GP-2250, a novel anticancer agent, inhibits the energy metabolism, activates AMP-Kinase and impairs the NF-kB pathway in pancreatic cancer cells

GP-2250, a novel anticancer agent, severely limits the energy metabolism, as demonstrated by the inhibition of hexokinase 2 and glyceraldehyde-3-phosphate dehydrogenase and a decrease of ATP. Rescue experiments with supplementary pyruvate or oxaloacetate demonstrated that a TCA cycle deficit largely contributed to cytotoxicity. Activation of the energy-deficit sensor, AMP-dependent protein kinase, was associated with increased phosphorylation of acetyl-CoA carboxylase and Raptor, pointing to a possible deficit in the synthesis of fatty acids and proteins as essential cell components. Binding of p65 to DNA was dose-dependently reduced in nuclear lysates. A transcriptional deficit of NF-?B (nuclear factor kappa-light-chain-enhancer of activated B cells) was substantiated by the downregulation of cyclin D1 and of the anti-apoptotic Bcl2, in line with reduction in tumour cell proliferation and induction of apoptosis, respectively. The upregulation of p53 concomitant with an excess of ROS supported apoptosis. Thus, the anticancer activity of GP-2250 is a result of disruption of energy metabolism and inhibition of tumour promotion by NF-?B.

Automated summary

GP-2250, a novel anticancer agent, inhibits energy metabolism by targeting hexokinase 2 and glyceraldehyde-3-phosphate dehydrogenase, resulting in a decrease in ATP level. It causes cytotoxicity primarily through a deficit in the tricarboxylic acid cycle, leading to impaired synthesis of fatty acids and proteins. In addition, GP-2250 disrupts NF-κB signaling, reducing tumour cell proliferation and promoting apoptosis.