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      Disulfiram modulated ROS–MAPK and NF κB pathways and targeted breast cancer cells with cancer stem cell-like properties

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          Abstract

          Background:

          Previous studies indicate that disulfiram (DS), an anti-alcoholism drug, is cytotoxic to cancer cell lines and reverses anticancer drug resistance. Cancer stem cells (CSCs) are the major cause of chemoresistance leading to the failure of cancer chemotherapy. This study intended to examine the effect of DS on breast cancer stem cells (BCSCs).

          Methods:

          The effect of DS on BC cell lines and BCSCs was determined by MTT, western blot, CSCs culture and CSCs marker analysis.

          Results:

          Disulfiram was highly toxic to BC cell lines in vitro in a copper (Cu)-dependent manner. In Cu-containing medium (1  μ), the IC 50 concentrations of DS in BC cell lines were 200–500 n. Disulfiram/copper significantly enhanced (3.7–15.5-fold) cytotoxicity of paclitaxel (PAC). Combination index isobologram analysis demonstrated a synergistic effect between DS/Cu and PAC. The increased Bax and Bcl2 protein expression ratio indicated that intrinsic apoptotic pathway may be involved in DS/Cu-induced apoptosis. Clonogenic assay showed DS/Cu-inhibited clonogenicity of BC cells. Mammosphere formation and the ALDH1 +VE and CD24 Low/CD44 High CSCs population in mammospheres were significantly inhibited by exposure to DS/Cu for 24 h. Disulfiram/copper induced reactive oxygen species (ROS) generation and activated its downstream apoptosis-related cJun N-terminal kinase and p38 MAPK pathways. Meanwhile, the constitutive NF κB activity in BC cell lines was inhibited by DS/Cu.

          Conclusion:

          Disulfiram/copper inhibited BCSCs and enhanced cytotoxicity of PAC in BC cell lines. This may be caused by simultaneous induction of ROS and inhibition of NF κB.

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          Most cited references42

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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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            NF-kappaB activation by reactive oxygen species: fifteen years later.

            The transcription factor NF-kappaB plays a major role in coordinating innate and adaptative immunity, cellular proliferation, apoptosis and development. Since the discovery in 1991 that NF-kappaB may be activated by H(2)O(2), several laboratories have put a considerable effort into dissecting the molecular mechanisms underlying this activation. Whereas early studies revealed an atypical mechanism of activation, leading to IkappaBalpha Y42 phosphorylation independently of IkappaB kinase (IKK), recent findings suggest that H(2)O(2) activates NF-kappaB mainly through the classical IKK-dependent pathway. The molecular mechanisms leading to IKK activation are, however, cell-type specific and will be presented here. In this review, we also describe the effect of other ROS (HOCl and (1)O(2)) and reactive nitrogen species on NF-kappaB activation. Finally, we critically review the recent data highlighting the role of ROS in NF-kappaB activation by proinflammatory cytokines (TNF-alpha and IL-1beta) and lipopolysaccharide (LPS), two major components of innate immunity.
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              NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation.

              Tumor necrosis factor alpha (TNF-alpha) binding to the TNF receptor (TNFR) potentially initiates apoptosis and activates the transcription factor nuclear factor kappa B (NF-kappaB), which suppresses apoptosis by an unknown mechanism. The activation of NF-kappaB was found to block the activation of caspase-8. TRAF1 (TNFR-associated factor 1), TRAF2, and the inhibitor-of-apoptosis (IAP) proteins c-IAP1 and c-IAP2 were identified as gene targets of NF-kappaB transcriptional activity. In cells in which NF-kappaB was inactive, all of these proteins were required to fully suppress TNF-induced apoptosis, whereas c-IAP1 and c-IAP2 were sufficient to suppress etoposide-induced apoptosis. Thus, NF-kappaB activates a group of gene products that function cooperatively at the earliest checkpoint to suppress TNF-alpha-mediated apoptosis and that function more distally to suppress genotoxic agent-mediated apoptosis.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                10 May 2011
                12 April 2011
                : 104
                : 10
                : 1564-1574
                Affiliations
                [1 ]simpleResearch Institute in Healthcare Science, School of Applied Sciences, University of Wolverhampton , Wolverhampton WV1 1LY, UK
                [2 ]simpleDepartment of Heamatology, Nanfang Hospital, The Southern Medical University , Guangzhou, People's Republic of China
                [3 ]simpleDepartment of Medical Oncology, Beatson Institute for Cancer Research , Glasgow, UK
                Author notes
                [4]

                These authors contributed equally to this work.

                Article
                bjc2011126
                10.1038/bjc.2011.126
                3101904
                21487404
                1f01eb18-cd92-49c1-9b32-b0ac3dcad30a
                Copyright © 2011 Cancer Research UK
                History
                : 11 March 2011
                : 18 March 2011
                Categories
                Translational Therapeutics

                Oncology & Radiotherapy
                breast cancer stem cells,nfκb,mapk pathway,paclitaxel,reactive oxygen species,disulfiram

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