Nitric oxide-induced cytostasis and cell cycle arrest of a human breast cancer cell line (MDA-MB-231): potential role of cyclin D1

DETA-NONOate, a nitric oxide (NO) donor, induced cytostasis in the human breast cancer cells MDA-MB-231, and the cells were arrested in the G(1) phase of the cell cycle. This cytostatic effect of the NO donor was associated with the down-regulation of cyclin D1 and hypophosphorylation of the retinoblastoma protein. No changes in the levels of cyclin E or the catalytic partners of these cyclins, CDK2, CDK4, or CDK6, were observed. This NO-induced cytostasis and decrease in cyclin D1 was reversible for up to 48 h of DETA-NONOate (1 mM) treatment. DETA-NONOate (1 mM) produced a steady-state concentration of 0.5 microM of NO over a 24-h period. Synchronized population of the cells exposed to DETA-NONOate remained arrested at the G(1) phase of the cell cycle whereas untreated control cells progressed through the cell cycle after serum stimulation. The cells arrested at the G(1) phase after exposure to the NO donor had low cyclin D1 levels compared with the control cells. The levels of cyclin E and CDK4, however, were similar to the control cells. The decline in cyclin D1 protein preceded the decrease of its mRNA. This decline of cyclin D1 was due to a decrease in its synthesis induced by the NO donor and not due to an increase in its degradation. We conclude that down-regulation of cyclin D1 protein by DETA-NONOate played an important role in the cytostasis and arrest of these tumor cells in the G(1) phase of the cell cycle.     

The cost-effectiveness of deep brain stimulation in combination with best medical therapy, versus best medical therapy alone, in advanced Parkinson’s disease

Parkinson’s disease (PD) is a complex progressive movement disorder leading to motor and non-motor symptoms that become increasingly debilitating as the disease advances, considerably reducing quality of life. Advanced treatment options include deep brain stimulation (DBS). While clinical effectiveness of DBS has been demonstrated in a number of randomised controlled trials (RCT), evidence on cost-effectiveness is limited. The cost-effectiveness of DBS combined with BMT, versus BMT alone, was evaluated from a UK payer perspective. Individual patient-level data on the effect of DBS on PD symptom progression from a large 6-month RCT were used to develop a Markov model representing clinical progression and capture treatment effect and costs. A 5-year time horizon was used, and an incremental cost-effectiveness ratio (ICER) was calculated in terms of cost per quality-adjusted life-years (QALY) and uncertainty assessed in deterministic sensitivity analyses. Total discounted costs in the DBS and BMT groups over 5 years were £68,970 and £48,243, respectively, with QALYs of 2.21 and 1.21, giving an incremental cost-effectiveness ratio of £20,678 per QALY gained. Utility weights in each health state and costs of on-going medication appear to be the key drivers of uncertainty in the model. The results suggest that DBS is a cost-effective intervention in patients with advanced PD who are eligible for surgery, providing good value for money to health care payers.