Cell cycle regulation of human pancreatic cancer by tamoxifen

Background: Clinical trials have suggested a survival advantage for selected patients with metastatic pancreatic cancer treated with tamoxifen. We sought to identify the molecular mechanism by which tamoxifen inhibits human pancreatic cancer cell (HPCC) growth. Methods: HPCCs were grown in tamoxifen and growth inhibition was determined by ³H-thymidine uptake and by the MTT assay; changes in cell viability were determined by cell counts. Cell cycle alterations were evaluated by FACS, and the induction of apoptosis was evaluated using the TUNEL assay. Total cellular RNA was isolated after tamoxifen treatment, and Northern blot analysis was performed for p21(wafI). Results: Tamoxifen inhibited HPCC growth as measured by inhibition of ³H- thymidine incorporation and by the MTT assay. However, there was no decrease in the total number of viable cells after 6 days of treatment with I 0 μM of tamoxifen and no evident apoptosis, confirming the absence of a cytotoxic effect. Cell cycle analysis revealed cellular arrest in the G(0)/G(1) phase, which correlated with p21(waft) mRNA upregulation in response to tamoxifen treatment. Conclusions: Tamoxifen inhibits HPCC growth by inducing G(o)/G(1) arrest with an associated increase in p21(waft) mRNA expression. Tamoxifen is an effective inhibitor of HPCC growth in vitro and warrants further in vivo study.