A1, an innovative fluorinated CXCR4 inhibitor, redefines the therapeutic landscape in colorectal cancer
Abstract Background 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,...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-01-01
|
| Series: | Cancer Cell International |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12935-024-03584-y |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841544280758288384 |
|---|---|
| author | Hossein Khorramdelazad Kowsar Bagherzadeh Ali Rahimi Ali Darehkordi Alireza Najafi Milad Karimi Majid Khoshmirsafa Gholamhossein Hassanshahi Elaheh Safari Reza Falak |
| author_facet | Hossein Khorramdelazad Kowsar Bagherzadeh Ali Rahimi Ali Darehkordi Alireza Najafi Milad Karimi Majid Khoshmirsafa Gholamhossein Hassanshahi Elaheh Safari Reza Falak |
| author_sort | Hossein Khorramdelazad |
| collection | DOAJ |
| description | Abstract Background 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-β) genes in tumor tissue. Additionally, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) techniques were employed to assess VEGF, IL-10, and TGF-β 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-β 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. |
| format | Article |
| id | doaj-art-5da0fff8ab244a0cb32fd339b146c1d4 |
| institution | Kabale University |
| issn | 1475-2867 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj-art-5da0fff8ab244a0cb32fd339b146c1d42025-01-12T12:40:39ZengBMCCancer Cell International1475-28672025-01-0125112410.1186/s12935-024-03584-yA1, an innovative fluorinated CXCR4 inhibitor, redefines the therapeutic landscape in colorectal cancerHossein Khorramdelazad0Kowsar Bagherzadeh1Ali Rahimi2Ali Darehkordi3Alireza Najafi4Milad Karimi5Majid Khoshmirsafa6Gholamhossein Hassanshahi7Elaheh Safari8Reza Falak9Department of Immunology, School of Medicine, Rafsanjan University of Medical SciencesEye Research Center, the Five Senses Health Institute, Rassoul Akram Hospital, University of Medical SciencesDepartment of Immunology, School of Medicine, Iran University of Medical SciencesDepartment of Chemistry, Faculty of Science, Vali-E-Asr University of RafsanjanDepartment of Immunology, School of Medicine, Iran University of Medical SciencesDepartment of Immunology, School of Medicine, Iran University of Medical SciencesDepartment of Immunology, School of Medicine, Iran University of Medical SciencesMolecular Medicine Research Centre, Institute of Basics Medical Sciences, Rafsanjan University of Medical SciencesDepartment of Immunology, School of Medicine, Iran University of Medical SciencesDepartment of Immunology, School of Medicine, Iran University of Medical SciencesAbstract Background 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-β) genes in tumor tissue. Additionally, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) techniques were employed to assess VEGF, IL-10, and TGF-β 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-β 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.https://doi.org/10.1186/s12935-024-03584-yAMD3100Colorectal cancerCXCR4 inhibitorCXCL12Fluorine |
| spellingShingle | Hossein Khorramdelazad Kowsar Bagherzadeh Ali Rahimi Ali Darehkordi Alireza Najafi Milad Karimi Majid Khoshmirsafa Gholamhossein Hassanshahi Elaheh Safari Reza Falak A1, an innovative fluorinated CXCR4 inhibitor, redefines the therapeutic landscape in colorectal cancer Cancer Cell International AMD3100 Colorectal cancer CXCR4 inhibitor CXCL12 Fluorine |
| title | A1, an innovative fluorinated CXCR4 inhibitor, redefines the therapeutic landscape in colorectal cancer |
| title_full | A1, an innovative fluorinated CXCR4 inhibitor, redefines the therapeutic landscape in colorectal cancer |
| title_fullStr | A1, an innovative fluorinated CXCR4 inhibitor, redefines the therapeutic landscape in colorectal cancer |
| title_full_unstemmed | A1, an innovative fluorinated CXCR4 inhibitor, redefines the therapeutic landscape in colorectal cancer |
| title_short | A1, an innovative fluorinated CXCR4 inhibitor, redefines the therapeutic landscape in colorectal cancer |
| title_sort | a1 an innovative fluorinated cxcr4 inhibitor redefines the therapeutic landscape in colorectal cancer |
| topic | AMD3100 Colorectal cancer CXCR4 inhibitor CXCL12 Fluorine |
| url | https://doi.org/10.1186/s12935-024-03584-y |
| work_keys_str_mv | AT hosseinkhorramdelazad a1aninnovativefluorinatedcxcr4inhibitorredefinesthetherapeuticlandscapeincolorectalcancer AT kowsarbagherzadeh a1aninnovativefluorinatedcxcr4inhibitorredefinesthetherapeuticlandscapeincolorectalcancer AT alirahimi a1aninnovativefluorinatedcxcr4inhibitorredefinesthetherapeuticlandscapeincolorectalcancer AT alidarehkordi a1aninnovativefluorinatedcxcr4inhibitorredefinesthetherapeuticlandscapeincolorectalcancer AT alirezanajafi a1aninnovativefluorinatedcxcr4inhibitorredefinesthetherapeuticlandscapeincolorectalcancer AT miladkarimi a1aninnovativefluorinatedcxcr4inhibitorredefinesthetherapeuticlandscapeincolorectalcancer AT majidkhoshmirsafa a1aninnovativefluorinatedcxcr4inhibitorredefinesthetherapeuticlandscapeincolorectalcancer AT gholamhosseinhassanshahi a1aninnovativefluorinatedcxcr4inhibitorredefinesthetherapeuticlandscapeincolorectalcancer AT elahehsafari a1aninnovativefluorinatedcxcr4inhibitorredefinesthetherapeuticlandscapeincolorectalcancer AT rezafalak a1aninnovativefluorinatedcxcr4inhibitorredefinesthetherapeuticlandscapeincolorectalcancer |