Novel polyamine based anticancer agents: evaluation of the mode of action.

Novel bisnaphthalimidopropyl polyamine analogues (BNIPPs) were previously synthesised and found to bis-intercalate to DNA via the major groove and have interesting anticancer properties prompting this study to evaluate their mode of action. All BNIPPs synthesised exert cytotoxicity in colon, breast and leukaemia cancer cell lines. The most active compound, BNIPSpd exhibits 24-hour IC50 values ranging from 0.47-2.40 mu M in Caco-2 and HT29 colon cancer cells and MCF7 breast cancer cells. Onset of action of these novel compounds is faster than similar compounds, whose effects are reported at 72 or 96-hour incubations. Increased polyamine levels are widely reported in cancer cells, while a reduction leads to decreased cell proliferation and/or cell death. Polyamine analogues can mimic natural polyamines and exploit their effects as potential anticancer agents by reducing polyamine pools. BNIPPs also dramatically reduce polyamine levels in a dose response from greater than or equal to 0.1 mu M. The most active compound, BNIPSpd, also inhibits uptake of the natural polyamines spermidine and spermine (Ki 1.2 and 4.4 mu M, respectively). Such inhibition of natural polyamine uptake and rapid BNIPP uptake indicates recognition via the polyamine transporter. For the first time, quantification of DNA damage incurred as a result of either polyamine analogues or bisnaphthalimides was evaluated, and revealed that these novel compounds significantly induce DNA damage in a dose response from greater than or equal to 1 mu M after 4 hours. This rapid onset of DNA damage is likely to be the primary mode of action of these novel compounds. BNIPPs also inhibit recovery of this endogenous damage and also significantly inhibit DNA repair of oxidative (H2O2) damage at concentrations (0.1 mu M) that do not themselves induce DNA damage. Finally, apoptosis was determined as the mechanism of cell death of BNIPSpd (greater than or equal to 0.5 mu M) based on caspase activation, chromatin condensation, loss of cell membrane integrity and DNA fragmentation analyses.

Author dc:creator

• Ralton, Lynda D.

Advisor dc:contributor.advisor

• P. Kong Thoo Lin, C. Bestwick and A. McPherson

Language dc:language

en

Identifier

oai:rgu-repository.worktribe.com:2807539
https://doi.org/10.48526/rgu-wt-2807539

OAI identifier oai:identifier

oai:rgu-repository.worktribe.com:2807539