Investigation into the effects of pioglitazone on apoptosis in cultured monocytic cells
University of Wales Institute Cardiff
MetadataShow full item record
The thiazolidinediones (TZDs) are a class of drugs used in the treatment of Type 2 Diabetes Mellitus (T2DM). TZDs are ligands of the transcription factor Peroxisome Proliferator-Activated Receptor gamma (PPAR) and are known to increase insulin sensitivity through PPAR-mediated regulation of target genes involved in carbohydrate metabolism. The TZD, rosiglitazone, was recently withdrawn from the market due to the risk of adverse cardiovascular outcomes and previous studies have shown that high-dose rosiglitazone treatment induces apoptosis in cultured monocytic cells, via a PPAR-independent pathway. Due to the increased risk of heart failure associated with the TZD pioglitazone, currently still being prescribed for the treatment of T2DM, it was hypothesised that pioglitazone may also induce apoptosis in cultured monocytic (THP-1) cells. Treatment of the cells with 3M pioglitazone over a 14-day period was shown by one-way ANOVA to induce significant levels of apoptosis from day 11 onwards (p<0.05). A two-way ANOVA demonstrated 3M pioglitazone treatment to have a significant effect on apoptosis levels over time compared with both the vehicle, DMSO and also the corresponding pharmacological plasma level of rosiglitazone (1 M) (p<0.05), indicating a possible build up of the drug in the cells over the 14 days. A western blot analysis using anti-CYP2C8 antibodies showed the relative expression of the degradative enzyme CYP2C8 to be far lower in the pioglitazone sample than either the controls or the rosiglitazone samples (1M and 10M), suggesting that the expression of the enzyme had been suppressed thus contributing to a build-up of the drug in the cells. Further research is required to discover if another CYP450 enzyme, CYP3A4, also involved in pioglitazone degradation, is possibly being suppressed. It would be of interest to investigate the apoptotic mechanism and to ascertain if Unfolded Protein Responses (UPRs) are being triggered due to ER stress, via a PPAR-independent pathway, as has been demonstrated in rosiglitazone-treated monocytic cells.
Showing items related by title, author, subject and abstract.
Conjugated linoleic acid, but not rosiglitazone and pioglitazone increase apoptosis/reduce viabillity in a monocytic cell line Klimach, Stefan (Cardiff Metropolitan University, 2011)Thiazolidinediones (TZDs) are a class of oral chemotherapeutics used in the treatment of type 2 diabetes mellitus (TTDM). TZDs improve insulin sensitivity in TTDM by modulating the transcriptional effects of peroxisome ...
Investigation into the effects of Rosiglitazone on apoptosis, cell viability and cytochrome p450 expression in THP1 cultured monocytic cells Dent, Suzanne (University of Wales Institute Cardiff, 2012)Rosiglitazone is a thiazolidione (TZD) drug used to treat type 2 diabetes mellitus (T2DM). It acts via Peroxisome Proliferator Activated Receptor-gamma (PPARG) to reduce the risk of macro-vascular disease through mechanisms ...
Willis, Gareth (Cardiff Metropolitan University, 2011)BACKGROUND: Conjugated linoleic acid (CLA) has been established as a natural peroxisome proliferator activated receptor (PPAR-y) ligand. Recent studies have explored the possible health benefits associated with CLA for ...