Portal de Periódicos da CAPES

Nitrogen Containing Bisphosphonates Induce Apoptosis and Inhibit the Mevalonate Pathway, Impairing Ras Membrane Localization in Prostate Cancer Cells

2003; Lippincott Williams & Wilkins; Volume: 170; Issue: 1 Linguagem: Inglês

10.1097/01.ju.0000070685.34760.5f

1527-3792

Grenville Oades, S G Senaratne, Ian Clarke, Roger Kirby, Kay W. Colston,

Bone and Joint Diseases

No AccessJournal of UrologyINVESTIGATIVE UROLOGY1 Jul 2003Nitrogen Containing Bisphosphonates Induce Apoptosis and Inhibit the Mevalonate Pathway, Impairing Ras Membrane Localization in Prostate Cancer Cells GRENVILLE M. OADES, SIDDHIKA G. SENARATNE, IAN A. CLARKE, ROGER S. KIRBY, and KAY W. COLSTON GRENVILLE M. OADESGRENVILLE M. OADES , SIDDHIKA G. SENARATNESIDDHIKA G. SENARATNE , IAN A. CLARKEIAN A. CLARKE , ROGER S. KIRBYROGER S. KIRBY , and KAY W. COLSTONKAY W. COLSTON View All Author Informationhttps://doi.org/10.1097/01.ju.0000070685.34760.5fAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Metastasis to bone is an important cause of morbidity in advanced prostate cancer. Despite the typically sclerotic nature of prostatic bone metastases osteolysis has a significant role in the pathogenesis of this disease. The nitrogen containing bisphosphonates (N-BPs), such as pamidronate and zoledronic acid, have greatly enhanced potency for inhibiting bone resorption and inducing apoptosis in osteoclasts. We investigated the effects of N-BPs on prostate cancer cells. Materials and Methods: Cell viability was determined with an MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymeyhoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) dye reduction assay. Cell cycle analysis, DNA fragmentation and caspase 3 activity were assessed using flow cytometry. Ras, Bcl-2 and Bax were quantified by Western blotting. Results: Pamidronate and zoledronic acid decreased cell viability in the 3 human cell lines DU145, PC3 and LNCaP. These effects were associated with changes in cell cycle distribution, induction of DNA fragmentation and a decrease in the Bcl-2-to-Bax ratio, which are features of apoptotic cell death. Pre-incubation with caspase inhibitors attenuated the effects of zoledronic acid and caspase 3 activity was demonstrated in treated DU145 cells. Zoledronic acid induced loss of cell viability in DU145 cells was prevented by co-treatment with farnesol, suggesting that N-BPs cause inhibition of the mevalonate pathway and Ras prenylation. A decrease in active, membrane bound Ras in zoledronic acid treated DU145 cells was shown by Western blot analysis. Conclusions: N-BPs induce apoptosis in prostate cancer via a caspase dependent mechanism. They have effects on protein prenylation via inhibition of the mevalonate pathway and impair membrane localization of Ras in prostate cancer cells. References 1 : Morphometric evidence for bone resorption and replacement in prostate cancer. Br J Urol1991; 68: 74. Google Scholar 2 : Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol2000; 163: 181. Link, Google Scholar 3 : Incidence of skeletal complications in patients with bone metastatic prostate cancer and hormone refractory disease: predictive role of bone resorption and formation markers evaluated at baseline. J Urol2000; 164: 1248. Link, Google Scholar 4 : Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med2001; 345: 948. Google Scholar 5 : Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer2000; 88: 1082. Google Scholar 6 : Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med1998; 339: 357. Google Scholar 7 : Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res1995; 10: 1478. Google Scholar 8 : Bisphosphonate treatment inhibits the growth of prostate cancer cells. Cancer Res2001; 61: 2602. Google Scholar 9 : Farnesol and geranylgeraniol prevent activation of caspases by aminobisphosphonates: biochemical evidence for two distinct pharmacological classes of bisphosphonate drugs. Mol Pharmacol1999; 56: 131. Google Scholar 10 : Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Commun1991; 3: 207. Google Scholar 11 : G-protein alpha-subunit expression, myristoylation, and membrane association in COS cells. Proc Natl Acad Sci USA1990; 87: 728. Google Scholar 12 : Novel salvage pathway utilizing farnesol and geranylgeraniol for protein isoprenylation. Biochem Biophys Res Commun1997; 237: 483. Google Scholar 13 : Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res2000; 60: 2949. Google Scholar 14 : Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest1991; 88: 2095. Google Scholar 15 : Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res1998; 13: 581. Google Scholar 16 : Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem Biophys Res Commun1999; 264: 108. Google Scholar 17 : Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci USA1999; 96: 133. Google Scholar 18 : Structural requirements for bisphosphonate actions in vitro. J Bone Miner Res1994; 9: 1875. Google Scholar 19 : Comparison of ras activation in prostate carcinoma in Japanese and American men. Prostate1997; 30: 53. Google Scholar 20 : A peptidomimetic inhibitor of farnesyl: protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res1995; 55: 5302. Google Scholar From the Departments of Urology (GMO, RSK) and Oncology (SGS, IAC, KWC), Gastroenterology, Endocrinology and Metabolism. St George’s Hospital and Medical School, London, United Kingdom© 2003 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited ByAtala A (2018) Re: Peroxiredoxin 4: A Novel Secreted Mediator of Cancer Induced OsteoclastogenesisJournal of Urology, VOL. 195, NO. 1, (220-221), Online publication date: 1-Jan-2016. Volume 170Issue 1July 2003Page: 246-252 Advertisement Copyright & Permissions© 2003 by American Urological Association, Inc.Keywordsmevalonic acidprostateneoplasm metastasisprostatic neoplasmsapoptosisMetricsAuthor Information GRENVILLE M. OADES More articles by this author SIDDHIKA G. SENARATNE More articles by this author IAN A. CLARKE More articles by this author ROGER S. KIRBY Financial interest and/or other relationship with Abbott, MSD, Pfizer and Yamanouchi. More articles by this author KAY W. COLSTON More articles by this author Expand All Advertisement PDF DownloadLoading ...