Zoledronic acid induces antiproliferative and apoptotic effects in human pancreatic cancer cells in vitro

Abstract

Bisphosphonates (BPs) are an emerging class of drugs mostly used in the palliative care of cancer patients. We investigated the in vitro activity of the most potent antiresorptive BP, zoledronic acid (ZOL), on the growth and survival of three human pancreatic cancer (PC) cell lines (BxPC-3, CFPAC-1 and PANC-1), Pancreatic cancer frequently has a dysregulated p21ras pathway and therefore appears to be a suitable target for BPs that interfere with the prenylation of small GTP-binding proteins such as p21ras. We found that ZOL induces growth inhibition (IC50:10-50 μM) and apoptotic death of PC cells. The proapoptotic effect was correlated to cleavage/activation of caspase-9 and poly(ADP)-ribose polymerase, but not of caspase-3. Moreover, we studied the p21ras signalling in cells exposed to ZOL and detected a reduction of p21ras and Raf-1 content and functional downregulation of the terminal enzyme ERK/MAPkinase and of the pKB/Akt survival pathway. Finally, we observed that ZOL induces significant cytoskeletal rearrangements. In conclusion, we demonstrated that ZOL induces growth inhibition and apoptosis on PC cells and interferes with growth and survival pathways downstream to p21ras. These findings might be relevant for expanding application of BPs in cancer treatment. © 2003 Cancer Research UK.