+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: not found

      Sorafenib induces autophagy and suppresses activation of human macrophage


      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.



          Sorafenib, a multi-kinase inhibitor approved for treatment of advanced renal cell carcinoma and other malignancies, has been shown as a modulator for dendritic cells. This study was designed to examine the effects of sorafenib on macrophages, the major ontogeny of innate immunity.

          Materials and methods

          Macrophages were derived from sorted CD14 + monocytes of human peripheral blood mononuclear cells. Cell viability and surface antigens were examined by trypan blue analysis. Autophagy was characterized by light microscopy and transmission electron microscopy for morphology, Western blotting for microtubule associated light chain protein 3B (LC-3B) I lipidation, and acridine orange staining for acidic component vacuoles. Soluble factors contained in culture medium and serum were measured by ELISA.


          We found that sorafenib inhibited the viability of macrophages accompanied by morphological changes characteristic of autophagy. This autophagy-inducing effect was validated by LC3B-I lipidation and autophagosome accumulation. The surface antigen expression and the function of activated macrophages were inhibited by sorafenib, including the expression of co-stimulatory molecule CD80, phagocytosis, and the production of reactive oxygen species. The secretion of IL-10, but not IL-6, TNF-α nor TGF-β, was reduced by sorafenib.


          Sorafenib, in addition to being a cancer targeted therapeutic agent, can induce autophagy and modulate the function of human macrophages.


          ► Sorafenib is a multi-kinase inhibitor approved for cancer treatment. ► We examine the immunomodulatory effect of sorafenib on macrophages. ► Sorafenib induces autophagy and alters functions of human macrophages.

          Related collections

          Most cited references10

          • Record: found
          • Abstract: found
          • Article: not found

          Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection.

          Viral proteins are usually processed by the 'classical' major histocompatibility complex (MHC) class I presentation pathway. Here we showed that although macrophages infected with herpes simplex virus type 1 (HSV-1) initially stimulated CD8(+) T cells by this pathway, a second pathway involving a vacuolar compartment was triggered later during infection. Morphological and functional analyses indicated that distinct forms of autophagy facilitated the presentation of HSV-1 antigens on MHC class I molecules. One form of autophagy involved a previously unknown type of autophagosome that originated from the nuclear envelope. Whereas interferon-gamma stimulated classical MHC class I presentation, fever-like hyperthermia and the pyrogenic cytokine interleukin 1beta activated autophagy and the vacuolar processing of viral peptides. Viral peptides in autophagosomes were further processed by the proteasome, which suggests a complex interaction between the vacuolar and MHC class I presentation pathways.
            • Record: found
            • Abstract: found
            • Article: not found

            Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses.

            The tyrosine kinase inhibitors sorafenib and sunitinib are approved for the treatment of patients with malignant diseases. To analyze the possible use of these compounds in combination with immunotherapeutic approaches, we analyzed the effects of both inhibitors on the immunostimulatory capacity of human dendritic cells (DCs) and the induction of primary immune responses in vivo. Sorafenib, but not sunitinib, inhibits function of DCs, characterized by reduced secretion of cytokines and expression of CD1a, major histocompatibility complex, and costimulatory molecules in response to TLR ligands as well as by their impaired ability to migrate and stimulate T-cell responses. These inhibitory effects are mediated by inhibition of PI3 and MAP kinases and NFkappaB signaling. In contrast, sorafenib had no influence on the phenotype and proliferation of T cells. To analyze the effects of both TKIs on cytotoxic T-cell induction in vivo, C57BL/6 mice were pretreated with sorafenib or sunitinib and immunized with OVA(257-264) peptide. Sorafenib, but not sunitinib, application significantly reduced the induction of antigen-specific T cells. Numbers of regulatory T cells were reduced in peripheral blood mononuclear cells from mice treated with sunitinib. These results indicate that sunitinib, but not sorafenib, is suitable for combination with immunotherapeutic approaches for treatment of cancer patients.
              • Record: found
              • Abstract: found
              • Article: not found

              Modulation of macrophage activation and programming in immunity.

              Macrophages are central mediators of the immune, contributing both to the initiation and the resolution of inflammation. The concept of macrophage activation and program has stimulated interest in its definition, and functional significance in homeostasis and diseases. It has been known that macrophages could be differently activated and programmed into different functional subtypes in response to different types of antigen stumuli or different kinds of cytokines present in the microenvironment and could thus profoundly influence immune responses, but little is known about the state and exact regulatory mechanism of macrophage activation and program from cell or molecular signaling level in immunity. In this review, we summarize the recent finding regarding the regulatory mechanism of macrophage activation and program toward M1 and M2, especially on M2 macrophages. Copyright © 2012 Wiley Periodicals, Inc.

                Author and article information

                Int Immunopharmacol
                Int. Immunopharmacol
                International Immunopharmacology
                Elsevier B.V.
                19 January 2013
                February 2013
                19 January 2013
                : 15
                : 2
                : 333-339
                [a ]Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
                [b ]Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan
                [c ]Mackay Medicine, Nursing, and Management College, Taipei, Taiwan
                [d ]Graduate Institute of Pharmacology, Taipei Medical University, Taipei, Taiwan
                [e ]Department of Medical Research, Genetics Center, China Medical University Hospital, Taichung, Taiwan
                [f ]Department of Surgery, School of Medicine, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan
                [g ]Department of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan
                [h ]Graduate Institute of Sport Coaching Science, Chinese Culture University, Taipei, Taiwan
                Author notes
                [* ]Correspondence to: C.H. Wu, Department of Surgery, School of Medicine, Taipei Medical University-Shuang Ho Hospital, No. 252, Wu-Hsing Street, Taipei 110, Taiwan. chwu@ 123456tmu.edu.tw
                [** ]Correspondence to: Y.J. Chen, Department of Radiation Oncology, Mackay Memorial Hospital, No. 92, Sec. 2, Chung-Shan North Road, Taipei, Taiwan. Tel.: + 886 2 2809 4661x2301; fax: + 886 2 2809 6180. chenmdphd@ 123456gmail.com
                Copyright © 2013 Elsevier B.V. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                : 8 October 2012
                : 2 January 2013
                : 7 January 2013

                Pharmacology & Pharmaceutical medicine
                Pharmacology & Pharmaceutical medicine
                sorafenib, macrophage, autophagy


                Comment on this article