The effects of a telomere destabilizing agent on cancer cell-cycle dynamics—Integrated modelling and experiments

Abstract

The pentacyclic acridinium salt RHPS4 displays anti-tumour properties in vitro as well as in vivo and is potentially cell-cycle specific. We have collected experimental data and formulated a compartmental model using ordinary differential equations to investigate how the compound affects cells in each stage of the cell cycle. In addition to a control case in which no drug was used, we treated colorectal cancer cells with three different concentrations of the drug and fitted simulations from our models to experimental observations. We found that RHPS4 caused a concentration-dependent, marked cell death in treated cells, which is best modelled by allowing the rate parameters corresponding to cell death to be sigmoidal functions of time. We have shown that the model is "identifiable", meaning that, at least in principle, the parameter values can be determined from observable quantities. We find that at low concentrations RHPS4 primarily affects the cells in the G(2)/M phase, and that the drug has a delayed effect with the delay decreasing at larger doses. Since the drug diffuses into the nucleus, the observed delayed effect of the compound is unexpected and is a novel finding of our research into this compound.

Modelling the regulation of telomere length: the effects of telomerase and G-quadruplex stabilising drugs

“…It also rapidly induces telomere dysfunction by telomere uncapping, which leads to short-term cell death through usage of higher doses. Integrative approaches to investigate the effects of RHPS4 experimentally and by means of mathematical modelling were proposed by Johnson et al (2011) and Hirt et al (2012). The precise cell-cycle specific behaviour of RHPS4 and its mechanism of action in cancer cells, however, are still to be elucidated.…”