Selenoprotein P, as a predictor for evaluating gemcitabine resistance in human pancreatic cancer cells

Gemcitabine is a new standard chemotherapeutic agent used in the treatment of pancreatic cancer, but the mechanisms of gemcitabine sensitivity are still controversial. In our study to determine a mechanism that regulates gemcitabine sensitivity, we carried out molecular analysis on the susceptibility of the pancreatic cancer cells. Using a gemcitabine‐sensitive pancreatic cancer cell line KLM1, we established a resistant cell line KLM1‐R exhibiting a 20‐fold IC 50 ‐value (the concentration of gemcitabine causing 50% growth inhibition). Microarray analysis of genes showed specific expression of selenoprotein P , one of the anti‐oxidants, in the KLM1‐R cell line but not in the KLM1 cell line. Administration of selenoprotein P inhibited the gemcitabine‐induced cytotoxicity in the pancreatic cell lines. The levels of intracellular reactive oxygen species (ROS) were increased in the KLM1 cells by gemcitabine, but selenoprotein P suppressed the gemcitabine‐induced ROS levels. Furthermore interferon‐γ suppressed the expression of selenoprotein P mRNA and increased intracellular ROS level, leading to the recovery of the gemcitabine sensitivity in KLM1‐R. These results suggest a novel mechanism that selenoprotein P reduces the intracellular ROS levels, resulting in the insusceptibility to gemcitabine. © 2004 Wiley‐Liss, Inc.