Lipopolysaccharides-stimulated macrophage products enhance Withaferin A-induced apoptosis via activation of caspases and inhibition of NF-κB pathway in human cancer cells

Mol Immunol. 2017 Jan:81:92-101. doi: 10.1016/j.molimm.2016.10.010. Epub 2016 Dec 1.


Macrophages, as a major cellular component in tumor microenvironment, play an important role in tumor progression. However, their roles in modulation of cytotoxic chemotherapy are still not fully understood. Here, we investigated the influence of Lipoplysaccharides (LPS)-stimulated macrophage products (LSMP) on Withaferin A (WA), a natural compound that derived from the medicinal plant Withania somnifera, as an antitumor agent in human breast cancer cells MDA-MB-231 and prostate cancer cells PC-3. Our results revealed that LSMP may enhance WA-induced apoptosis in both cell lines, the underlying mechanisms of which are closely associated with activation of caspase-8, -9 and -3, cleavage of poly ADP-ribose polymerase (PARP), as well as specifically inhibiting the translocation of nuclear factor-κB (NF-κB) and down-regulation of anti-apoptotic proteins X-linked inhibitor of apoptosis protein (XIAP) and inhibitor of apoptosis protein (cIAP1/2). These findings demonstrate that macrophages in tumor microenvironment can modulate tumor responses to chemotoxic agents, providing an effective strategy that targets macrophages to enhance the antitumor efficacy of cytotoxic chemotherapy.

Keywords: Apoptosis; Macrophage; NF-κB pathway; Withaferin A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / immunology
  • Blotting, Western
  • Caspases / immunology
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Culture Media, Conditioned / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Activation / immunology
  • Female
  • Flow Cytometry
  • Gene Knockdown Techniques
  • Humans
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / pharmacology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred BALB C
  • NF-kappa B / immunology*
  • NF-kappa B / metabolism
  • Neoplasms / immunology*
  • Neoplasms / metabolism
  • Polymerase Chain Reaction
  • Signal Transduction / immunology
  • Tumor Microenvironment / immunology
  • Withanolides / pharmacology*


  • Antineoplastic Agents
  • Culture Media, Conditioned
  • Lipopolysaccharides
  • NF-kappa B
  • Withanolides
  • Caspases
  • withaferin A