Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis

摘要: Bortezomib (PS-341, Velcade) is a potent and selective inhibitor of the proteasome that currently under investigation for treatment solid malignancies. We have shown previously bortezomib has activity in pancreatic cancer models drug induces endoplasmic reticulum (ER) stress but also suppresses unfolded protein response (UPR). Because UPR an important cytoprotective mechanism, we hypothesized would sensitize cells to ER stress-mediated apoptosis. Here, show promotes apoptosis triggered by classic inducers (tunicamycin thapsigargin) via c-Jun NH(2)-terminal kinase (JNK)-dependent mechanism. cisplatin stimulates interacts with increase dilation, intracellular Ca(2+) levels, cell death. Importantly, combined therapy plus induced JNK activation orthotopic tumors resulting reduction tumor burden. Taken together, our data establish sensitizes stress-induced strongly enhances anticancer cisplatin.