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Novel Adamantane-Sclareol Hybrids Exploit ROS Vulnerability to Overcome Multidrug-Resistance in Glioblastoma Cells.
Ema Lupšić1, Pavle Stojković2, Marija Grozdanić1
1Institute for Biological Research "Siniša Stanković"-National Institute of the Republic of Serbia, University of Belgrade, Despota Stefana 142, 11108 Belgrade, Serbia.
Molecules (Basel, Switzerland)
|December 31, 2025
Summary
Novel adamantane-sclareol hybrids overcome multidrug resistance in glioblastoma by targeting P-glycoprotein and inducing apoptosis via reactive oxygen species, offering new treatment avenues.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Multidrug resistance (MDR) is a major obstacle in glioblastoma treatment.
- P-glycoprotein (P-gp) overexpression contributes significantly to MDR in glioblastoma.
- Novel therapeutic strategies are needed to overcome MDR in glioblastoma.
Purpose of the Study:
- To synthesize and evaluate novel adamantane-sclareol hybrids for overcoming glioblastoma MDR.
- To investigate the mechanism of action of these hybrids in MDR glioblastoma cells.
- To assess the in vivo efficacy and safety of promising hybrid compounds.
Main Methods:
- Synthesis of six novel adamantane-sclareol hybrids.
- Evaluation of compounds in P-gp-overexpressing U87-TxR glioblastoma cells.
- Mechanistic studies including apoptosis induction, reactive oxygen species (ROS) generation, mitochondrial membrane potential assessment, and gene expression analysis.
- P-gp inhibition assays and chemosensitization studies with paclitaxel.
- In vivo efficacy study using a Rag1 xenograft model.
Main Results:
- Compounds 2, 5, and 6 bypassed P-gp-mediated resistance and induced collateral sensitivity.
- Compound 2 showed higher selectivity for glioblastoma cells over normal glial cells.
- Compounds 2 and 5 triggered apoptosis, increased ROS and peroxynitrite levels, and disrupted mitochondrial membrane potential.
- These compounds modulated antioxidant defense systems (GSH, Trx) and activated ROS-driven apoptosis via ASK1.
- Compounds inhibited P-gp, enhanced rhodamine 123 accumulation, and sensitized cells to paclitaxel.
- Compound 5 suppressed tumor growth in vivo without significant weight loss.
Conclusions:
- Adamantane-sclareol hybrids, particularly compounds 2 and 5, are promising agents against MDR glioblastoma.
- These hybrids exploit ROS vulnerability, disrupt redox balance, and modulate P-gp function.
- They offer a dual approach of selective cytotoxicity and enhanced chemotherapeutic efficacy for resistant glioblastoma.
