Astragaloside IV inhibits progression of lung cancer by mediating immune function of Tregs and CTLs by interfering with IDO

J Cancer Res Clin Oncol. 2014 Nov;140(11):1883-90. doi: 10.1007/s00432-014-1744-x. Epub 2014 Jul 1.

Abstract

Purpose: Tumor cells have developed multiple mechanisms to escape immune recognition mediated by T cells. Indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme inducing immune tolerance, is involved in tumor escape from host immune systems in mice. Astragaloside IV (AS-IV), an extract from a commonly used Chinese medicinal plant Astragalus membranaceus, has been shown to be capable of restoring the impaired T-cell functions in cancer patients. The purpose of this study was to investigate the mechanisms underlying the anticancer properties of AS-IV.

Methods: Here, we used IDO-overexpressed murine Lewis lung carcinoma cells to establish an orthotopic lung cancer model in C57BL/6 mice. Next, tumor growth was evaluated in several different treatment groups: control (saline), AS-IV, paclitaxel, and 1-methyl tryptophan (an inhibitor of IDO). We then analyzed the percentages of various immune cell subsets among the splenic lymphocytes of lung cancer mice by flow cytometry. The level of IDO was measured by real-time PCR and Western blot.

Results: We showed that the growth of tumor was suppressed by AS-IV treatment in vivo. AS-IV also could down-regulate regulatory T cells (Tregs) and up-regulate cytotoxic T lymphocytes (CTLs) in vivo and in vitro. Consistent with its ability to interfere with T-cell immunity, AS-IV blocked IDO induction both in vitro and in vivo.

Conclusions: The results of these studies indicate that AS-IV has in vivo anticancer activity and can enhance the immune response by inhibiting the Tregs frequency and induce the activity of CTLs, which might be related to the inhibition of IDO expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Lewis Lung / drug therapy
  • Carcinoma, Lewis Lung / enzymology
  • Carcinoma, Lewis Lung / immunology*
  • Carcinoma, Lewis Lung / pathology
  • Cell Line, Tumor
  • Coculture Techniques
  • Disease Progression
  • Drug Screening Assays, Antitumor
  • Female
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
  • Mice, Inbred C57BL
  • Neoplasm Transplantation
  • Paclitaxel / pharmacology
  • Paclitaxel / therapeutic use
  • Saponins / pharmacology*
  • Saponins / therapeutic use
  • T-Lymphocytes, Cytotoxic / drug effects*
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • Triterpenes / pharmacology*
  • Triterpenes / therapeutic use
  • Tryptophan / analogs & derivatives
  • Tryptophan / pharmacology
  • Tryptophan / therapeutic use
  • Tumor Burden / drug effects
  • Tumor Escape / drug effects

Substances

  • Antineoplastic Agents
  • IDO1 protein, mouse
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Saponins
  • Triterpenes
  • astragaloside A
  • Tryptophan
  • Paclitaxel
  • 1-methyltryptophan