Anti-tumour activity of bisphosphonates in preclinical models of breast cancer

Ingunn Holen, Robert E Coleman, Ingunn Holen, Robert E Coleman

Abstract

There is increasing evidence of anti-tumour effects of bisphosphonates from pre-clinical studies, supporting a role for these drugs beyond their traditional use in treatment of cancer-induced bone disease. A range of model systems have been used to investigate the effects of different bisphosphonates on tumour growth, both in bone and at peripheral sites. Most of these studies conclude that bisphosphonates cause a reduction in tumour burden, but that early intervention and the use of high and/or repeated dosing is required. Successful eradication of cancer may only be achievable by targeting the tumour cells directly whilst also modifying the tumour microenvironment. In line with this, bisphosphonates are demonstrated to be particularly effective at reducing breast tumour growth when used in combination with agents that directly target cancer cells. Recent studies have shown that the effects of bisphosphonates on breast tumours are not limited to bone, and that prolonged anti-tumour effects may be achieved following their inclusion in combination therapy. This has opened the field to a new strand of bisphosphonate research, focussed on elucidating their effects on cells and components of the local, regional and distal tumour microenvironment. This review highlights the recent developments in relation to proposed anti-tumour effects of bisphosphonates reported from in vitro and in vivo models, and summarises the data from key breast cancer studies. Evidence for effects on different processes and cell types involved in cancer development and progression is discussed, and the main outstanding issues identified.

Figures

Figure 1
Figure 1
The main components of the tumour microenvironment.
Figure 2
Figure 2
Potential anti-tumour effects of bisphosphonates (BPs) outside the skeleton.
Figure 3
Figure 3
Potential anti-tumour effects of bisphosphonates (BPs) in bone.

References

    1. Clézardin P, Ebetino FH, Fournier PG. Bisphosphonates and cancer-induced bone disease: beyond their antiresorptive activity. Cancer Res. 2005;65:4971–4974.
    1. Roelofs AJ, Thompson K, Gordon S, Rogers MJ. Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res. 2006;12:6222s–6230s. doi: 10.1158/1078-0432.CCR-06-0843.
    1. Brown HK, Holen I. Anti-tumour effects of bisphosphonates - what have we learned from in vivo models? Curr Cancer Drug Targets. 2009;9:807–823. doi: 10.2174/156800909789760339.
    1. Santini D, Caraglia M, Vincenzi B, Holen I, Scarpa S, Budillon A, Tonini G. Mechanisms of disease: Preclinical reports of antineoplastic synergistic action of bisphosphonates. Nat Clin Pract Oncol. 2006;3:325–338. doi: 10.1038/ncponc0520.
    1. AZURE, does Adjuvant Zoledronic acid redUce REcurrence in patients with high-risk, localized breast cancer? Trial Protocol. 2005. pp. 3–57. (ISRCTN79831382)
    1. Winter MC, Cross SS, Ingram CE, Jolley IJ, Holen I, Hatton MQ, Horsman JM, Coleman R. ANZAC: a neoadjuvant biomarker study exploring the anti-tumour activity of the AdditioN of Zoledronic Acid to Chemotherapy in breast cancer. Ann Oncol. 2009;20(Suppl 2):165P.
    1. Neville-Webbe H, Coleman RE. The use of zoledronic acid in the management of metastatic bone disease and hypercalcaemia. Palliat Med. 2003;17:539–553. doi: 10.1191/0269216303pm800ra.
    1. Chen T, Berenson J, Vescio R , Swift R , Gilchick A , Goodin S , LoRusso P, Ma P, Ravera C , Deckert F , Schran H, Seaman J, Skerjanec A. Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases. J Clin Pharmacol. 2002;42:1228–1236. doi: 10.1177/009127002762491316.
    1. Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone. 1996;18:75–85. doi: 10.1016/8756-3282(95)00445-9.
