Novel Adamantane-Sclareol Hybrids Exploit ROS Vulnerability to Overcome Multidrug-Resistance in Glioblastoma Cells

作者：Lupšić E, Stojković P, Grozdanić M, Terzić-Jovanović N, Pajović M, Koutsougianni F, Alexopoulou D, Opsenica IM, Pešić M, Podolski-Renić A · 发表于：Molecules (Basel, Switzerland) · 年份：2025 · 被引用次数：51 · 研究领域：Glioblastoma、Adamantane、Drug Resistance, Neoplasm、Reactive Oxygen Species、Drug Resistance, Multiple、Diterpenes、Humans、Animals、Cell Line, Tumor、Mice、Apoptosis、Xenograft Model Antitumor Assays

Multidrug resistance (MDR) presents a significant challenge in the treatment of glioblastoma. We evaluated six novel adamantane-sclareol hybrids that integrate a natural labdane diterpene scaffold with an adamantane moiety to address this issue. Compounds 2, 5, and 6 demonstrated the ability to bypass P-glycoprotein (P-gp)-mediated resistance in resistant U87-TxR cells and induced collateral sensitivity, with compound 2 exhibiting the highest selectivity for glioblastoma compared to normal glial cells. Mechanistic studies revealed that compounds 2 and 5 selectively triggered early apoptosis in MDR cells, significantly elevated levels of H2O2 and peroxynitrite, and disrupted mitochondrial membrane potential. Additionally, these compounds altered the expression of key genes involved in glutathione (GSH) and thioredoxin (Trx) antioxidant defense systems and increased ASK1 protein levels, indicating the activation of ROS-driven apoptotic signaling. Both compounds inhibited P-gp function, leading to enhanced intracellular accumulation of rhodamine 123 (Rho 123) and synergistically sensitized U87-TxR cells to paclitaxel (PTX). A preliminary Rag1 xenograft study demonstrated that compound 5 effectively suppressed tumor growth without causing significant weight loss. Collectively, these findings position adamantane-sclareol hybrids, particularly compounds 2 and 5, as promising strategies that exploit an MDR-associated reactive oxygen species (ROS) vulnerability, combining selective c...