Subject(s)
Food, Fortified , Iodine/pharmacology , Iron/pharmacology , Adolescent , Anemia/epidemiology , Child , Child, Preschool , Female , Humans , India/epidemiology , Male , Prevalence , Sodium ChlorideABSTRACT
Survivin inhibits apoptosis during development and carcinogenesis and is absent in differentiated cells. To determine whether survivin inhibition induces cell death in neural tumor cells, survivin antisense oligonucleotides (SAO) were administered to a human neuroblastoma (MSN) and an oligodendroglioma (TC620) resulting in a dose-dependent reduction in survivin protein. Although 74% of the SAO-treated MSN cells were trypan blue(+), PARP cleavage or activated caspase-3 was not observed. However nuclear translocation of AIF occurred and XIAP increased dramatically. Co-administration of z-Val-Ala-Asp(OMe)-fluoromethyl ketone (zVAD-fmk) with SAO did not inhibit cell death suggesting a caspase-independent mechanism of cell death. Propidium iodide (PI) staining revealed multiple large macronuclei with no apoptotic bodies supporting a role for survivin in cell division. By contrast, while 70% of the SAO-treated TC620 cells were trypan blue(+), PARP was cleaved, cells were TUNEL(+) and PI-staining revealed macronuclei and numerous apoptotic bodies. Co-treatment of the TC620 cells with SAO and zVAD-fmk blocked cell death. While no macronuclei or apoptotic bodies were observed there was a two-fold increase in metaphase cells. Our results suggest that survivin inhibition decreases the viability of human neural tumor cells and as a result of mitotic catastrophe, cell death can be initiated by either a classic apoptotic mechanism or a caspase-independent mechanism.
Subject(s)
Brain Neoplasms/physiopathology , Caspases/physiology , Chromosomal Proteins, Non-Histone/antagonists & inhibitors , Microtubule-Associated Proteins , Neuroblastoma/physiopathology , Oligodendroglioma/physiopathology , Apoptosis , Brain Neoplasms/pathology , Caspase 3 , Caspases/metabolism , Cell Death/physiology , Cell Nucleus/ultrastructure , Chromosomal Proteins, Non-Histone/genetics , G2 Phase , Humans , Inhibitor of Apoptosis Proteins , Mitosis , Neoplasm Proteins , Neuroblastoma/pathology , Oligodendroglioma/pathology , Oligonucleotides, Antisense/pharmacology , Proteins/metabolism , Survivin , Tumor Cells, Cultured , X-Linked Inhibitor of Apoptosis ProteinABSTRACT
Metabolic hypofunction is a common finding in a number of neurodegenerative diseases, including Alzheimer's disease (AD). The strong linkage between the amyloid precursor protein (APP) and AD led us to examine whether over-expression of this protein in CNS-type cells had an effect on mitochondria. We found abnormal morphology in mitochondria of the neuroectodermal progeny of P19 cells stably transfected with human APP751. In addition, the mitochondria of APP-transfected clones had a decreased mitochondrial membrane potential. These changes were independent of Abeta toxicity and distinct from complex I inhibition. Our results have important implications for the earliest events in the pathophysiology of AD and, by extrapolation, for intervention therapies.