    1. Weiss HM, Pfaar U, Schweitzer A, Wiegand H, Skerjanec A, Schran H. Biodistribution and plasma protein binding of zoledronic acid. Drug Metab Dispos. 2008;36:2043–2049. doi: 10.1124/dmd.108.021071.
    1. Hirbe AC, Roelofs AJ, Floyd DH, Deng H, Becker SN, Lanigan LG, Apicelli AJ, Xu Z, Prior JL, Eagleton MC, Piwnica-Worms D, Rogers MJ, Weilbaecher K. The bisphosphonate zoledronic acid decreases tumor growth in bone in mice with defective osteoclasts. Bone. 2009;44:908–916. doi: 10.1016/j.bone.2009.01.010.
    1. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2:584–593. doi: 10.1038/nrc867.
    1. Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Pöstlberger 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. ABCSG-12 Trial Investigators. Marth C. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009;360:679–691. doi: 10.1056/NEJMoa0806285.
    1. Dai J, Lu Y, Yu C, Keller JM, Mizokami A, Zhang J, Keller ET. Reversal of chemotherapy-induced leukopenia using granulocyte macrophage colony-stimulating factor promotes bone metastasis that can be blocked with osteoclast inhibitors. Cancer Res. 2010;70:5014–5023. doi: 10.1158/0008-5472.CAN-10-0100.
    1. Aft R, Naughton M, Trinkaus K, Watson M, Ylagan L, Chavez-MacGregor M, Zhai J, Kuo S, Shannon W, Diemer K, Herrmann V, Dietz J, Ali A, Ellis M, Weiss P, Eberlein T, Ma C, Fracasso PM, Zoberi I, Taylor M, Gillanders W, Pluard T, Mortimer J, Weilbaecher K. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol. 2010;11:421–428. doi: 10.1016/S1470-2045(10)70054-1.
    1. 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. AZURE (BIG01/04) Investigators. 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. 2010;102:1099–1105. doi: 10.1038/sj.bjc.6605604.
    1. Wood J, Bonjean K, Ruetz S, Bellahcène A, Devy L, Foidart JM, Castronovo V, Green JR. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther. 2002;302:1055–1061. doi: 10.1124/jpet.102.035295.
    1. Melani C, Sangaletti S, Barazzetta FM, Werb Z, Colombo MP. Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma. Cancer Res. 2007;67:11438–11446. doi: 10.1158/0008-5472.CAN-07-1882.
    1. Thompson K, Roelofs AJ, Jauhiainen M, Mönkkönen H, Mönkkönen J, Rogers MJ. Activation of gammadelta T Cells by bisphosphonates. Adv Exp Med Biol. 2010;658:11–20. full_text.
    1. Simon MJ, Niehoff P, Kimmig B, Wiltfang J, Açil Y. Expression profile and synthesis of different collagen types I, II, III, and V of human gingival fibroblasts, osteoblasts, and SaOS-2 cells after bisphosphonate treatment. Clin Oral Investig. 2010;14:51–58. doi: 10.1007/s00784-009-0312-2.
    1. Walter C, Klein MO, Pabst A, Al-Nawas B, Duschner H, Ziebart T. Influence of bisphosphonates on endothelial cells, fibroblasts, and osteogenic cells. Clin Oral Investig. 2010;14:35–41. doi: 10.1007/s00784-009-0266-4.
    1. Coscia M, Quaglino E, Iezzi M, Curcio C, Pantaleoni F, Riganti C, Holen I, Mönkkönen H, Boccadoro M, Forni G, Musiani P, Bosia A, Cavallo F, Massaia M. Zoledronic acid repolarizes tumor-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway. J Cell Mol Med. 2009. in press .
    1. Santini D, Vincenzi B, Dicuonzo G, Avvisati G, Massacesi C, Battistoni F, Gavasci M, Rocci L, Tirindelli MC, Altomare V, Tocchini M, Bonsignori M, Tonini G. Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res. 2003;9:2893–2897.
