An investigation of the cellular responses to the unsymmetrically substituted polyamine analogues and identification of the pathway to cell death

The unsymmetrically substituted spermine analogues, CHENSpm, CPENSpm and IPENSpm were tested for their cytotoxic potential in a human HL-60 leukaemic cell model. Their effects were compared with the cytotoxic drug, etoposide. The analogues CHENSpm and IPENSpm induced cytotoxicity, and CPENSpm produced growth inhibitory effects, as a result of increased polyamine catabolic enzyme activity and export, and intracellular polyamine depletion. Intracellular analogue accumulation was essential for the observed toxicity, and co-exposure with analogue and a polyamine transport inhibitor produced decreased toxicity, decreased intracellular analogue accumulation, and demonstrated the polyamine transporter as the route of analogue uptake. The analogues tested showed selective toxicity in transformed cells, and induced cell death through the induction of apoptosis. Closer investigation of the apoptotic pathway using bcl-2 overexpressing HL-60 cells (HL-60+), revealed the apoptosis was triggered by these analogues at the mitochondria through the mitochondrial release of cytochrome c. These studies show the polyamine analogues CHENSpm and IPENSpm to be effective cytotoxic agents in HL-60 cells, and this supports their potential as chemotherapeutic agents.EThOS - Electronic Theses Online ServiceGBUnited Kingdo