RESUMEN
The α-ketoglutarate-dependent (AlkB) superfamily of FeII/2-oxoglutarate (2-OG)-dependent dioxygenases consists of a unique class of nucleic acid repair enzymes that reversibly remove alkyl substituents from nucleobases through oxidative dealkylation. Recent studies have verified the involvement of AlkB dioxygenases in a variety of human diseases. However, the development of small organic molecules that can function as enzyme inhibitors to block the action of oxidative dealkylation is still in its infancy. These purposeful chemical motifs, if capable of influencing the dealkylation activity, would have a potential clinical value by controlling genetic information expression. In this Perspective, we will summarize some of the most updated inhibitors of AlkB family demethylases and hope to provide a thought for the follow-up screening optimization.
Asunto(s)
Enzimas AlkB/genética , Inhibidores Enzimáticos/farmacología , Complejo Cetoglutarato Deshidrogenasa/genética , Enzimas AlkB/antagonistas & inhibidores , Enzimas AlkB/química , Daño del ADN/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Complejo Cetoglutarato Deshidrogenasa/antagonistas & inhibidores , Ácidos Cetoglutáricos/antagonistas & inhibidoresRESUMEN
Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death. In addition, low glutamine-induced DNA damage is abolished in ALKBH deficient cells. Importantly, we show that glutaminase inhibitors, 6-Diazo-5-oxo-L-norleucine (DON) or CB-839, hypersensitize cancer cells to alkylating agents both in vitro and in vivo. Together, the crosstalk between glutamine metabolism and the DNA repair pathway identified in this study highlights a potential role of metabolic stress in genomic instability and therapeutic response in cancer.