The Anti-tumoral Effect of β-D-Mannuronic Acid (M2000) as a Novel NSAID on Treg Cells Frequency and MMP-2, MMP-9, CCL22 and TGFβ1 Gene Expression in Pre-surgical Breast Cancer Patients

Iran J Allergy Asthma Immunol. 2019 Feb;18(1):80-90.

Abstract

With respect to the role of chronic inflammation in the induction and progression of breast cancer (BC). The relationship between tumor and tumor microenvironment may be a hopeful strategy for BC therapy. According to the effect of β-D-Mannuronic acid (M2000) as a novel non-steroidal anti-inflammatory drug (NSAID) on BC murine model and 4T1 cell line, we started to study that was a phase II, randomized, controlled clinical trial. 24 women with BC were included in this study and were followed by fixed oral doses of M2000, 500 mg two times a day (6-8 weeks). Blood samples were collected at baseline and weeks 6-8. To compare the patterns of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), C-C motif chemokine ligand 22 (CCL22) and The transforming growth factor-beta 1 (TGFβ1) gene expression and T regulatory cells (Tregs) frequency of healthy women normal controls with BC patients, a set of 10 blood samples of women healthy volunteers was collected. The gene expression was evaluated by quantitative Real-time PCR (qRT-PCR) and the frequency of Tregs was assessed by flow cytometry. Our results showed, reduction in MMP-2 (p=0.08), MMP-9 (p=0.03), CCL22 (p=0.003) and TGFβ1 (p=0.1) gene expression and Tregs frequency (p=0.01) which play a main role in the development of chronic inflammation, angiogenesis, tumorigenesis and metastasis. Our findings demonstrated that M2000 therapy as a novel designed NSAID had valuable therapeutic effects on BC. No adverse effects were observed following the use of M2000 after 6-8 weeks.

Keywords: Breast Cancer; Chemopreventive; M2000; Non-steroidal anti-inflammatory drug; β-D-Mannuronic acid.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Carcinoma, Ductal, Breast / drug therapy
  • Carcinoma, Ductal, Breast / genetics
  • Chemokine CCL22 / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Hexuronic Acids / pharmacology*
  • Humans
  • Lymphocyte Count
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 9 / genetics
  • T-Lymphocytes, Regulatory / drug effects
  • Transforming Growth Factor beta1 / genetics

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents
  • CCL22 protein, human
  • Chemokine CCL22
  • Hexuronic Acids
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • mannuronic acid
  • MMP2 protein, human
  • Matrix Metalloproteinase 2
  • MMP9 protein, human
  • Matrix Metalloproteinase 9