ساخت اکانت کاربری رایگان

مقالات پذیرفته شده کنگره

  • صفحه نخست
  • مقالات پذیرفته شده اولین کنگره بین المللی ژنتیک سرطان
بازنشر

  • A1, an innovative fluorinated CXCR4 inhibitor, redefines the therapeutic landscape in colorectal cancer

  • Asma Maleki,1,* Hossein Khorramdelazad,2
    1. Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
    2. Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.


  • Introduction: Colorectal cancer (CRC) is a globally prevalent malignancy, primarily affecting the colon and rectum, characterized by uncontrolled cellular changes in the intestinal wall lining. Recent evidence underlines the significant role of the CXCL12/CXCR4 axis in the development of CRC, suggesting that inhibiting this pathway could be a promising therapeutic approach. This study focuses on investigating the potential of N, N’’-thiocarbonylbis (N’-(3,4-dimethyl phenyl)-2,2,2-trifluoroacetimidamide) (A1), a novel fluorinated CXCR4 inhibitor, through a comprehensive analysis encompassing in silico, in vitro, and in vivo studies.
  • Methods: The molecular dynamic simulation method was employed to compute A1 binding affinity and energy for the CXCR4 receptor compared to AMD3100. In vitro experiments utilized the CT-26 mouse CRC cell line to compare the inhibitory effects of A1 and AMD3100 on tumor cell proliferation and migration. Following the development of the CRC animal model in BALB/c mice, immune system responses within the tumor microenvironment (TME) were evaluated. Flow cytometry and real-time PCR (RT-PCR) were used to measure the effects of AMD3100 and A1 on regulatory T-cell (Treg) infiltration and the expression of CXCR4, vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF), interleukin-10 (IL-10), and tumor growth factor-beta (TGF-beta) genes in tumor tissue. Additionally, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) techniques were employed to assess VEGF, IL-10, and TGF-beta tissue levels at the protein level.
  • Results: Molecular dynamic simulation studies with molecular mechanics Poisson-Boltsman surface area (MM-PBSA) analysis revealed that A1 exhibits significantly lower binding energy for the CXCR4 receptor than AMD3100. A1 effectively inhibited the proliferation of CT-26 cells, significantly reduced tumor cell migration, attenuated Treg infiltration, and suppressed IL-10 and TGF-beta expression at both mRNA and protein levels in vivo. Notably, A1 outperformed AMD3100 in reducing tumor size and increasing survival rate in treated animals, with minimal side effects.
  • Conclusion: These findings emphasize the potential of A1 as a favorable anti-tumor small molecule in CRC. Further validation through rigorous preclinical and clinical studies may position A1 as a promising alternative to AMD3100 in human cancers.
  • Keywords: AMD3100, Colorectal cancer, CXCR4 inhibitor, CXCL12, Fluorine

به خانواده بزرگ کنسر ژنتیکس و ژنومیکس سرطان بپیوندید!

ایجاد حساب کاربری رایگان