Abstract B57: Modulation of prostaglandin E2 by statins in human bronchial epithelial cells harboring K-ras mutation: The potential advantage of combination therapy

Abstract

Statin drugs, such as lovastatin and simvastatin, block cholesterol synthesis by inhibiting the function of HMG-CoA reductase in the cellular cholesterol biosynthesis pathway. In a recent large case-control study, statins reduced the risk of lung cancer suggesting the utility of statins for lung cancer chemoprevention. In our studies, while both lovastatin and simvastatin dose-dependently decreased proliferation in both histologically normal and K-ras mutated human bronchial epithelial cells (HBECs), it also unexpectedly increased expression of PGE2 in mutated HBECs. The statin-mediated upregulation of PGE2 is most pronounced in K-ras mutated HBECs compared to P53 deleted or EGFR mutated HBECs. Treatment with the cholesterol precursor, mevalonic acid, inhibited statin mediated up-regulation of PGE2 indicating that the effect of the statins on PGE2 is sterol-dependent. We found that the suppression of proliferation by statins is also sterol dependent. Statins up-regulate the production of PGE2 by up-regulating mRNA and protein expression of COX-2. The addition of the MEK inhibitor (U0126) revealed the potential involvement of the ERK pathway for statin-mediated upregulation of PGE2 in HBECs. The combination of statins and a low dose of celecoxib (0.1 micro molar), a COX-2 inhibitor, suppressed the increased production of PGE2 by K-ras mutated HBECs. Studies are underway to determine the effect of statin-mediated upregulation of PGE2 on apoptosis resistance and invasion in K-ras mutated HBECs. Our studies suggest that the combination of statins with a low dose of celecoxib overcomes the upregulation of PGE2 induced by statins alone. Thus the combination represents a potentially effective lung cancer chemopreventative regimen worthy of further investigation. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B57.

Therapeutic effect of simvastatin on DMBA‐induced breast cancer in mice

“…Consistent with our results, in a study by Stamford et al , tamoxifen showed little effect on PGE2 levels of tumor tissue in mice, which was acclaimed to be due to weak inhibition of cyclooxygenase by the drug. Effect of statins on PGE2 levels has been inconsistent, for instance although statin treatment of microglial‐like cells (In vitro ) significantly reduced PGE2 levels , lovastatin and simvastatin treatment on K‐ras mutated human bronchial epithelial cells (HBECs) has increased PGE2 production . An explanation for the trivial change that was observed in PGE2 level of tumor tissue in our study may be the relatively short period of treatment, although this needs to be further investigated.…”

Effects of Statins on Renin–Angiotensin System

“…Statins regulate renin secretion by affecting these cAMP activators. For example, in some studies, it has been shown that statins can induce prostaglandin I2 and E2 production by inhibiting geranylgeranylation, the process of attaching geranylgeranyl diphosphate to cysteine residues at the C-terminus of specific proteins, and inducing mRNA expression of COX-2, which metabolizes arachidonic acid into prostaglandins [ 31 , 32 , 33 ]. Induction of COX-2 expression by statins is driven by sterol-dependent and ERK1/2- and p38 MAPK-dependent pathways [ 34 ].…”