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J Urol. 2006 Nov;176(5):2255-61.

Antitumor effects of aminobisphosphonates on renal cell carcinoma cell lines.

Author information

1
Department of Oncology, St. George's, University of London and Targeted Therapy Laboratory, London, United Kingdom. hpandha@sghms.ac.uk

Abstract

PURPOSE:

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.

MATERIALS AND 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.

PMID:
17070308
DOI:
10.1016/j.juro.2006.07.053
[Indexed for MEDLINE]

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