Disrupting microtubule dynamics to rewire apoptosis, differentiation, and EMT programs in oral squamous cell...

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Oral squamous cell carcinoma (OSCC) presents a significant global health challenge with limited therapeutic strategies and frequent recurrence.
• Existing treatments for OSCC have limitations, necessitating the development of novel therapeutic agents.

Purpose of the Study:

• To identify and characterize novel indenamine derivatives with potent and selective anticancer activity against OSCC.
• To elucidate the molecular mechanisms underlying the observed cytotoxicity of these compounds in OSCC cells.

Main Methods:

• Screening of 22 synthesized indenamine derivatives for cytotoxicity against OSCC cell lines.
• Assessment of cell cycle progression, microtubule organization, and apoptosis induction.
• Transcriptomic analysis to identify modulated genes and pathways.
• Molecular docking studies to investigate binding interactions with α,β-tubulin.

Main Results:

• Three lead compounds (SSB2, SSB21, SSB22) demonstrated potent cytotoxicity against OSCC cells while sparing normal epithelial cells.
• Compounds induced G2/M cell cycle arrest, microtubule disruption, and apoptosis.
• Transcriptomic analysis revealed downregulation of oncogenes, upregulation of tumor suppressors, and modulation of epithelial-to-mesenchymal transition (EMT)-related genes.
• Molecular docking confirmed binding of indenamines to the colchicine binding site of α,β-tubulin.

Conclusions:

• Indenamine derivatives exhibit potent and selective anticancer effects in OSCC by targeting microtubules and reprogramming key cellular pathways.
• These compounds show potential for limiting OSCC metastasis by modulating EMT.
• The identified indenamine derivatives represent promising candidates for the development of novel OSCC therapeutics.