FN-1501 Inhibits Diffuse Large B-Cell Lymphoma Tumor Growth by Inducing Cell Cycle Arrest And Apoptosis.

in Anti-cancer agents in medicinal chemistry by Dan Zou, Bowen Hu, Sitong Feng, Rujia Si, Bei Zhong, Bo Shen, Yuxin Du, Jifeng Feng

TLDR

  • FN-1501 shows promise as a new therapeutic option for patients with refractory or relapsed DLBCL, with potential mechanisms of action involving the inhibition of the MAPK and PI3K/AKT/mTOR pathways.

Abstract

Due to its high degree of aggressiveness, diffuse large B-cell lymphoma (DLBCL) presents a treatment challenge because 30% to 50% of patients experience resistance or relapse following standard chemotherapy. FN-1501 is an effective inhibitor of cyclin-dependent kinases and Fms-like receptor tyrosine kinase 3. This study aimed to examine the anti-tumor impact of FN-1501 on DLBCL and clarify its molecular mechanism. This study used the cell counting kit-8 assay to evaluate cell proliferation, along with western blotting and flow cytometry to analyze cell cycle progression and apoptosis influenced by FN-1501 in vitro. Afterward, the effectiveness of FN-1501 was evaluated in vivo utilizing the xenograft tumor model. In addition, we identified the potential signaling pathways and performed rescue studies using western blotting and flow cytometry. We found that FN-1501 inhibited cell proliferation and induced cell cycle arrest and apoptosis in DLBCL cells in vitro. Its anti-proliferative effects were shown to be time- and dose-dependent. The effect on cell cycle progression resulted in G1/S phase arrest, and the apoptosis induction was found to be caspase-dependent. FN-1501 treatment also reduced tumor volumes and weights and was associated with a prolonged progressionfree survival in vivo. Mechanistically, the MAPK and PI3K/AKT/mTOR pathways were significantly inhibited by FN-1501. Additional pathway inhibitors examination reinforced that FN-1501 may regulate cell cycle arrest and apoptosis through these pathways. FN-1501 shows promising anti-tumor activity against DLBCL in vivo and in vitro, suggesting its potential as a new therapeutic option for patients with refractory or relapsed DLBCL.

Overview

  • The study aimed to examine the anti-tumor impact of FN-1501 on diffuse large B-cell lymphoma (DLBCL) and clarify its molecular mechanism.
  • The study used cell-based assays, western blotting, and flow cytometry to evaluate the effects of FN-1501 on DLBCL cells in vitro and a xenograft tumor model to evaluate its anti-tumor activity in vivo.
  • The study identified the potential signaling pathways and performed rescue studies using western blotting and flow cytometry to clarify the mechanisms of action of FN-1501.

Comparative Analysis & Findings

  • FN-1501 inhibited cell proliferation, inducing cell cycle arrest and apoptosis in DLBCL cells in vitro, with anti-proliferative effects being time- and dose-dependent.
  • FN-1501 treatment reduced tumor volumes and weights and was associated with a prolonged progression-free survival in vivo.
  • The MAPK and PI3K/AKT/mTOR pathways were significantly inhibited by FN-1501, suggesting that these pathways may be involved in the anti-tumor activity of FN-1501.

Implications and Future Directions

  • The study suggests that FN-1501 may have potential as a new therapeutic option for patients with refractory or relapsed DLBCL.
  • Further studies are needed to investigate the optimal dosing and timing of FN-1501 and to compare its efficacy to existing treatments for DLBCL.
  • The study's findings may also inform the development of combination therapies that combine FN-1501 with other anticancer agents.
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