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Discovery of Novel Agents on Spindle Assembly Checkpoint to Sensitize Vinorelbine-Induced Mitotic Cell Death Against

Ya-Ching Chang1, Yu-Ling Tseng1,2, Wohn-Jenn Leu1

  • 1School of Pharmacy, College of Medicine, National Taiwan University, No. 33, Linsen S. Rd, Taipei 100, Taiwan.

International Journal of Molecular Sciences
|August 9, 2020
PubMed

Insights

A novel compound, YL-9, enhances the cancer-killing effects of vinorelbine in non-small cell lung cancer (NSCLC) cells. This combination therapy boosts apoptosis by activating the spindle assembly checkpoint and increasing cell cycle arrest.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Non-small cell lung cancer (NSCLC) represents 80% of lung cancer cases, with many patients presenting with advanced or metastatic disease.
  • There is a critical need for non-toxic agents that can synergistically enhance the efficacy of existing chemotherapeutic drugs against NSCLC.
  • YL-9 is a novel, non-cytotoxic compound structurally related to sildenafil but with significantly lower phosphodiesterase type 5 (PDE5) inhibitory activity.

Purpose of the Study:

  • To investigate the synergistic effects of YL-9 in combination with vinorelbine on NSCLC cells.
  • To elucidate the underlying mechanisms by which YL-9 potentiates vinorelbine's anti-cancer activity.

Main Methods:

  • Utilized the NCI-H460 NSCLC cell line (low PDE5 expression) and A549 NSCLC cell line (PDE5 expression) for in vitro studies.
  • Assessed anti-proliferative and apoptotic effects of YL-9 and vinorelbine, alone and in combination.
  • Analyzed key molecular markers including tubulin acetylation, Bub1-related kinase (BUBR1) phosphorylation and cleavage, cyclin B1 expression, and B-cell lymphoma 2 (Bcl-2) phosphorylation.

Main Results:

  • YL-9 synergistically enhanced vinorelbine-induced anti-proliferative and apoptotic effects in both NCI-H460 and A549 cells.
  • Co-treatment with YL-9 and vinorelbine amplified vinorelbine-induced tubulin acetylation and BUBR1 phosphorylation, leading to increased mitotic arrest.
  • Combinatorial treatment resulted in enhanced mitotic spindle abnormalities, increased cyclin B1 expression, and elevated Bcl-2 phosphorylation.

Conclusions:

  • YL-9 acts as a novel potentiator of vinorelbine's anti-cancer activity in NSCLC.
  • The synergy observed is mediated through the activation of the spindle assembly checkpoint and increased mitotic cell cycle arrest.
  • YL-9 demonstrates significant potential for further development as a combinational therapy agent against NSCLC.
Keywords:
BUBR1Novel sildenafil mimeticapoptotic synergismspindle assembly checkpointvinorelbine

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