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.

Redox-directed cancer therapeutics: Taurolidine and Piperlongumine as broadly effective antineoplastic agents (review).

Targeting the oxygen stress response pathway is considered a promising strategy to exert antineoplastic activity in a broad spectrum of tumor types. Supporting this view, we summarize the mechanism of action of Taurolidine and Piperlongumine, two antineoplastic agents with strikingly broad tumor selectivity. Taurolidine enhances the oxidative stress (ROS) selectively in tumor cells.

The GABA system in anxiety and depression and its therapeutic potential.

In the regulation of behavior, the role of GABA neurons has been extensively studied in the circuit of fear, where GABA interneurons play key parts in the acquisition, storage and extinction of fear. Therapeutically, modulators of α(2)/α(3) GABA(A) receptors, such as TPA023, have shown clinical proof of concept as novel anxiolytics, which are superior to classical benzodiazepines by their lack of sedation and much reduced or absent dependence liability. In view of the finding that anxiety disorders and major depression share a GABAergic deficit as a common pathophysiology, the GABA hypothesis of depression has found increasing support.

The rise of a new GABA pharmacology.

Key developments in GABA pharmacology over the last 30 years are reviewed with special reference to the advances pioneered by Erminio Costa. His passion for innovative science, and his quest for novel therapies for psychiatric disorders are particularly apparent in his fundamental contributions to the field of GABA research, with a focus on anxiety disorders and schizophrenia. He was a cofounder of the GABAergic mechanism of action of benzodiazepines.