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      Matrine effectively inhibits the proliferation of breast cancer cells through a mechanism related to the NF-κB signaling pathway

      research-article
      , , ,
      Oncology Letters
      D.A. Spandidos
      matrine, breast cancer, NF-κB, IKKβ

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          Abstract

          Matrine is an alkaloid isolated from Sophora flavescens. The present study aimed to determine whether matrine effectively inhibits the proliferation of breast cancer cells, and the underlying mechanism(s) of its antitumor function. The effects of matrine on the cell viability of ER-positive MCF7 cells, HER2-positive BT-474 cells and highly metastatic MDA-MB-231 cells were measured using MTT and apoptosis assays. Western blot analysis was performed to investigate the expression levels of the inhibitor of κB (IκB) kinase β (IKKβ) in cells treated with or without matrine. It was observed that the matrine treatment resulted in the death of the three types of cancer cells, but significantly less toxicity was observed in the control cancer cells. The experimental results also suggested that the antitumor effects of matrine on breast cancer cells may be associated with the downregulation of IKKβ expression by matrine, as indicated by the western blot analysis results. The present results suggested that matrine may be used as an effective drug candidate for treating breast cancers in the future, following further research.

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          Most cited references15

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          Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases.

          TNFalpha is a pleiotropic cytokine that induces either cell proliferation or cell death. Inhibition of NF-kappaB activation increases susceptibility to TNFalpha-induced death, concurrent with sustained JNK activation, an important contributor to the death response. Sustained JNK activation in NF-kappaB-deficient cells was suggested to depend on reactive oxygen species (ROS), but how ROS affect JNK activation was unclear. We now show that TNFalpha-induced ROS, whose accumulation is suppressed by mitochondrial superoxide dismutase, cause oxidation and inhibition of JNK-inactivating phosphatases by converting their catalytic cysteine to sulfenic acid. This results in sustained JNK activation, which is required for cytochrome c release and caspase 3 cleavage, as well as necrotic cell death. Treatment of cells or experimental animals with an antioxidant prevents H(2)O(2) accumulation, JNK phosphatase oxidation, sustained JNK activity, and both forms of cell death. Antioxidant treatment also prevents TNFalpha-mediated fulminant liver failure without affecting liver regeneration.
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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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              The death domain kinase RIP mediates the TNF-induced NF-kappaB signal.

              The death domain serine/threonine kinase RIP interacts with the death receptors Fas and tumor necrosis receptor 1 (TNFR1). In vitro, RIP stimulates apoptosis, SAPK/JNK, and NF-kappaB activation. To define the physiologic role(s) that RIP plays in regulating apoptosis in vivo, we introduced a rip null mutation in mice through homologous recombination. RIP-deficient mice appear normal at birth but fail to thrive, displaying extensive apoptosis in both the lymphoid and adipose tissue and dying at 1-3 days of age. In contrast to a normal thymic anti-Fas response, rip-/- cells are highly sensitive to TNFalpha-induced cell death. Sensitivity to TNFalpha-mediated cell death in rip-/- cells is accompanied by a failure to activate the transcription factor NF-kappaB.
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                Author and article information

                Journal
                Oncol Lett
                Oncol Lett
                OL
                Oncology Letters
                D.A. Spandidos
                1792-1074
                1792-1082
                August 2013
                14 June 2013
                14 June 2013
                : 6
                : 2
                : 517-520
                Affiliations
                Department of Oncology, Hospital of Traditional Chinese Medicine, Yantai, Shandong 264000, P.R. China
                Author notes
                Correspondence to: Dr Hongmin Shao, Department of Oncology, Hospital of Traditional Chinese Medicine, No. 39 Xingfu Road, Yantai, Shandong 264000, P.R. China, E-mail: shaohongmin2012@ 123456163.com
                Article
                ol-06-02-0517
                10.3892/ol.2013.1399
                3789031
                24137358
                4397521e-1527-4a33-8d5a-38d0164d3700
                Copyright © 2013, Spandidos Publications

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                : 26 December 2012
                : 17 May 2013
                Categories
                Articles

                Oncology & Radiotherapy
                matrine,breast cancer,nf-κb,ikkβ
                Oncology & Radiotherapy
                matrine, breast cancer, nf-κb, ikkβ

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