Cholesterol Analogs Ginsenosides Rg1 and Compound K Control Temozolomide Resistance in Glioblastoma Cells by Regulating Cholesterol Efflux and Lipid Raft Distribution

Abstract Enriched cholesterol in brain is involved in the resistance of glioblastoma to temozolomide treatment. Cholesterol efflux and lipid raft redistribution contribute to improving resistance. Ginsenosides are structurally similar to cholesterol and can alter cholesterol metabolism and lipid raft distribution, whose subtypes Rb1, Rg1, Rg3 and Compound K showed brain permeability. From CGGA database, the expression of cholesterol efflux gene NR1H3 (LXRα) in tumor tissues of patients treated with temozolomide was positively correlated with long-term survival, and was negatively correlated with multidrug resistance protein (MDR)-1 located in lipid rafts. MDR1 level was correlated with cholesterol uptake (LDLR) and synthesis (SREBF2) genes, suggesting that cholesterol is involved in temozolomide resistance. We demonstrated that cholesterol protected the survival of resistant U251 cells from temozolomide stress, and upregulated MDR1. Resistant U251 cells tended to store cholesterol intracellularly, with weaker cholesterol efflux and LXRα expression to maintain a uniform distribution of lipid rafts. Ginsenosides Rb1, Rg1, Rg3 and Compound K reduced intracellular cholesterol content and promoted cholesterol efflux in resistant cells, making lipid raft distribution no longer uniform. Rg1 and Compound K also upregulated LXRα expression and induced the cytotoxicity of temozolomide in the presence of cholesterol. We further found that cholesterol efflux induction, lipid raft redistribution, and temozolomide sensitization by Rg1 and Compound K were induced through stimulation of LXRα. Therefore, ginsenoside Rg1 and Compound K can control temozolomide resistance in glioblastoma cells by regulating cholesterol metabolism, which are potential synergists for temozolomide therapy.