    1. Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, Ruggiero SL, Shafer DM, Shum L, Silverman SL, Van Poznak CH, Watts N, Woo SB, Shane E. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22:1479–1491. doi: 10.1359/jbmr.0707onj.
    1. Aghaloo TL, Felsenfeld AL, Tetradis S. Osteonecrosis of the jaw in a patient on Denosumab. J Oral Maxillofac Surg. 2010;68:959–963. doi: 10.1016/j.joms.2009.10.010.
    1. Michailidou M, Brown HK, Lefley DV, Evans A, Cross SS, Coleman RE, Brown NJ, Holen I. Microvascular endothelial cell responses in vitro and in vivo: modulation by zoledronic acid and paclitaxel? J Vasc Res. 2010;47:481–493. doi: 10.1159/000313876.
    1. Ziebart T, Pabst A, Klein MO, Kämmerer P, Gauss L, Brüllmann D, Al-Nawas B, Walter C. Bisphosphonates: restrictions for vasculogenesis and angiogenesis: inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro. Clin Oral Investig. 2009. [Epub ahead of print]
    1. Yamada J, Tsuno NH, Kitayama J, Tsuchiya T, Yoneyama S, Asakage M, Okaji Y, Shuno Y, Nishikawa T, Tanaka J, Takahashi K, Nagawa H. Anti-angiogenic property of zoledronic acid by inhibition of endothelial progenitor cell differentiation. J Surg Res. 2009;151:115–120. doi: 10.1016/j.jss.2008.01.031.
    1. Luckman SP, Hughes DE, Coxon FP, Graham R, Russell G, Rogers MJ. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res. 1998;13:581–589. doi: 10.1359/jbmr.1998.13.4.581.
    1. Bäuerle T, Merz M, Komljenovic D, Zwick S, Semmler W. Drug-induced vessel remodeling in bone metastases as assessed by dynamic contrast enhanced magnetic resonance imaging and vessel size imaging: a longitudinal in vivo study. Clin Cancer Res. 2010;16:3215–3225.
    1. Provenzano PP, Eliceiri KW, Keely PJ. Multiphoton microscopy and fluorescence lifetime imaging microscopy (FLIM) to monitor metastasis and the tumor microenvironment. Clin Exp Metastasis. 2009;26:357–370. doi: 10.1007/s10585-008-9204-0.
    1. Croucher PI, De Hendrik R, Perry MJ, Hijzen A, Shipman CM, Lippitt J, Green J, Van Marck E, Van Camp B, Vanderkerken K. Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. J Bone Miner Res. 2003;18:482–492. doi: 10.1359/jbmr.2003.18.3.482.
    1. Tang X, Zhang Q, Shi S, Yen Y, Li X, Zhang Y, Zhou K, Le AD. Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1alpha/VEGF signaling pathways in human breast cancer cells. Int J Cancer. 2010;126:90–103. doi: 10.1002/ijc.24710.
    1. Tuomela JM, Valta MP, Väänänen K, Härkönen PL. Alendronate decreases orthotopic PC-3 prostate tumor growth and metastasis to prostate-draining lymph nodes in nude mice. BMC Cancer. 2008;8:81. doi: 10.1186/1471-2407-8-81.
    1. Soltau J, Zirrgiebel U, Esser N, Schächtele C, Totzke F, Unger C, Merfort I, Drevs J. Antitumoral and antiangiogenic efficacy of bisphosphonates in vitro and in a murine RENCA model. Anticancer Res. 2008;28:933–941.
    1. Coffelt SB, Hughes R, Lewis CE. Tumor-associated macrophages: effectors of angiogenesis and tumor progression. Biochim Biophys Acta. 2009;1796:11–18.
    1. Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res. 1996;56:4625–4629.
    1. Lin EY, Pollard JW. Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res. 2007;67:5064–5066. doi: 10.1158/0008-5472.CAN-07-0912.
    1. Benford HL, Frith JC, Auriola S, Mönkkönen J, Rogers MJ. Farnesol and geranylgeraniol prevent activation of caspases by aminobisphosphonates: biochemical evidence for two distinct pharmacological classes of bisphosphonate drugs. Mol Pharmacol. 1999;56:131–140.
