Probenecid as a sensitizer of bisphosphonate-mediated effects in breast cancer cells

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• 作者：Regina Ebert ; Jutta Meissner-Weigl ; Sabine Zeck ; Jorma M??tt?…
• 关键词：Bisphosphonates ; Caspase 3/7 activity ; Cell viability ; Probenecid ; Novobiocin ; Breast cancer cells
• 刊名：Molecular Cancer
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：13
• 期：1
• 全文大小：1,115 KB
• 参考文献：1. Hofbauer, LC, Rachner, T, Singh, SK (2008) Fatal attraction: why breast cancer cells home to bone. Breast Cancer Res 10: pp. 101 CrossRef
  2. Kakonen, SM, Mundy, GR (2003) Mechanisms of osteolytic bone metastases in breast carcinoma. Cancer 97: pp. 834-839 CrossRef
  3. Russell, RG, Xia, Z, Dunford, JE, Oppermann, U, Kwaasi, A, Hulley, PA, Kavanagh, KL, Triffitt, JT, Lundy, MW, Phipps, RJ, Barnett, BL, Coxon, FP, Rogers, MJ, Watts, NB, Ebetino, FH (2007) Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann N Y Acad Sci 1117: pp. 209-257 CrossRef
  4. Russell, RG, Watts, NB, Ebetino, FH, Rogers, MJ (2008) Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 19: pp. 733-759 CrossRef
  5. Monkkonen, H, Auriola, S, Lehenkari, P, Kellinsalmi, M, Hassinen, IE, Vepsalainen, J, Monkkonen, J (2006) A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates. Br J Pharmacol 147: pp. 437-445 CrossRef
  6. Costa, L, Major, PP (2009) Effect of bisphosphonates on pain and quality of life in patients with bone metastases. Nat Clin Pract Oncol 6: pp. 163-174 CrossRef
  7. Holen, I, Coleman, RE (2010) Bisphosphonates as treatment of bone metastases. Curr Pharm Des 16: pp. 1262-1271 CrossRef
  8. Clines, GA, Guise, TA (2008) Molecular mechanisms and treatment of bone metastasis. Expert Rev Mol Med 10: pp. e7 CrossRef
  9. Diel, IJ, Solomayer, E-F, Costa, SD, Gollan, C, Goerner, R, Wallwiener, D, Kaufmann, M, Bastert, G (1998) Reduction in New Metastases in Breast Cancer with Adjuvant Clodronate Treatment. N Engl J Med 339: pp. 357-363 CrossRef
  10. Gnant, M, Mlineritsch, B, Schippinger, W, Luschin-Ebengreuth, G, Postlberger, S, Menzel, C, Jakesz, R, Seifert, M, Hubalek, M, Bjelic-Radisic, V, Samonigg, H, Tausch, C, Eidtmann, H, Steger, G, Kwasny, W, Dubsky, P, Fridrik, M, Fitzal, F, Stierer, M, Rücklinger, E, Greil, R, Marth, C (2009) Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360: pp. 679-691 CrossRef
  11. Diel, IJ, Jaschke, A, Solomayer, EF, Gollan, C, Bastert, G, Sohn, C, Schuetz, F (2008) Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up. Ann Oncol 19: pp. 2007-2011 CrossRef
  12. Coleman, RE, Winter, MC, Cameron, D, Bell, R, Dodwell, D, Keane, MM, Gil, M, Ritchie, D, Passos-Coelho, JL, Wheatley, D, Burkinshaw, R, Marshall, SJ, Thorpe, H (2010) The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer 102: pp. 1099-1105 CrossRef
  13. Coleman, R, de Boer, R, Eidtmann, H, Llombart, A, Davidson, N, Neven, P, von Minckwitz, G, Sleeboom, HP, Forbes, J, Barrios, C, Frassoldati, A, Campbell, I, Paija, O, Martin, N, Modi, A, Bundred, N (2013) Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann Oncol 24: pp. 398-405 CrossRef
  14. Hofbauer, LC, Rachner, T, Coleman, R, Jakob, F (2014) Endocrine aspects of bone matastases. Lancet Diabetes Endocrinol.
  15. Ebert, R, Zeck,
• 刊物主题：Cancer Research; Oncology;
• 出版者：BioMed Central
• ISSN：1476-4598

文摘

Background Anti-resorptive bisphosphonates (BP) are used for the treatment of osteoporosis and bone metastases. Clinical studies indicated a benefit in survival and tumor relapse in subpopulations of breast cancer patients receiving zoledronic acid, thus stimulating the debate about its anti-tumor activity. Amino-bisphosphonates in nM concentrations inhibit farnesyl pyrophosphate synthase leading to accumulation of isopentenyl pyrophosphate (IPP) and the ATP/pyrophosphate adduct ApppI, which induces apoptosis in osteoclasts. For anti-tumor effects μM concentrations are needed and a sensitizer for bisphosphonate effects would be beneficial in clinical anti-tumor applications. We hypothesized that enhancing intracellular pyrophosphate accumulation via inhibition of probenecid-sensitive channels and transporters would sensitize tumor cells for bisphosphonates anti-tumor efficacy. Method MDA-MB-231, T47D and MCF-7 breast cancer cells were treated with BP (zoledronic acid, risedronate, ibandronate, alendronate) and the pyrophosphate channel inhibitors probenecid and novobiocin. We determined cell viability and caspase 3/7 activity (apoptosis), accumulation of IPP and ApppI, expression of ANKH, PANX1, ABCC1, SLC22A11, and the zoledronic acid target gene and tumor-suppressor KLF2. Results Treatment of MDA-MB-231 with BP induced caspase 3/7 activity, with zoledronic acid being the most effective. In MCF-7 and T47D either BP markedly suppressed cell viability with only minor effects on apoptosis. Co-treatment with probenecid enhanced BP effects on cell viability, IPP/ApppI accumulation as measurable in MCF-7 and T47D cells, caspase 3/7 activity and target gene expression. Novobiocin co-treatment of MDA-MB-231 yielded identical results on viability and apoptosis compared to probenecid, rendering SLC22A family members as candidate modulators of BP effects, whereas no such evidence was found for ANKH, ABCC1 and PANX1. Conclusions In summary, we demonstrate effects of various bisphosphonates on caspase 3/7 activity, cell viability and expression of tumor suppressor genes in breast cancer cells. Blocking probenecid and novobiocin-sensitive channels and transporters enhances BP anti-tumor effects and renders SLC22A family members as good candidates as BP modulators. Further studies will have to unravel if treatment with such BP-sensitizers translates into preclinical and clinical efficacy.