dinoprost and carfilzomib

Carfilzomib's (Cfz) adverse events in myeloma patients include cardiovascular toxicity. Since carfilzomib's vascular effects are elusive, we investigated the vascular outcomes of carfilzomib and metformin (Met) coadministration.. Mice received: (i) saline; (ii) Cfz; (iii) Met; (iv) Cfz+Met for two consecutive (acute) or six alternate days (subacute protocol). Leucocyte-derived reactive oxygen species (ROS) and serum NO. Acutely, carfilzomib alone led to vascular hypo-contraction and increased ROS release. Subacutely, carfilzomib increased ROS release without vascular manifestations. Cfz+Met increased PGF2α-vasoconstriction and LC3-B-dependent autophagy in both young and aged mice. In vitro, Cfz+Met led to cytotoxicity and autophagy, while Met and Cfz+Met shifted cellular metabolism.. Carfilzomib induces a transient vascular impairment and oxidative burst. Cfz+Met increased vascular contractility and synergistically induced autophagy in all settings. Therefore, carfilzomib cannot be accredited for a permanent vascular dysfunction, while Cfz+Met exert vasoprotective potency.

Topics: Actins; AMP-Activated Protein Kinase Kinases; Animals; Antineoplastic Agents; Autophagy; Cell Survival; Cobalt; Dinoprost; Drug Therapy, Combination; Endoplasmic Reticulum; Glucose; Glycolysis; Humans; Male; Metformin; Mice; Mice, Inbred C57BL; Myocytes, Smooth Muscle; Nitric Oxide; Oligopeptides; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Kinases; Reactive Oxygen Species; Tumor Suppressor Protein p53