Treatment of glioblastoma multiforme (GBM)， the most common and aggressive lethal brain tumor， represents a great challenge. Despite decades of research， the survival prognosis of GBM patients is unfavorable and more effective therapeutics are sorely required. Archazolid B， a potent vacuolar H(+)-ATPase inhibitor influencing cellular pH values， is a promising new compound exerting cytotoxicity in the nanomolar range on wild-type U87MG glioblastoma cells and U87MG.∆EGFR cells transfected with a mutant epidermal growth factor receptor (EGFR) gene. Gene expression profiling using microarray technology showed that archazolid B caused drastic disturbances in cholesterol homeostasis. Cholesterol， a main... More
Treatment of glioblastoma multiforme (GBM)， the most common and aggressive lethal brain tumor， represents a great challenge. Despite decades of research， the survival prognosis of GBM patients is unfavorable and more effective therapeutics are sorely required. Archazolid B， a potent vacuolar H(+)-ATPase inhibitor influencing cellular pH values， is a promising new compound exerting cytotoxicity in the nanomolar range on wild-type U87MG glioblastoma cells and U87MG.∆EGFR cells transfected with a mutant epidermal growth factor receptor (EGFR) gene. Gene expression profiling using microarray technology showed that archazolid B caused drastic disturbances in cholesterol homeostasis. Cholesterol， a main component of cellular membranes， is known to be essential for GBM growth and cells bearing EGFRvIII mutation are highly dependent on exogenous cholesterol. Archazolid B caused excessive accumulation of free cholesterol within intracellular compartments thus depleting cellular cholesterol and leading to up-regulation of SREBP targeted genes， including LDLR and HMGCR， the key enzyme of cholesterol biosynthesis. This cholesterol response is considered to be a novel resistance mechanism induced by archazolid B. We surmise that re-elevation of cholesterol levels in archazolid B treated cells may be mediated by newly synthesized cholesterol， since the drug leads to endosomal/lysosomal malfunction and cholesterol accumulation.