    1. Mönkkönen H, Ottewell PD, Kuokkanen J, Mönkkönen J, Auriola S, Holen I. Zoledronic acid-induced IPP/ApppI production in vivo. Life Sci. 2007;81:1066–1070.
    1. Ottewell PD, Monkkonen H, Jones M, Lefley DV, Coleman RE, Holen I. Antitumor effects of doxorubicin followed by zoledronic acid in a mouse model of breast cancer. J Natl Cancer Inst. 2008;100:1167–1178. doi: 10.1093/jnci/djn240.
    1. Ottewell PD, Coleman RE, Holen I. From genetic abnormality to metastases: murine models of breast cancer and their use in the development of anticancer therapies. Breast Cancer Res Treat. 2006;96:101–113. doi: 10.1007/s10549-005-9067-x.
    1. Kunzmann V, Bauer E, Wilhelm M. Gamma/delta T-cell stimulation by pamidronate. N Engl J Med. 1999;340:737–738. doi: 10.1056/NEJM199903043400914.
    1. Meraviglia S, Eberl M, Vermijlen D, Todaro M, Buccheri S, Cicero G, La Mendola C, Guggino G, D'Asaro M, Orlando V, Scarpa F, Roberts A, Caccamo N, Stassi G, Dieli F, Hayday AC. In vivo manipulation of Vgamma9Vdelta2 T cells with zoledronate and low-dose interleukin-2 for immunotherapy of advanced breast cancer patients. Clin Exp Immunol. 2010;161:290–297.
    1. Sasaki A, Boyce BF, Story B, Wright KR, Chapman M, Boyce R, Mundy GR, Yoneda T. Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Res. 1995;55:3551–3557.
    1. Sasaki A, Kitamura K, Alcalde RE, Tanaka T, Suzuki A, Etoh Y, Matsumura T. Effect of a newly developed bisphosphonate, YH529, on osteolytic bone metastases in nude mice. Int J Cancer. 1998;77:279–285. doi: 10.1002/(SICI)1097-0215(19980717)77:2<279::AID-IJC18>;2-6.
    1. van der Pluijm G, Que I, Sijmons B, Buijs JT, Lowik CW, Wetterwald A, Thalmann GN, Papapoulos SE, Cecchini MG. Interference with the microenvironmental support impairs the de novo formation of bone metastases in vivo. Cancer Res. 2005;65:7682–7690.
    1. Ottewell PD, Deux B, Mönkkönen H, Cross S, Coleman RE, Clezardin P, Holen I. Differential effect of doxorubicin and zoledronic acid on intraosseous versus extraosseous breast tumor growth in vivo. Clin Cancer Res. 2008;14:4658–4666. doi: 10.1158/1078-0432.CCR-07-1545.
    1. Hiraga T, Williams PJ, Mundy GR, Yoneda T. The bisphosphonate ibandronate promotes apoptosis in MDA-MB-231 human breast cancer cells in bone metastases. Cancer Res. 2001;61:4418–4424.
    1. Neudert M, Fischer C, Krempien B, Bauss F, Seibel MJ. Site-specific human breast cancer (MDA-MB-231) metastases in nude rats: model characterisation and in vivo effects of ibandronate on tumour growth. Int J Cancer. 2003;107:468–477. doi: 10.1002/ijc.11397.
    1. Mundy GR, Yoneda T, Hiraga T. Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment. Semin Oncol. 2001;28:35–44. doi: 10.1016/S0093-7754(01)90263-5.
    1. Daubiné F, Le Gall C, Gasser J, Green J, Clézardin P. Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst. 2007;99:322–330.
    1. Hiraga T, Ueda A, Tamura D, Hata K, Ikeda F, Williams PJ, Yoneda T. Effects of oral UFT combined with or without zoledronic acid on bone metastasis in the 4T1/luc mouse breast cancer. Int J Cancer. 2003;106:973–979. doi: 10.1002/ijc.11330.
