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CT2-3 induces cell cycle arrest and apoptosis in rheumatoid arthritis fibroblast-like synoviocytes through regulating

Jian Chen1, Xian Lin1, Kangdi Liu2

  • 1Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, 518036, China; Institute of Immunology and Inflammatory Diseases, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Shenzhen, 518036, China.

European Journal of Pharmacology
|July 5, 2023
PubMed

Insights

CT2-3, a novel compound, halts rheumatoid arthritis fibroblast-like synoviocyte proliferation and induces apoptosis by targeting the PI3K/AKT pathway. This offers a potential new drug candidate for rheumatoid arthritis therapy.

Area of Science:

  • Immunology
  • Pharmacology
  • Cell Biology

Background:

  • Rheumatoid arthritis (RA) is a chronic autoimmune disease with unmet therapeutic needs.
  • Fibroblast-like synoviocytes (RA-FLSs) play a critical role in RA pathogenesis through dysregulated proliferation and apoptosis.
  • Novel therapeutic strategies targeting RA-FLSs are essential for effective RA treatment.

Purpose of the Study:

  • To investigate the anti-rheumatoid arthritis (RA) effects of the novel compound CT2-3.
  • To elucidate the mechanism of CT2-3 in regulating the function of RA-fibroblast-like synoviocytes (RA-FLSs).
  • To evaluate CT2-3 as a potential lead compound for RA drug development.

Main Methods:

  • Primary RA-FLSs and MH7A cells were treated with CT2-3.
  • Cell proliferation, DNA replication, cell cycle, and apoptosis were assessed.
  • Expression of cell cycle regulators (CDK2, Cyclin A2, Cyclin B1) and apoptosis markers (Bcl-2, Bax) were analyzed.
  • RNA-sequencing, Western blot, and network pharmacology identified the targeted signaling pathway.

Main Results:

  • CT2-3 significantly inhibited proliferation and DNA replication in RA-FLSs and MH7A cells.
  • CT2-3 induced cell cycle arrest by downregulating CDK2, Cyclin A2, and Cyclin B1.
  • CT2-3 promoted apoptosis by decreasing Bcl-2 and increasing Bax levels.
  • CT2-3 was confirmed to inhibit the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway in RA-FLSs.

Conclusions:

  • CT2-3 effectively induces cell cycle arrest and apoptosis in RA-FLSs.
  • The anti-RA mechanism of CT2-3 involves the modulation of the PI3K/AKT signaling pathway.
  • CT2-3 demonstrates potential as a novel small molecule therapeutic agent for rheumatoid arthritis.
Keywords:
ApoptosisCT2-3Cell cycle arrestFibroblast-like synoviocytesRheumatoid arthritis

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