

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      Andrographolide enhanced 5-fluorouracil-induced antitumor effect in colorectal cancer via inhibition of c-MET pathway

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          Abstract

          Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide. 5-Fluorouracil (5-Fu) is the most important chemotherapeutic drug used for the treatment of CRC. However, resistance to 5-Fu therapies is a growing concern in CRC clinical practice recently. Andrographolide (Andro) is a main bioactive constituent of the herb Andrographis paniculata, which has various biological effects including anti-inflammation and antitumor activities. In the present study, we investigated the effects of combined Andro with 5-Fu against CRC HCT-116 cells. In vitro studies showed that Andro synergistically enhanced the anti-proliferation effect of 5-Fu on HCT-116 cells due to increased apoptotic cells. Meanwhile, results of the enzyme linked immunosorbent assay indicated that the level of phosphorylated cellular-mesenchymal to epithelial transition factor (p-MET) was decreased by the combination treatment. Further study suggested that Andro promoted the antitumor effect of 5-Fu by down-regulating the level of p-MET. In conclusion, these results confirmed the synergistic antitumor activity of Andro on CRC and provide evidence for possible clinical application of Andro for enhancing the antitumor effect of 5-Fu in CRC treatment.

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

          P Talalay, T C Chou (1984)
          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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            Preclinical versus clinical drug combination studies.

            Kuei-Ting Chou (2008)
            This brief review provides a practical guide for drug combination studies and delineates its essence in terms of the mass-action-based theory, experimental design and automated computerised data analysis. The combination index (CI) method of Chou-Talalay is based on the multiple drug effect equation derived from the median-effect principle of the mass-action law. It provides quantitative determination for synergism (CI 1), and provides the algorithm for computer software for automated simulation for drug combinations. It takes into account both the potency (the D(m) value) and the shape of the dose-effect curve (the m value) of each drug alone and their combination. The best feature is that it allows for small size experiments. The automated computer simulation reveals whether there is a synergism, determines how much synergism (the CI value) at any effect levels (the F(a)-CI plot), or at any dose levels (the isobologram), provides the information regarding how many folds of dose-reduction is allowed for each drug, at a given effect for a synergistic combination, comparing with the dose required for each drug alone (the F(a)-DRI plot), and the optimal combination ratio and schedule dependency for synergy. The 'polygonogram' dissects the component drug interactions or projects the make-ups of cocktails in complicated combinations. Based on scientific, practical and ethical reasons, it is not possible to 'determine' synergism in humans, and thus prior to the drug combination clinical trials, preclinical drug combination studies in vitro and/or in animals should be carried out to obtain the basis and rationale for studies in humans.
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              Measurement of cell death in mammalian cells.

              Rick G. Schnellmann, Brian Cummings (2004)
              This unit presents methods used to assess cell death in mammalian cells. The unit is divided into five sections: (1) a brief overview of cytotoxicity and pathways of cell death, (2) an improved method to measure cell death using lactate dehydrogenase (LDH) release as a marker of membrane integrity, (3) a flow cytometry method that simultaneously measures two types of cell death, oncosis and apoptosis, (4) use of nuclear morphology to assess apoptosis and oncosis, and (5) a brief discussion of the use of cytotoxicity assays to determine the mechanisms of cell death.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Drug Des Devel Ther
                Journal ID (iso-abbrev): Drug Des Devel Ther
                Journal ID (publisher-id): Drug Design, Development and Therapy
                Title: Drug Design, Development and Therapy
                Publisher: Dove Medical Press
                ISSN (Electronic): 1177-8881
                Publication date Collection: 2017
                Publication date (Electronic): 23 November 2017
                Volume: 11
                Pages: 3333-3341
                Affiliations
                [1 ]Department of Internal Medicine
                [2 ]Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Liaoning, China
                Author notes
                Correspondence: Rui Zhang, Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, China, Tel +86 024 3191 6293, Email rui_zhang11@ 123456126.com
                Article
                Publisher ID: dddt-11-3333
                DOI: 10.2147/DDDT.S140354
                PMC ID: 5703152
                PubMed ID: 29200829
                SO-VID: 7617bc74-8320-4d4f-a0e0-e5a8ee3b3d0a
                Copyright © © 2017 Su et al. This work is published and licensed by Dove Medical Press Limited
                License:

                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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                Subject: Original Research

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: andro,5-fu,hct-116 cells,apoptosis,p-met
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: andro, 5-fu, hct-116 cells, apoptosis, p-met

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