Antitumor effects of aminobisphosphonates on renal cell carcinoma cell lines.
OBJECTIVE
Bisphosphonates are established as a supportive therapy for a number of malignancies that metastasize to bone. Previous reports have also suggested potent antitumor and anti-angiogenic properties. We investigated the in vitro activity of the 2 aminobisphosphonates pamidronate (Faulding Pharmaceuticals, Paramus, New Jersey) and zoledronic acid (Novartis, Basel, Switzerland) on the growth and survival of the 3 renal cell carcinoma cell lines Caki-2, 769-P (American Type Culture Collection, Manassas, Virginia) and D69581.


METHODS
Cell lines were exposed to bisphosphonates in vitro and evaluated by MTS (3-(4,5-dimethylahiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay and cell cycle analysis. Mechanisms of apoptotic cell death were investigated by ApoDIRECT assay (BioVision, Mountain View, California) and Kinetworks analysis.


RESULTS
Zoledronic acid was consistently more potent than pamidronate for inducing apoptotic cell death. Zoledronic acid was capable of overcoming resistance to pamidronate in 1 cell line. Although it was ultimately less potent, the inhibitory effects of pamidronate appeared earlier than those of zoledronic acid. The pro-apoptotic effect of zoledronic acid was achieved through nonmitochondrial pathways and it was associated with the activation of caspase 6 and 3, and poly adenosine diphosphate-ribosyltransferase polymerase cleavage. Furthermore, we observed a marked decrease in and intracellular distribution of MSH2, a protein involved in DNA mismatch repair, as well as evidence of a greater cellular response to zoledronic acid as increased expression of superoxide dismutase.


CONCLUSIONS
These findings add further support to the clinical use of aminobisphosphonates, particularly zoledronic acid, in patients with renal cell carcinoma with disease metastatic to bone.
Pandha
Hardev
H
Department of Oncology, St. George's, University of London and Targeted Therapy Laboratory, London, United Kingdom. hpandha@sghms.ac.uk
Birchall
Lindsay
L
Meyer
Brendan
B
Wilson
Natalie
N
Relph
Kate
K
Anderson
Christopher
C
Harrington
Kevin
K
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D000077268:Pamidronate; D014407:Tumor Cells, Cultured; D000077211:Zoledronic Acid
D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D000077268:Pamidronate