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PMID: 12799645 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

British journal of cancer ·Vol. 88 ·No. 12 ·2003-06-16 ·Pages 1971-8

Tassone P, Tagliaferri P, Viscomi C, Palmieri C, Caraglia M, D'Alessandro A, Galea E, Goel A, Abbruzzese A, Boland CR, Venuta S

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 micro M) 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.

MeSH Terms
Apoptosis/drug effects Cell Division/drug effects Diphosphonates/pharmacology Humans Imidazoles/pharmacology MAP Kinase Kinase 1 Mitogen-Activated Protein Kinase Kinases/metabolism Mitogen-Activated Protein Kinases/metabolism Pancreatic Neoplasms/drug therapy Protein Serine-Threonine Kinases/metabolism Proto-Oncogene Proteins c-raf/metabolism Tumor Cells, Cultured Zoledronic Acid
Chemicals
Diphosphonates Imidazoles Zoledronic Acid Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-raf Mitogen-Activated Protein Kinases MAP Kinase Kinase 1 MAP2K1 protein, human Mitogen-Activated Protein Kinase Kinases
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Tassone P
Oncology Unit, Department of Experimental and Clinical Medicine, Via T. Campanella, 115 'Magna Graecia' University, 88100 Catanzaro, Italy. [email protected]
Tagliaferri P
Viscomi C
Palmieri C
Caraglia M
D'Alessandro A
Galea E
Goel A
Abbruzzese A
Boland C R
Venuta S
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Article Info
Journal
British journal of cancer
Abbr.
Br J Cancer
ISSN
0007-0920
DOI
10.1038/sj.bjc.6600986
Email
[email protected]
Published
2003-06-16
Pages
1971-8
Language
English
Region
England
NLM ID
0370635
PMCID
PMC2741108
Subset
IM
External Links
PubMed source DOI: 10.1038/sj.bjc.6600986 PMC Full Text View journal details
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