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 p21 ras pathway and therefore appears to be a suitable target for BPs that interfere with the prenylation of small GTP-binding proteins such as p21 ras . We found that ZOL induces growth inhibition (IC 50 :10 -50 mM) 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 p21 ras signalling in cells exposed to ZOL and detected a reduction of p21 ras 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 p21 ras . These findings might be relevant for expanding application of BPs in cancer treatment.

Antitumor Effects of Aminobisphosphonates on Renal Cell Carcinoma Cell Lines

“…After ZOL exposure however, the distribution of MSH2 protein changed markedly and adopted a peri-nuclear and cytoplasmic distribution, figure 7. Similarly, for PARP-1, its fulllength form p116 exhibited an 81% decrease in the ZOL-treated sample and more than 400% increase in the PAM-treated sample, indicating a higher degree of (27), prostate cancer (28) and multiple myeloma (33), pancreas (24). We found evidence of significant antiproliferative effects in a range 10-100 mol, consistent with previous studies.…”

“…In pancreatic cancer lines, commonly associated with p21ras dysregulation, the effects of BP was to interfere with growth and survival pathways downstream of p21 ras. ZOL treatment resulted in apoptotic death and caspase 9 (but not caspase 3) activation (24).…”

“…They may also exert an antiangiogenic effect (21). In addition, aminobisphosphonates have been found to dramatically increase apoptosis in macrophage, myeloma-derived, prostate and pancreatic cancer cell lines (22,23) (24) Third generation nitrogen-containing BP such as ZOL inhibit farnesyldiphosphate synthase, an enzyme involved in the mevalonate pathway preventing the posttranslational events of prenylation of small GTP-binding proteins such as p21 ras.…”

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

“…48 However, in most of these studies, long incubation periods and high concentrations of zoledronic acid were used, conditions not achievable in vivo. Following i.v.…”

Anticancer effects of zoledronic acid against human osteosarcoma cells

“…25,26 Both molecules are involved in the post-translational isoprenylation of key regulator proteins including small GTPbinding proteins such as Ras, Rho, and Rap1, thus inhibiting their proper localization to membranes. 27 Previous studies suggested inhibition of Ras prenylation as the key molecular mechanism underlying ZOL anticancer activity, 11,28,29 leading to blockade of anti-apoptotic and promitotic downstream signals including the MAPK-and the PI3K/ Akt pathways. 30 Also in osteosarcoma cells, we detected a loss of membrane-associated Ras following ZOL treatment (data not shown).…”