Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophages participate in several inflammatory pathologies such as sepsis and arthritis. We examined the effect of simvastatin on the LPS-induced proinflammatory macrophage RAW264.7 cells. Co-treatment of LPS and a non-toxic dose of simvastatin induced cell death in RAW264.7 cells. The cell death was accompanied by disruption of mitochondrial membrane potential (MMP), genomic DNA fragmentation, and caspase-3 activation. Surprisingly, despite caspase-dependent apoptotic cascade being completely blocked by Z-VAD-fmk, a pan-caspase inhibitor, the cell death was only partially repressed. In the presence of Z-VAD-fmk, DNA fragmentation was blocked, but DNA condensation, disruption of MMP, and nuclear translocation of apoptosis inducing factor were obvious. The cell death by simvastatin and LPS was effectively decreased by both the FPP and GGPP treatments as well as mevalonate. Our findings indicate that simvastatin triggers the cell death of LPS-treated RAW264.7 cells through both caspase-dependent and -independent apoptotic pathways, suggesting a novel mechanism of statins for the severe inflammatory disease therapy.
 ...
PMID:Simvastatin induces caspase-independent apoptosis in LPS-activated RAW264.7 macrophage cells. 1632 79

Novel therapeutic strategies are still urgently expected for leukemia despite undisputed success of various targeted therapeutics. The antileukemia activity of Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on human leukemia cells was investigated. Atorvastatin inhibited K562 and HL60 cell proliferation, induced G2/M cell cycle arrest in K562 cells by down-regulating cyclinB1 and cdc2, but G0/G1 arrest in HL60 cells by up-regulating p27 and down-regulating cyclinD1 and p-pRb. Atorvastatin also induced apoptosis in both cell lines, in which the reactive oxygen species (ROS)-related mitochondrial apoptotic signaling might be involved, with increase of ROS and Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (MMP), release of cytochrome C into cytosol, and activation of Bax/Caspase-9/Caspase-3/PARP pathway. Inhibition of YAP nuclear localization and activation by Atorvastatin was reversed by the addition of mevalonate, GGPP, or FPP. Further, the effects on cell cycle arrest- and apoptosis- related proteins by Atorvastatin were alleviated by addition of mevalonate, suggesting the antileukemia effect of Atorvastatin might be through mevalonate-YAP axis in K562 and HL60 cells. Our results suggest that Atorvastatin might be used for leukemia therapy while evidence of clinical efficacy is required.
 ...
PMID:Atorvastatin Exerts Antileukemia Activity via Inhibiting Mevalonate-YAP Axis in K562 and HL60 Cells. 3164 88