    1. Duivenvoorden WC, Vukmirović-Popović S, Kalina M, Seidlitz E, Singh G. Effect of zoledronic acid on the doxycycline-induced decrease in tumour burden in a bone metastasis model of human breast cancer. Br J Cancer. 2007;96:1526–1531. doi: 10.1038/sj.bjc.6603740.
    1. Ottewell PD, Woodward JK, Lefley DV, Evans CA, Coleman RE, Holen I. Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone. Mol Cancer Ther. 2009;8:2821–2832. doi: 10.1158/1535-7163.MCT-09-0462.
    1. van Beek ER, Lowik CW, van Wijngaarden J, Ebetino FH, Papapoulos SE. Synergistic effect of bisphosphonate and docetaxel on the growth of bone metastasis in an animal model of established metastatic bone disease. Breast Cancer Res Treat. 2009;118:307–313. doi: 10.1007/s10549-008-0236-6.
    1. Hiraga T, Williams PJ, Ueda A, Tamura D, Yoneda T. Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model. Clin Cancer Res. 2004;10:4559–4567. doi: 10.1158/1078-0432.CCR-03-0325.
    1. Ottewell PD, Lefley DV, Cross SS, Evans CA, Coleman RE, Holen I. Sustained inhibition of tumor growth and prolonged survival following sequential administration of doxorubicin and zoledronic acid in a breast cancer model. Int J Cancer. 2010;126:522–532. doi: 10.1002/ijc.24756.
    1. Eidtmann H, de Boer R, Bundred N, Llombart A, Davidson N, Neven P, von Minckwitz G, Miller J, Schenk N, Coleman R. Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST study. Ann Oncol. 2010;21:2188–2194. doi: 10.1093/annonc/mdq217.
    1. Powles T, Paterson A, McCloskey E, Schein P, Scheffler B, Tidy A, Ashley S, Smith I, Ottestad L, Kanis J. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026] Breast Cancer Res. 2006;8:R13. doi: 10.1186/bcr1384.
    1. Chlebowski R, Chen Z, Cauley J, Rodabough R, McTiernan A, Lane D, Manson J, Snetselaar L, Yasmeen S, O'Sullivan M, Stafford M, Hendrix S, Wallace R. Oral bisphosphonate and breast cancer: prospective results from the Women's Health Initiative (WHI) Cancer Res. 2009;69(Meeting abstract suppl)
    1. Rennert G, Pinchev M, Rennert HS. Use of bisphosphonates and risk of postmenopausal breast cancer. J Clin Oncol. 2010;28:3577–3581. doi: 10.1200/JCO.2010.28.1113.
    1. Newcomb PA, Trentham-Dietz A, Hampton JM. Bisphosphonates for osteoporosis treatment are associated with reduced breast cancer risk. Br J Cancer. 2010;102:799–802. doi: 10.1038/sj.bjc.6605555.
    1. Morgan G, Davies F, Gregory W, Bell SE, Szubert A, Navarro Coy N, Drayson M, Owen RG, Jackson GH, Child JA. Evaluating the effects of zoledronic acid (ZOL) on overall survival (OS) in patients (Pts) with multiple myeloma (MM): Results of the Medical Research Council (MRC) Myeloma IX study. J Clin Oncol. 2010;28(suppl):15s. (abstr 8021)
    1. Facchini G, Caraglia M Morabito A, Marra M, Piccirillo MC, Bochicchio AM, Striano S, Marra L, Nasti G, Ferrari E, Leopardo D, Vitale G, Gentilini D, Tortoriello A, Catalano A, Budillon A, Perrone F, Iaffaioli RV. Metronomic administration of zoledronic acid and taxotere combination in castration resistant prostate cancer patients: phase/ZANTE trial. Cancer Biol Ther. 2010;10:543–548. doi: 10.4161/cbt.10.6.12611.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj