Repurposed Drugs Celecoxib and Fmoc-L-Leucine Alone and in Combination as Temozolomide-Resistant Antiglioma...

Area of Science:

• Oncology
• Pharmacology
• Cell Biology

Background:

• Glioblastoma multiforme (GBM) therapy faces challenges due to limited effective treatments.
• Overexpression of cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptors γ (PPARγ) in gliomas presents potential therapeutic targets.
• Repurposing existing drugs like celecoxib (CXB) and Fmoc-L-Leucine-FL (FL) offers a novel therapeutic strategy.

Purpose of the Study:

• To evaluate the in vitro and in vivo efficacy and safety of COX-2 inhibitor (celecoxib-CXB) and PPARγ agonist (Fmoc-L-Leucine-FL) against temozolomide-resistant glioblastoma cells.
• To investigate the mechanism of action of CXB and FL on glioma cells, normal fibroblasts, and keratinocytes.
• To assess the toxicity of CXB and FL in a C. elegans model.

Main Methods:

• In vitro studies on U-118 MG glioma cells, BJ normal fibroblasts, and HaCaT keratinocytes.
• Assessment of antiproliferative, pro-apoptotic, and anti-migratory activities.
• In vivo studies using C. elegans to evaluate toxicity and effects on lifespan and body length.

Main Results:

• Both CXB and FL demonstrated antiproliferative, pro-apoptotic, and anti-migratory effects on U-118 MG glioma cells at 50-100 µM.
• The mechanism involved COX-2 and PPARγ dependent pathways, leading to their up-regulation in glioma cells.
• Neither drug exhibited selective toxicity towards glioma cells over normal BJ fibroblasts and HaCaT keratinocytes; HaCaTs were resistant to FL.
• CXB and FL showed no significant toxicity in C. elegans up to 100 µM for 4 days.
• Prolonged CXB exposure (7 days) reduced C. elegans lifespan and body length at concentrations of 25-400 µM.

Conclusions:

• Celecoxib and Fmoc-L-Leucine-FL show promise as glioblastoma therapeutics by targeting COX-2 and PPARγ.
• Lack of selectivity and potential toxicity in C. elegans warrant further investigation before clinical application.
• The observed effects differ from previous reports, suggesting context-dependent drug mechanisms.