We previously reported that elevated expression of phospholipid hydroperoxide glutathione peroxidase 4, an enzyme that regulates membrane lipid hydroperoxides, can mitigate sarcopenia in mice. However, it is still unknown whether a pharmacological intervention designed to modulate lipid hydroperoxides might be an effective strategy to reduce sarcopenia in aged mice. Here we asked whether a newly developed compound, CMD-35647 (CMD), can reduce muscle atrophy induced by sciatic nerve transection.
View Article and Find Full Text PDFFerroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q.
View Article and Find Full Text PDFBackground: Aberrant DNA methylation, which results in leukemogenesis, is frequent in patients with myelodysplastic syndromes (MDS) and is a potential target for pharmacologic therapy. Decitabine indirectly depletes methylcytosine and causes hypomethylation of target gene promoters.
Methods: A total of 170 patients with MDS were randomized to receive either decitabine at a dose of 15 mg/m2 given intravenously over 3 hours every 8 hours for 3 days (at a dose of 135 mg/m2 per course) and repeated every 6 weeks, or best supportive care.
Semin Oncol
October 2005
This review highlights decitabine as a prototype epigenetic modifying drug to show how the clinical development of epigenetic agents differs from that of traditional cytotoxic chemotherapies. Decitabine, a cytosine analogue, is cytotoxic at high doses but has selective DNA demethylating activity at low doses. The focus of current decitabine investigations is twofold: to elucidate all of the mechanisms of action and to determine the optimal dose, schedule, and concomitant therapies.
View Article and Find Full Text PDFCurr Opin Investig Drugs
December 2003
Decitabine (DAC) is a small molecule nucleotide analog that is incorporated into DNA and traps human DNA methyltransferases. Although initially developed as a cytotoxic agent, low-dose DAC is enjoying a revival as a specific inhibitor of hypermethylation in cancer. DAC has activity in several hematological diseases, especially myelodysplastic syndrome, chronic myelogenous leukemia and acute myeloid leukemia.
View Article and Find Full Text PDFDecitabine (5-aza-2'-deoxycytidine) inhibits DNA methylation and has dual effects on neoplastic cells, including the reactivation of silenced genes and differentiation at low doses and cytotoxicity at high doses. We evaluated, in a phase 1 study, low-dose prolonged exposure schedules of decitabine in relapsed/refractory leukemias. Patient cohorts received decitabine at 5, 10, 15, or 20 mg/m2 intravenously over one hour daily, 5 days a week for 2 consecutive weeks, doses 5- to approximately 30-fold lower than the maximum tolerated dose (MTD).
View Article and Find Full Text PDFIn low risk myelodysplastic syndrome (MDS), increased apoptosis of marrow cells is a reproducible finding. Cytokines may drive this apoptosis. Several studies have demonstrated elevated levels of tumor necrosis factor-alpha (TNF-alpha) in MDS.
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