A Novel AMPK Inhibitor Sensitizes Pancreatic Cancer Cells to Ferroptosis Induction.

Cancer cells must develop strategies to adapt to the dynamically changing stresses caused by intrinsic or extrinsic processes, or therapeutic agents. Metabolic adaptability is crucial to mitigate such challenges. Considering metabolism as a central node of adaptability, it is focused on an energy sensor, the AMP-activated protein kinase (AMPK). In a subtype of pancreatic ductal adenocarcinoma (PDAC) elevated AMPK expression and phosphorylation is identified. Using drug repurposing that combined screening experiments and chemoproteomic affinity profiling, it is identified and characterized PF-3758309, initially developed as an inhibitor of PAK4, as an AMPK inhibitor. PF-3758309 shows activity in pre-clinical PDAC models, including primary patient-derived organoids. Genetic loss-of-function experiments showed that AMPK limits the induction of ferroptosis, and consequently, PF-3758309 treatment restores the sensitivity toward ferroptosis inducers. The work established a chemical scaffold for the development of specific AMPK-targeting compounds and deciphered the framework for the development of AMPK inhibitor-based combination therapies tailored for PDAC.

[Congenital hemolytic anemias due to erythrocyte membrane and enzyme defects]. / Kongenitale hämolytische Anämien durch Membran- und Enzymdefekte der Erythrozyten.

Erythrocyte membrane and enzyme defects are the most common cause of congenital hemolytic anemias in the Central European population. Diagnostics include erythrocyte morphology, special biochemical tests such as osmotic fragility (AGLT) and EMA. For enzymopenic hemolytic anemias, cost-effective biochemical analysis remains the gold standard, supplemented by molecular genetic diagnostics when appropriate. Therapeutically, near complete splenectomy reduces hemolysis significantly for spherocytosis. The residual spleen at least provides a considerable phagocytic function and better response to immunisation and by inference possibly better protection against severe post-splenectomy infection. For pyruvate kinase deficiency, which is not so rare, a new molecular therapy (Mitapivat) is currently being introduced. In G6PD deficiency, there are very few drugs that cause hemolytic crisis. Sudden onset of hemoglobinuria is an early important hallmark of severe hemolytic crisis in G6PD deficiency and these patients should be hospitalized. Aplastic crises in the setting of parvovirus B19 infection occur in all congenital hemolytic anemias. Transfusion is not preventable in most cases. Iron-excreting treatment is required in the rare patients in need of chronic transfusion.