Recent clinical trials utilizing autologous dendritic cells for the treatment of early stage breast cancer (ductal carcinoma in situ; DCIS) induced strong immune responses characterized by production of Th1 cytokines including Interferon-gamma (IFN-γ). About 30% of vaccinated subjects showed complete regression of tumor by the time of surgery. Follow-up in vitro studies showed that two principal Th1 cytokines, IFN-γ and TNF-α, were capable of inducing apoptosis in breast cancer cell lines, thus suggesting that Th1 cytokines are at least in part responsible for the tumor regression seen in vivo. Furthermore, recent data shows that combinational therapy using small-molecule inhibitors could enhance Th1 mediated cell death in breast cancer. Thus, we hypothesized that simvastatin, a HMG-CoA reductase inhibitor that also interferes with Ras oncogene activity, could enhance the apoptotic effect of Th1 cytokines in pancreatic cancer cell lines. Each cell line was cultured either without treatment, with cytokines only, with simvastatin only, or with both for 3 days. Metabolic activity via the Alamar Blue assay, vital staining with Trypan Blue, and Flow cytometry-based apoptotic cell death assays indicated strong additive effects between cytokines and Simvastatin.
Effects of an autologous dendritic cell vaccine used to treat early stage breast cancer may be mediated, in part, through the action of Th-1 cell secreted cytokines Interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). We therefore sought to determine if the addition of a HMG-CoA reductase inhibitor (simvastatin) would enhance the effects of Th1 cytokines in pancreatic cancer cell lines. We observed evidence of impaired metabolic activity, fewer viable cells, and apoptotic cell death induced by simvastatin plus cytokine treatment as compared with cells treated only with individual agents. These studies suggest that vaccines may be enhanced by addition of targeted drugs like simvastatin.
Key words: Cancer, cytokine, Interferon-gamma, Tumor necrosis factor-alpha, vaccine, apoptosis, T lymphocyte, flow cytometry, simvastatin